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ISBN: 978-1-4160-3204-5
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The Publisher
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
To my wonderful wife, Susan, and Baby Grace, who make coming home early my daily goal.
I will always be grateful to my teachers and role models, Roy Witherington, J. Herbert Johnston,
Patrick C. Walsh, and Robert Douglas Jeffs.
John P. Gearhart, MD
To my wife, Kanda, and my children, Andy and Stephanie, who have been a constant source of love and support,
and to my brother Larry, who has shown the way. I am forever grateful for the encouragement and teachings of
my mentorsAlan Retik, Hardy Hendren, and Mike Mitchelland the support of my present and past partners,
as well as my former residents and fellows. I dearly miss my first mentor, Dr. John Donohue, and my brother Skip,
both of whom we lost this past year.
Richard C. Rink, MD
To my wife, Jessica, my children, David and Caroline, and stepchildren, Emma and Sophie:
Thank you for your patience and love.
To the memory of my father, Claude, who left us in November 2008:
He held my hand along beautiful paths.
To Philip Ransley, David Frank, and Maggie Godley, who are my essential companions.
To Captain and his indestructible joy of life.
Pierre D. E. Mouriquand, MD
Contributors
Mark C. Adams, MD
Professor of Pediatrics,
James Whitcomb Riley Hospital for Children and Indiana
University School of Medicine;
Byron P. and Frances D. Hollett
Professor of Pediatrics,
Director, Division of Pediatric Nephrology,
Indiana University School of Medicine,
Indianapolis, Indiana
Chapter 18: Glomerulonephritis in Children
Chapter 46: Acute Kidney Injury and Chronic Kidney
Disease in Children
Linda A. Baker, MD
David Bloom, MD
Full Professor,
Katholieke Universiteit Leuven;
Clinical Chief, Pediatric Urology, and Medical Manager,
Ambulatory Surgery Center, Leuven University Hospitals,
Leuven, Belgium
Chapter 34: Urethral Duplication and Other Urethral
Anomalies
Claire Bouvattier, MD
Clinical Instructor,
Ankara University School of Medicine,
Department of Urology, Division of Pediatric Urology,
Ankara, Turkey
Chapter 43: Cryptorchidism
Chapter 51: Rhabdomyosarcoma
Anthony J. Casale, MD
Marc Cendron, MD
George Chiang, MD
vii
viii
Contributors
Delphine Demde, MD
Steven G. Docimo, MD
Clare E. Close, MD
Christopher S. Cooper, MD
Consultant Gynaecologist,
University College Hospital,
London, United Kingdom
Chapter 37: Adolescent Urogynecology
M. Daudon, PhD
Jack S. Elder, MD
Fernando A. Ferrer, MD
Dominic Frimberger, MD
Contributors
M. F. Gagnadoux, MD
Daniela Gorduza, MD
Kenneth I. Glassberg, MD
Professor of Urology,
Columbia University, College of Physicians and Surgeons;
Director, Division of Pediatric Urology,
Morgan Stanley Childrens Hospital of New York
Presbyterian, New York, New York
Chapter 17: Multicystic Dysplastic Kidney Disease
Jens Goebel, MD
Ricardo Gonzlez, MD
Professor of Urology,
Thomas Jefferson University,
Philadelphia, Pennsylvania;
Senior Consultant, University Childrens Hospital Zurich,
Zurich, Switzerland
Chapter 59: Artificial Urinary Sphincter
ix
J. Damien Grattan-Smith, MD
Saul P. Greenfield, MD
Anna-Lena Hellstrm, MD
Terry W. Hensle, MD
Contributors
Professor of Surgery,
University of Alabama at Birmingham;
Chief of Pediatric Urology,
University of Alabama at Birmingham,
Childrens Hospital, Birmingham, Alabama
Chapter 21: Ureterovisical Junction Anomalies:
Megaureters
Appendix
Antoine E. Khoury, MD
Stanley J. Kogan, MD
Kristin A. Kozakowski, MD
Bradley P. Kropp, MD
Erica H. Lambert, MD
Michael E. Mitchell, MD
Pierre-Yves Mure, MD
Contributors
Kenneth G. Nepple, MD
Hiep T. Nguyen, MD
John Park, MD
Craig A. Peters, MD
Lisandro Piaggio, MD
Philip G. Ransley, MD
William G. Reiner, MD
Alan B. Retik, MD
Jonathan H. Ross, MD
xi
Consultant Nurse,
Alder Hey Childrens Hospital, NHS Foundation Trust,
Liverpool, United Kingdom
Chapter 14: Nursing Intervention in Pediatric Urology
xii
Contributors
Sovrin M. Shah, MD
Curtis Sheldon, MD
Tatum Tarin, MD
Urology Resident,
Stanford University, Department of Urology,
Stanford, California
Chapter 13: Pediatric Urinary Tract Infections
A. A. Thakre, MD
Clinical Instructor,
Stanford University Medical Center, Stanford, California;
Associate Chief of Urology, Santa Clara Valley Medical
Center, San Jose, California
Chapter 13: Pediatric Urinary Tract Infections
Julian Wan, MD
Rajesh Shinghal, MD
Ulla Silln, MD
Specialist Registrar,
University College Hospital,
London, United Kingdom
Chapter 37: Adolescent Urogynecology
Consultant Obstetrician,
University College London, NHS Foundation Trust,
London, United Kingdom
Chapter 4: Prenatal Diagnosis of Fetal Renal Abnormalities
John R. Woodard, MD
Contributors
Adrian S. Woolf, MD
Elizabeth B. Yerkes, MD
xiii
C. K. Yeung, MD
Paul Zelkovic, MD
Clinical Instructor,
Department of Urology,
New York Medical College,
Valhalla, New York
Chapter 45: The Pediatric Varicocele
J. Michael Zerin, MD
Foreword
The field of pediatric urology continues to change dramatically. Certainly there have been very significant advances
since the first edition of this book was published in 2001. In
this new edition, previous chapters have been updated and an
impressive number of new chapters has been added. The new
edition continues to be an international one edited by three
well-known pediatric urologists from the United States and
abroad.
The philosophy of the textbook is similar to that of the first
editionin other words, the editors and authors provide upto-date information on the entire spectrum of pediatric urology, including new chapters devoted to magnetic resonance
imaging of the pediatric urinary tract, tissue engineering,
and neonatal emergencies. The second edition has been redesigned in a full-color format that is more readable. In addition,
the content of the chapters has been updated with new topics,
techniques, and procedures. The text and images will also be
available online with the purchase of the book.
In summary, the second edition continues to be an excellent, updated, and comprehensive textbook edited by worldrenowned pediatric urologists who have compiled a group of
international experts to contribute to the textbook. This book
should be of great benefit to all physicians caring for infants
and children with pediatric urologic disorders.
Alan B. Retik, MD
xv
Preface
Pediatric urology has matured a great deal over the last decade,
and, with the onset of the third millennium, this new textbook
is an important milestone not only for the third generation of
pediatric urologists but also for all related specialists. This edition is more than a comprehensive update; in it, the leading
specialists from around the world have shed new light on the
various aspects of pediatric urology.
With the growing importance of new imaging, molecular
biology, genetics, experimental surgery, minimally invasive
surgery, antenatal uronephrology, and evidence-based medicine in the field, different and more pertinent approaches to
many familiar but also less common situations are detailed
here with a constant wish for clarity and honesty.
Such an enormous amount of data would not exist without
the outstanding work done by three generations of pediatric
urologists from all over the world, who have built our beautiful specialty brick by brick, article after article, textbook after
textbook. They should all be thanked warmly. It is impossible
to mention all of them here, but we could not preface this
xvii
P A R T
BASICS
S E C T I O N
Amniotic cavity
Buccopharyngeal
membrane
Ectoderm
Mesoderm
Endoderm
Yolk sac
Cloacal membrane
Figure 1-1 An early cross section of the human embryonic disc. The
disc separates the ectoderm-lined amniotic cavity from the endodermlined yolk sac. Ingrowth of cells from the primitive streak forms a third
layer between them, the mesoderm. This is deficient at the head and
tail ends, the locations, respectively, of the buccopharyngeal membrane and the cloacal membrane.
Head
Tail fold
Yolk sac
Allantois
Cloacal
membrane
Figure 1-2 The embryonic disc has folded, including an endoderm
layer from the yolk sac that will form the hindgut and foregut. The
cloacal membrane faces anteriorly, and the cloaca is defined distal to
the confluence of the hindgut and allantois.
part
I: Basics
rapidly, its dorsal surface bulges into the amniotic cavity, and
its head and tail ends fold forward to form the head and the
tail folds, respectively. During this process, the lining or endoderm of the yolk sac is included within the two folds, where
it is the precursor of the foregut and the hindgut, respectively
(Fig. 1-2). As folding of the tail end continues, the connecting
stalk and allantois are formed and displaced onto the front
surface of the embryo (see Fig. 1-2). The cloacal membrane is
also brought to the front of the tail fold, below the allantois.
The allantois gains continuity with the developing hindgut
and defines the cloaca as the portion of hindgut distal to their
confluence (Fig. 1-3). The cloacal membrane is seen on the
surface of the embryo at the center of a depression called the
proctodeum. On either side of this are two surface elevations,
the urogenital folds, which join at their upper ends in the
genital tubercle. Growth of the anterior abdominal wall above
the cloacal membrane, coupled with regression of the tail fold,
causes its relative displacement toward the tail end of the
embryo, facing downward (Figs. 1-4 and 1-5).
Allantois
RENAL DEVELOPMENT
From early in the 4th week of gestation, three nephric structures develop in succession from the intermediate mesoderm
that runs the length of the embryo. The first, or pronephros,
appears in the cervical portion and rapidly regresses, without forming any nephronlike structures (although it does
develop excretory function in amphibian larvae and some
fish). Subsequently, the appearance of tubular structures in the
midportion (thoracic and lumbar sections) of the intermediate mesoderm heralds the development of the mesonephros.
Gonad
Gonad
Mesonephros
Genital
tubercle
Mesonephric duct
Paramesonephric duct
Urogenital
sinus
Blastema
Tail fold
Ureteric bud
Cloacal
membrane
Urogenital
sinus
Ureteric bud
Cloaca
Mllerian tubercle
Septum
Figure 1-3 A, The tail end of the human embryo during the 5th week of gestation (lateral view). The ureteric bud begins to grow posteriorly from
the distal part of the mesonephric duct. The urorectal septum advances forward to divide the cloaca into an anterior urogenital sinus and a posterior rectum. As it does so, infolding of the lateral walls of the cloaca helps to complete the division. The gonad precursors are visible anteromedial
to the mesonephroi; their paired ducts descend lateral to the mesonephric ducts and join at the urogenital sinus to form the mllerian tubercle.
The cloacal membrane faces forward and upward. B, The same gestation looking from behind the urogenital sinus. The mesonephric ducts enter
the sinus posteriorly. The mllerian ducts come together and indent the sinus at the mllerian tubercle.
Mesonephros
Allantois
Gonad
Mesonephric
duct
Genital
tubercle
Cloacal
membrane
Metanephros
Urogenital sinus
Septum
Rectum
Figure 1-4 A, The tail end of the embryo during the 6th week of gestation (lateral view, mllerian and genital development not shown). The urorectal septum advances toward the cloacal membrane. The kidneys are forming, and the origin of the ureteric bud approaches the urogenital sinus
as the end of the mesonephric duct is incorporated into its posterior wall. Growth of the anterior abdominal wall is accompanied by expansion of
the vesicourethral canal. The orientation of the cloacal membrane is beginning to change. B, Same gestation, posterior view.
chapter
Gonad
Allantois
Kidney
Urogenital
membrane
Trigone
Anal
membrane
Figure 1-5 A, The tail end of the embryo during the 8th week of gestation (lateral view, mllerian and genital development not shown). The kidney ascends from the pelvis as the mesonephric duct, and its ureteric origins are further incorporated into the urogenital sinus. Cloacal septation is
complete, and the membranes, which have started to degenerate, are facing downward. B, Same gestation, from behind the urogenital sinus. The
trigone is formed with separation of the mesonephric ducts and ureteric orifices.
1o
2o
3B
3o
2B
1B
Figure 1-6 Development of the kidney and the final position of the
the amniotic cavity and is important for its lung and skeletal
development.
part
I: Basics
Figure 1-7 Cystogram (A) and technetium 99m dimercaptosuccinic acid (Tc99-DMSA) scan (B) characterizing unilateral reflux in a boy. This
condition manifested antenatally, and there was no history of urinary tract infection. The refluxing kidney is small and functions poorly, which is
typical of the dysplasia that accompanies reflux.
Duplex Kidney
Duplex kidney, the most common of renal anomalies, arises
when two ureteric buds occur on one side and induce
upperand lower renal moieties. If a single bud divides
closeto its origin, the result is an incomplete duplex kidney
with a common distal ureter (Fig. 1-8). If two separate buds
form, the kidney is drained by two separate ureters. As it
reaches the urogenital sinus, the lower ureter migrates laterally and crosses the upper ureter (the Weigert-Meyer law)
(see Fig. 1-8). The lower moiety of the kidney is therefore
more prone to reflux. The upper ureter, because it arrives at
the urogenital sinus later, retains a closer association with
the mesonephric duct opening and is prone to ectopia. The
mechanism of ureterocele formation is unclear, but it may
result from failure of involution of the Chwalla membrane
(Fig. 1-9).
Fused Kidneys
If the two kidneys come together during their development
in the pelvis, they may fuse. Most commonly, this results
in a horseshoe kidney, in which fusion usually takes place
between the lower poles (Fig. 1-11). Occurring in 1 in 500
members of the population, this anomaly is usually asymptomatic and is characterized by malrotated calyces seen at
urography.
chapter
Mesonephric duct
Ureteric bud
Urogenital sinus
Metanephric blastema
Kidney
Urogenital sinus
Figure 1-8 The embryogenesis of ureteric duplication. Partial duplication occurs when the ureteric bud divides after its origin to
form two collecting systems with ureters that join above the bladder to terminate in a single orifice (top left). If two separate buds
arise, complete duplication is the result (top right). As the bottom
three images illustrate, the two ureteric origins are incorporated into
the urogenital sinus at different times, so that they cross, causing the
lower pole ureter to lie above and lateral to the upper pole ureter
(the Weigert-Meyer law).
the common excretory ducts) widen and become incorporated into the posterior aspect of the primitive urogenital
sinus (see Fig. 1-4). As this continues, the posterior wall of
the canal widens. The ureteric orifices arrive on the surface
of this posterior wall early and become separated from the
mesonephric duct orifices. As further incorporation of the
lower mesonephric ducts occurs, the ureteric orifices move
superolaterally relative to the mesonephric duct orifices
(see Fig. 1-5). These stay close to the midline and descend
into the developing posterior urethra. The epithelia of
both ducts fuse in the midline, and the triangular area
between them and the ureteric orifices defines the trigone
(see Fig. 1-5).
During the ascent of the kidneys from the pelvis, the ureters rapidly elongate. Initially, their lumen is not apparent,
but it develops cranially and caudally from the midpoint
until early in the 8th week, when only a membrane persists
between the lower ureter and the urogenital canal. By the
girl. The ureter from the poorly functioning upper pole drains ectopically into a ureterocele that is seen as a filling defect in the bladder.
part
I: Basics
Cloacal Exstrophy
If the septum and Rathke folds also fail to partition the cloaca, the bladder plate is separated into two halves by a central hindgut plate. In this most severe variant of exstrophy,
the phallus is often divided in two halves that may be widely
separated.
Figure 1-11 Intravenous urogram of a horseshoe kidney. The collecting system is malrotated, and the calyces face forward, giving a classic
appearance. The lower poles are joined across the midline.
Cloacal Anomalies
Incomplete septation of the cloaca leads to continued communication between the rectum and the urogenital sinus. The
urethra, vagina, and rectum join into a common distal channel. The perineum is characterized by an imperforate anus
and a single anterior opening.
chapter
vagina are thought to arise from the paramesonephric system, whereas the lower third derives from the urogenital
sinus itself. The vaginal lumen remains separated from the
vestibule by the hymen.
The mesonephric ducts regress, leaving vestigial remnants
at their proximal and distal ends. These are the epophoron
and the parophoron in the mesentery of the ovary and the
Gartner cyst in the wall of the vagina. A mesodermal band,
the gubernaculum, extends from the lower pole of the ovary
toward the inguinal region, crossing the inguinal canal and
terminating in the labium majorum. As the ovary descends
into the pelvis, the gubernaculum is folded within the broad
ligament of the uterus and attaches in its midpoint to the junction of the uterine body and tube. Proximal to this attachment,
it becomes the ovarian ligament, and distally it is the round
ligament of the uterus.
Male Development
Figure 1-12 Intravenous urogram demonstrating bilateral single ectopic ureters. These drain into the urethra below an incompetent and
abnormal-looking bladder neck. Although they appear to function
well in this case, the kidneys in individuals with this rare anomaly
may be dysplastic.
from the cortex of the indifferent gonad and their duct system
from the paramesonephric (mllerian) duct, whereas the
mesonephric (wolffian) duct degenerates. In contrast, the
testis develops from the medulla of the indifferent gonad and
its ducts from the mesonephric duct, whereas the paramesonephric duct degenerates (Fig. 1-13).
Female Development
Female development is the default pathway for genital
development that is followed in the absence of the SRY gene
product or testis-determining factor. The primitive sex cords
degenerate, and secondary sex cords grow out from the
cortex of the gonad into the surrounding tissue. The germ
cells are incorporated into these, and primary oocytes form.
These undergo meiotic division and then become quiescent
until puberty. The paramesonephric ducts develop open,
funnel-shaped, proximal ends that will become the fimbriated open ends of the uterine tubes. Distally, their merged
portion enlarges to form the fundus and body of the uterus.
At the mllerian tubercle, there is first a downgrowth of
solid tissue within the urorectal septum, toward the fetal
perineum, called the vaginal plate. This develops a lumen
by the 20th week of gestation. The upper two thirds of the
part
I: Basics
Gonad
Paramesonephric duct
Mesonephros
Gubernaculum
Ureteric bud
Urogenital sinus
Female
Appendix
of testis
Appendix
of epididymis
Testis
Male
Paraophoron
Ovary
Ophoron
Vas
deferens
Uterine tube
Ureter
Gubernaculum
Seminal
vesicle
Uterus
Utriculus
Ureter
Upper vagina
Uterus
Urethra
Vas
Tube
Ovary
Broad
ligament
Utriculus
Urethra
Figure 1-13 Internal genital development. After an indifferent phase, development follows a male or female pathway. In the female, the gonad dif-
ferentiates into an ovary, and the paramesonephric ducts form the tubes, uterus, and upper vagina. The mesonephric duct degenerates and forms the
ovarian and round ligaments, with vestigial remnants persisting as the epophoron, the parophoron, and Gartner cyst. In the male, the gonad differentiates into a testis and the mesonephric duct into the epididymis and vas deferens. The testis is united with its duct system through remnant tubules
from the mesonephros, and the upper end of the mesonephric duct forms the vestigial appendix of the epididymis. The paramesonephric duct persists
as the vestigial appendix testis and the prostatic utricle.
chapter
Testis
Processus vaginalis
Muscle
Gubernaculum
Scrotum
Hernia
Hydrocele
Figure 1-14 A-D, Development of the processus vaginalis and testicular descent. The gubernaculum traverses the abdominal wall musculature.
The processus vaginalis extends along the gubernaculum, and the testis descends on its posterior wall, so that the body of the testis lies within
it. The connection with the abdominal cavity is obliterated, leaving a peritoneum-lined space anterior to the testis, the tunica vaginalis. Failure of
obliteration of the processus vaginalis results in a hernia or hydrocele, depending on the lumen of the connection. Occasionally, a cyst forms along
the inguinal canal, representing a hydrocele of the cord.
vagina may be double or single. Occasionally, one of the uterine horns is rudimentary or missing.
Female Development
In females, enlargement and subsequent folding of the genital tubercle forms the clitoris. The structures of the perineum
do not fuse across the midline. The urogenital folds persist on
either side of the introitus as the labia minora. The labioscrotal folds form the labia majora, which meet posteriorly at the
fourchette. The urethra opens anterior to the vaginal opening,
which is obscured by the hymen until late in gestation (see
Fig. 1-15).
Male Development
Male external genital development depends on the conversion of testosterone to the more active dihydrotestosterone
and its subsequent action via tissue receptors. The genital
tubercle enlarges into the penis, and as it does, cells grow
into its inferior surface to form the solid urethral plate. Subsequent involution results in a deep groove on the undersurface of the penis. The tip of the penis expands to form
the glans. Unlike in females, male development continues by
fusion of first the urogenital and then the labioscrotal folds
across the midline. The penile urethra forms by fusion of the
genital folds across the groove proximally. Distally, canalization occurs from the tip of the glans to complete the urethra
and the expanded fossa navicularis. This process is complete
by the end of the 20th week of gestation. The labioscrotal
10
part
I: Basics
6th week
Clitoris
Labia minora
Urethra
Vagina
Hymen
Labia majora
Genital tubercle
Female
Anus
20th week
Urethral folds
Cloacal membrane
Genital folds
Male
Raphe
Scrotum
Figure 1-15 External genital development. After an indifferent phase, male and female paths diverge. In females, the genital tubercle enlarges
and folds to form the clitoris. The genital folds form the minor labia, and the labioscrotal folds form the major labia. In males, the genital tubercle
enlarges to form the penis. The genital folds fuse in the midline to form the penile urethra. The glanular urethra forms by invagination. The labioscrotal folds fuse across the midline to form the scrotum.
folds enlarge into the scrotum and fuse behind the penile urethra in a midline raphe. The foreskin arises from the base of
the glans and grows more on the dorsal surface of the penis.
As it advances distally, it also grows ventrally, covering the
glans and meeting and fusing in a continuation of the midline raphe (see Fig. 1-15).
REFERENCES
For complete list of references log onto www.expertconsult.
com
CHAPTER
During the 20th century, much was learned about the nature
of renal function in adult humans and animal models, and
methods for measuring it are well established. By contrast,
reliable information concerning renal function in infancy and
early childhood has been available for only about 50 years,
and for less than that in the premature infant. For obvious reasons, access to the human fetus for the purpose of physiologic
studies is difficult, and therefore very little was known about
fetal renal function until the last decade of the 20th century.
The introduction of high-resolution ultrasound examination
of the fetus during pregnancy has made it possible to identify urinary tract malformations quite early in gestation. Consequently, it has become desirable to identify tests capable of
predicting renal functional outcome after birth in fetuses in
whom a urinary tract anomaly has been detected. This has
provided an incentive for more intensive physiologic study of
both human and animal fetuses, and although much remains
to be learned, it is now possible to summarize what is known
about fetal renal function and to compare it with that observed
in the infant after birth. This chapter focuses mainly on information available from investigations in human subjects, supplemented occasionally by the results of animal studies when
data of human origin are lacking.
12
part
I: Basics
Distal convoluted
tubule
Pars
convoluta
Proximal
tubule
Juxtaglomerular
apparatus
Pars recta
Inner
stripe
Inner
medulla
Loop of Henle
Descending limb
Papillary collecting duct
chapter
1.4
Nephrons 106
1.2
Collecting ducts
complete (XV)
1/3 nephrons
1/10 mass
1.0
First nephron
0.8
Nephrogenesis complete
Continued growth
20
0.6
0.4
10
0.2
0
12
16
20
24
28
32
36
40
Fetus
Newborn
3
2
1
0
20
44
5
4
13
30
Renal mass (g)
1.6
Sodium Excretion
25
30
35
40
the text) and in newborn premature infants at comparable postconceptional ages. (Data from references 5 through 8.)
The same data sources used to calculate fetal GFR5,7 can also
be used to calculate FENa, the proportion of filtered sodium
excreted in the urine. FENa is the excretion rate of sodium
divided by its filtration rate, which reduces to
FENa =
CCr =
UCr V
PCr
where U is the urine concentration, P is the plasma concentration, and V is the urine flow rate. Results for fetuses from
20 weeks gestation to term are shown in Figure 2-3 and are
compared with those for newborn babies of the same absolute gestational age who were born at least 3 days before the
study.8 At all ages within the study period, creatinine clearance is substantially greater in the fetus than in the neonate.
Although creatinine clearance has not been directly validated
as a measure of glomerular filtration rate (GFR) in human
fetuses, the agreement with clearance of sodium iothalamate,
a well-documented marker for GFR, has been shown to be
excellent in the sheep fetus.9
UNa PCr
UCr PNa
100
No information is available as to the ability of the fetus to concentrate or dilute urine. The fact that urinary sodium concentration falls and that of nitrogenous substances such as urea
and creatinine rises during the second half of pregnancy in
fetuses with a good renal prognosis7 suggests that the tubular
transport processes that underlie the concentrating and diluting processes are developing during this period. It is likely
that the capacity of the fetus to produce concentrated or dilute
urine is similar to that of the prematurely born infant of a similar degree of maturity.
Fetal urine output has been measured by ultrasonography6 and is remarkably high compared with that of the
postnatal infant. The urine flow rate can be as high as 20% to
25% of GFR, a value never seen in extrauterine life except in
extraordinary circumstances. Presumably, like the very high
14
part
I: Basics
20
Fetus
Newborn
15
10
5
0
20
25
30
Gestational age (wk)
35
40
Figure 2-4 Fractional sodium excretion in fetuses (calculated as described in the text) and in newborn premature infants at comparable
postconceptional ages. (Data from references 5 through 8.)
is reached somewhere between the first and the second birthdays.14-17 Normal values for GFR during the first 2 years of life
are summarized in Table 2-1.
Formal measurement of GFR is laborious and is not often
done for clinical purposes. The most widely used proxy
measurement for GFR is the plasma creatinine concentration (PCr), which in a steady state is inversely proportional
to GFR. In utero, the maternal and fetal blood are in equilibrium with respect to the concentration of small solutes such
as creatinine,5,18 and therefore, the infants PCr at birth (e.g.,
in cord blood) reflects the mothers, not the babys, renal
function. In term infants, the PCr at birth is typically 70 to 90
mol/L (about 1 mg/dL), falling to about half of this value
by 1 week of age and remaining steady for the remainder
of the first month. There is considerable variation among
published series as to absolute values for PCr, mainly reflecting difficulties in laboratory measurement of PCr at the low
concentrations typically observed in healthy infants. For
modern methods giving a good approximation to true PCr,
the mean stable concentration after the first week is about
30 mol/L (0.3 mg/dL), with a range of 15 to 40 mol/L (0.17
to 0.45 mg/dL).19
Table 2-1 Normal Values for Glomerular Filtration Rate during the First 2 Years of Life*
Mean GFR (2 SD)
Age
mL/min
mL/min/kg
mL/min/1.73 m2
1 wk
3.75 (2.5-5)
1.2 (0.8-1.6)
30 (20-40)
1 mo
6 (4-8)
1.5 (1-2)
50 (30-70)
3 mo
10.5 (7-14)
1.9 (1.2-2.4)
60 (40-80)
6 mo
18.5 (12.5-25)
2.4 (1.6-3.2)
80 (60-100)
1 yr
30 (20-40)
3 (2-4)
100 (75-125)
2 yr
45 (30-60)
3.3 (2.2-4.4)
120 (90-150)
*Values are presented uncorrected, factored by body weight, and corrected to a body surface area of 1.73 m2. Data are pooled from multiple sources
and rounded off to the nearest 2 or 3 significant figures.
GFR, glomerular filtration rate.
chapter
Sodium Excretion
Healthy term infants are able to produce virtually Na-free
urine (FENa much less than 1%).8,21 The importance of this fact
is difficult to overestimate. The baby fed on her or his mothers
milk has a low Na intake, in the region of 1 to 1.5 mmol/kg
daily, which is close to the amount needed for growth. Virtually all of this Na must therefore be retained. Conversely,
many studies have shown that the ability to excrete an Na load
is less well developed than in older individuals.22 When this
observation was first made, it was interpreted as meaning that
renal function in the newborn was immature; however, it is
unusual and unphysiologic for such an infant to be in a situation in which there is a need to excrete a salt load. In all but
exceptional circumstances, the prime requirement of the neonatal kidney is conservation, not excretion, of Na.
1600
1400
1200
Concentration of osmotically
active solutes in urine (mOsm/L)
15
1200
1000
800
600
Urea
800
High
protein
Low
protein
Urea
Urea
400
400
0
200
Children
Newborn infant
Figure 2-6 The effect of high and low protein feeding on the ability
15
30
61
122
244 365
16
part
I: Basics
be required. This may seem a small amount, but in the subsistence conditions in which humans probably evolved, it is
likely that this requirement would entail a significant selective
disadvantage. Furthermore, the highly anabolic condition of
the infant means that almost all ingested proteins and minerals are incorporated in new tissue, leaving very little solute
remaining for excretion.28 As a pioneer of developmental
physiology put it, Growth is the third kidney (Fig. 2-7).32 It
can be seen, therefore, that the optimal level of renal function
in the newborn infant is the minimum that meets the infants
limited excretory and homeostatic needs, whereas anything
in excess of this would pose an unnecessary energy cost to
the mother-baby dyad. The only negative consequence of
low GFR for the infant is that, if growth ceases and she or he
becomes catabolic, the increased rate of input of solute to the
ECF could easily lead to metabolic derangement, as in the
syndrome of late metabolic acidosis of prematurity.
Growth
(anabolism)
Growth
(anabolism)
Dietary input
Dietary input
Renal
solute load
Renal
solute load
Figure 2-7 The inverse relationship between growth and the rate of
generation of urinary solute for excretion, assuming a constant dietary
input.
chapter
(mL/min/1.73 m2)
Creatinine clearance
(mL/min)
50
40
30
0.373e0.0159x
0.70
84
0.001
20
10
5
4
3
2
0.5
0.4
0.3
0.00462e0.023x
0.83
85
0.001
0.2
0.1
17
100
y
r
n
P
28
30
32
34
36
38
40
42
Conceptional age (wk)
Figure 2-8 Glomerular filtration rate, measured as creatinine clearance, in newborn infants from 28 to 42 weeks gestational age. The
filled circles and upper regression line represent GFR expressed as
mL/min/1.73 m2, and the open circles and lower regression line represent GFR uncorrected for body size (mL/min). The scale on the Y axis
is logarithmic. (Redrawn from Al-Dahhan J, Haycock GB, Chantler C,
Stimmler L. Sodium homeostasis in term and preterm neonates. I. Renal aspects. Arch Dis Child. 1983;58:335-342.)
at 40 weeks.8 Normal values of GFR, both uncorrected and corrected for BSA, are shown in Figure 2-8.
Several studies have proposed that premature and term
infants follow different patterns of postnatal development of
GFR. In general, these reports have lumped together preterm
infants across a wide range of gestational ages and compared
them, as a group, with term infants. However, if infants born
at different stages of gestation are compared at the same
absolute or postconceptional age, they follow similar tracks,
once they have passed the transitional period of adjustment
to the change from intrauterine to extrauterine life (the first
few postnatal days).8,36 For example, two groups of infants
with identical postconceptional ages (245 23 and 247 19
days, respectively) had identical GFR, both corrected and
uncorrected for BSA, even though the first group were studied at 5 to 6 days postnatal age and the second at 26 to 68
days.8 This is consistent with the observation, based on careful postmortem studies, that preterm infants with weights
appropriate for gestational age who died in the first year of
postnatal life had the same complement of nephrons as term
infants.37
Conversely, LGA
infants born with a diagnosis of intrauterine growth retardation have smaller kidneys and higher
blood pressure,38 as well as significantly reduced nephron
Sodium Excretion
Investigations from several groups8,48,49 have consistently
shown that infants born at or after 32 to 33 weeks gestation
can produce virtually Na-free urine, equivalent to an FENa of
much less than 1% of the filtered load, from the first few days
of life. Infants born before 32 weeks are less efficient in this
respect, and during their first 2 weeks of extrauterine life FENa
is high, often greater than 1%, with the most immature infants
having the highest values (Fig. 2-10). FENa values of 5% or
even higher are seen in some infants born at 26 to 28 weeks.8,50
In consequence, with a dietary Na intake in the range of 1.3
to 1.5 mmol/kg/day (equivalent to that provided by mature
human milk), which is sufficient to allow for normal growth
18
part
I: Basics
10
1.0
0.8
0.7
0.6
0.4
0.3
0.2
0.1
2
10 14 18 22 26 30 34 38 42 46
Age (d)
2400
1
0.5
0.4
0.3
0.2
0.1
2200
2000
0.05
0.04
1800
0.03
1600
0.02
1400
1200
0.01
32
34
36
38
40
42
Conceptional age (wk)
Figure 2-10 Fractional sodium excretion plotted against postconceptional age in newborn infants from 23 to 42 weeks gestational
age. The scale on the Y axis is logarithmic. (Redrawn from Al-Dahhan
J, Haycock GB, Chantler C, Stimmler L. Sodium homeostasis in term
and preterm neonates: I. Renal aspects. Arch Dis Child. 1983;58:
335-342.)
1000
800
600
400
200
12 16 20 24 28 32 36 40 44 48
Age (d)
Figure 2-9 Change in renal blood flow (A) and renal vascular resistance (B) with postnatal age in piglets. (Redrawn from Gruskin AB,
Edelmann CM Jr, Yuan S. Maturational changes in renal blood flow in
piglets. Pediatr Res. 1970;4:7-13.)
2582.86e0.0354x (d)
100
0.80
0.001
0.5
y
n
r
P
5
4
0.9
28
30
NaCl supplementation
80
70
60
50
40
30
20
10
Urinary aldosterone
excretion (g/24 hr)
Plasma aldosterone
concentration (ng/mL)
56
7
6
5
4
3
2
1
chapter
1060
1050
1040
1030
1020
1010
1000
990
980
970
960
950
940
***
56
30
25
20
15
10
5
1
2
3
4
56
Postnatal age in weeks
Figure 2-11 Postnatal changes in plasma renin activity, plasma aldosterone concentration, and urinary aldosterone excretion rate in premature infants. The high levels shown by the shaded bars are those
found in infants with a low sodium intake (<1.5 mmol/kg/day). The
postnatal rise in renin and aldosterone levels was fully suppressed
by salt supplementation beginning at 2 weeks postnatal age (open
bars), suggesting that the rise is a response to extracellular fluid volume contraction. For the first two weeks, sodium supplements were
given at 3-5 mmoL/kg/day (thick bar) then halved for the remainder of supplementation period (thin bar). (Redrawn from Sulyok E,
Nmeth M, Tenyi I, et al. Relationship between the postnatal development of the renin-angiotensin-aldosterone system and the electrolyte
and acid-base status in the sodium chloride supplemented premature
infant. Acta Paediatr Acad Sci Hung. 1981;22:109-121.)
**
***
*
Group A
Group B
P
P
P
0.01
0.005
0.001
*
**
***
Sodium supplementation
0
19
12
16
20
29
Age (d)
Figure 2-12 Postnatal change in weight expressed per kilogram
of birth weight in premature infants receiving (solid circles) and not
receiving (open circles) salt supplementation from the 4th to the 14th
postnatal day. Note that the difference between the two groups persists beyond the end of the period of supplementation. (Redrawn from
Al-Dahhan J, Haycock GB, Nicol B, et al. Sodium homeostasis in term
and preterm neonates: III. The effect of salt supplementation. Arch Dis
Child. 1984;59:945-950.)
20
part
I: Basics
CNa,
CH2O
28
r
P
0.64
0.001
r
P
0.02
NS
24
20
16
12
Infants
Children
0
12
16 2
6
10
14
8
Age (mo)
Age (yr)
Figure 2-13 Proportion of filtered sodium escaping reabsorption in
the proximal tubule (i.e., delivered to the distal tubule) in infants (solid
circles and regression line) and in children (open circles and regression
line) of various ages. The studies were performed in maximal water
diuresis, in which the sum of sodium clearance (CNa) and free water
clearance (CH2O) represents the amount of sodium delivered to the
distal nephron beyond the loop of Henle. (Redrawn from RodriguezSoriano J, Vallo A, Oliveros R, Castillo G. Renal handling of sodium in
premature and full-term neonates: a study using clearance methods
during water diuresis. Pediatr Res. 1983;17:1013-1016.)
4
chapter
70
2 SD
1 SD
1 SD
21
2 SD
Number of infants
60
50
40
30
20
10
10.5 12.5 14.5 16.5 18.5 20.5 22.5 24.5 26.5 28.5 30.5
tCO2 (mmol)
chronic acidosis, and preterm infants can synthesize ammonium quite well, but the maximum capacity to excrete hydrogen ions is nevertheless lower than that of term infants or
older individuals when related to body weight. This is partly
due to low GFR.
The most abundant nonvolatile acid that must be excreted
in the urine is sulfuric acid, which is derived from the catabolism of sulfur-containing amino acids. In the strongly anabolic
state that is normal for all growing infants, including those
born prematurely, virtually all the dietary protein is incorporated into new tissue, and little or no sulfuric acid is formed.
The low bicarbonate threshold seen in healthy term infants,
referred to previously, is exaggerated in preterm infants. In a
study of healthy, thriving preterm infants, the mean threshold
was found to be 19 to 20 mmol/L (Fig. 2-14).65 As with term
infants, this is probably a consequence of expanded ECF volume, which is even more marked in the preterm than in the
full-term infant.
Although the renal acidifying capacity of the preterm
infant is sufficient for his or her normal needs, there is
little reserve available to deal with unphysiologic demands.
Metabolic acidosis occurs readily in preterm infants in two
circumstances: when they become sick and therefore catabolic,
and when the dietary load of potential nonvolatile acid is
inappropriately high. In the 1960s, when modern neonatology was on an early segment of its learning curve, very-lowbirth-weight infants were often fed very high protein diets,
sometimes as much as 3 to 5 g/kg/day, in the belief that this
would improve growth. One consequence was the generation of more sulfuric acid than the immature kidneys could
excrete, leading to the syndrome of late metabolic acidosis of
prematurity.66 In this condition, babies appeared to do well for
the first week or two, but then became unwell with interruption of weight gain and metabolic acidosis. The disorder then
became self-perpetuating: the acidosis prevented growth and
further increased the input of acid into the ECF. It was found
that either reducing the protein content of the feed or treating
the acidosis with alkali was curative; once the protein intake
had been reduced to physiologic amounts, a single dose of
bicarbonate was often enough to restore normal growth and
prevent recurrence of acidosis.66
Because of changes in nutritional practice, the fullblown syndrome of late metabolic acidosis is now seen only
occasionally. However, borderline late metabolic acidosis may
be more common than is recognized. It has been reported that
babies who are excreting maximally acid urine, although not
k Height
Plasma creatinine
22
part
I: Basics
proportional to GFR, and the overall decline in renal function probably reflects a reduction in total nephron number
rather than failure of any particular aspect of tubular function. Renal function and disease in the elderly is the subject
of a book by Macas-Nez and Cameron74 and of a review
chapter by the same authors in a standard textbook of renal
medicine.75
The formula given earlier for rough estimation of GFR
from creatinine in children has not been validated and should
not be used in adults. A number of formulas have been produced to achieve the same estimation in adults, and these
were reviewed in a recent article.76 The most satisfactory
one, which also gives an estimate corrected for BSA, is the
abbreviated Modification of Diet in Renal Disease (MDRD)
study group formula,77 which incorporates plasma creatinine
concentration, age, gender, and ethnicity:
1.154
0.203
Age
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
RENAL FUNCTION
The kidneys function to excrete water, solutes, and metabolic
wastes in order to maintain a homeostatic internal environment despite fluctuations in diet and fluid balance. The integrity of cells depends on the osmolality of the extracellular fluid
(ECF). This is kept under tight control through osmoreceptors
and volume receptors that allow the brain and kidneys to produce hormones and vasoactive substances to regulate salt and
water excretion. The kidneys receive 20% of the cardiac output.
Each nephron receives the ultrafiltrate of plasma, which passes
through the Bowman space into the renal tubule. More than
99% of the filtered water, sodium, chloride, and bicarbonate
is reabsorbed by the renal tubules and returned to the plasma.
Failure to reabsorb virtually all the sodium can result in lifethreatening hyponatremia and volume depletion.
The rate of formation of the ultrafiltrate is the GFR, which
is calculated from cardiac output and renal plasma flow. GFR
is an important measure of renal function. Calculation of GFR
is required in situations indicative of renal disease, such as
abnormal urinary findings, peripheral edema, or hypertension. GFR in newborn term and preterm infants is less than
UCr V
PCr
24
part
I: Basics
Activity
Caloric Requirement
(kcal/kg BW)
Protein Requirement
(g/kg BW)
0-1
90-120
2.0-3.5
10
1-7
75-90
2.0-2.5
75
7-12
60-75
2.0
12-18
30-60
1.5
>18
25-30
1.0
Resting expenditure
50
Intermittent activity
15
Adapted from Hensle TW. Metabolic Care of the Neonate and Infant with
Urologic Abnormalities: Clinical Pediatric Urology. Philadelphia: WB Saunders;
1985.
Age (yr)
3-10
100 kcal/kg
10-20
>20
Fluid Requirement
(per 24 hr)
Premature
<2
150 mL/kg
Neonates and
infants
2-10
100 mL/kg
Infants and
children
10-20
1000 mL + 50 mL/
kg >10 kg
Children
>20
1500 mL + 20 mL/
kg >20 kg
BODY COMPOSITION
support
CALORIC MAINTENANCE
Body composition and metabolic rate change with growth
and postnatal age. Infants and children have proportionally
higher water content, a higher metabolic rate, and a greater
body surface per unit of weight than adults. Calories, water,
and electrolytes are required by infants and children for both
maintenance of body metabolism and growth. Premature
infants have a high water content due to their relatively large
extracellular compartment and low fat reserves.12 In addition,
chapter
25
Table 3-5 Recommended Ranges of Electrolyte Supplementation (mEq/kg/24 hr) for Pediatric and Adolescent
Electrolyte
Calcium
0.5-3.0
5-20
10-15
Magnesium
0.5-1.0
4-24
8-24
Potassium
2-4
20-240
90-240
Sodium
2-4
20-150
60-150
Acetate
2-8
20-120
80-120
4-12
20-150
60-150
0.5-1.0
6-50
30-50
Chloride
Phosphorus
Adapted from Teitelbaum DH, Coran AG. Perioperative nutritional support in pediatrics. Nutrition. 1998;14:130-142.
in Children
Requirement*
(mL/kg/hr)
Requirement*
(mL/kg/day)
First 10 kg
100
Second 10 kg
50
Each additional kg
25
Body Weight
*Add amounts obtained for each portion of the childs weight to obtain the
total requirement.
Adapted from Filston HC, Edwards CH III, Chitwood WR Jr, et al.
Estimation of postoperative fluid requirements in infants and children.
Ann Surg. 1982;196:76.
Dermal
14-20
Urine
25-62
Stool
Total
2
48-94
Adapted from Hensle TW. Metabolic Care of the Neonate and Infant with
Urologic Abnormalities: Clinical Pediatric Urology. Philadelphia: WB Saunders;
1985.
26
part
I: Basics
Na (mEq/L)
Cl (mEq/L)
Glucose (g/L)
Osmolality (mOsm/kg)
Ringer lactate
130
109
272
154
154
50
308
77
77
50
154
33
33
50
75
Hypovolemia
Hypovolemia in infants and children is often caused by diarrhea but can be the result of any other process that does not
allow the net intake to match losses. The degree of hypovolemia can often be gauged from the history, physical examination, and supplementary laboratory data. Weight loss,
tachycardia, hypotension, dry mucous membranes, a lack of
tears, a sunken fontanelle, and decreased skin turgor are all
clinical signs of moderate to severe dehydration. A urine specific gravity greater than 1.0020, an increased hematocrit, and
an increased blood urea nitrogen level are also suggestive of
significant dehydration. In patients with mild dehydration (5%
body weight loss), these clinical findings are often not present
and laboratory studies are not indicated. However, if any of
these signs are present, electrolyte abnormalities and acid-base
disturbances should be evaluated by laboratory testing.9
Replacement of mild dehydration (<5% body weight loss)
can often be managed by oral rehydration therapy, even in
patients with diarrhea and vomiting.17 Two types of oral
replacement fluids are used; oral maintenance solutions and
oral rehydrational solutions. Maintenance fluids are commonly used along with parenteral rehydration to supplement losses from common problems such as gastroenteritis.
Rehydrational fluids have a higher sodium concentration and
are typically given in small doses (50 mL/kg) over 4 hours in
mild dehydration.9 Once rehydration is accomplished, maintenance fluids are then introduced.
In patients with moderate to severe hypovolemia (>5% body
weight loss), which can exist perioperatively due to a loss of
intravascular volume, the goal is to rapidly expand the extracellular volume, prevent shock, and improve renal perfusion.
Replacement is initially given in boluses of normal saline or
Ringer lactate. The urine output is then monitored as a measurement of the patients improved intravascular volume. As
mentioned previously, an adequate urine output in children is
considered to be between 1 and 2 mL/kg/hr.15 As the replacement fluid is given, the urine output is monitored closely. These
fluid boluses rapidly expand the intravascular volume and
then equilibrate with the rest of the extracellular space. An estimation of the overall deficit can be made using the knowledge
that 10% dehydration correlates with a loss of approximately
100 mL/kg.9 Typically, half the deficit is replaced over the first
8 hours, and the second half is given over the next 19 hours.
The replacement of sodium losses is calculated to be 8 to 10
mEq/kg/day plus the maintenance amount.9
Serial measurements of weight, clinical signs of dehydration, and urine output should all be made at regular intervals.
Sodium Abnormalities
Sodium is the major cation of the ECF. Fluctuations in the
serum sodium concentration can cause major fluid shifts and
metabolic abnormalies.10
Hyponatremia
Hyponatremia is one of the most frequent electrolyte abnormalities that occur in hospitalized patients. Symptoms
associated with hyponatremia include nausea, anorexia,
vomiting, apathy, muscle aches, headache, and weakness.18
Severe hyponatremia can cause irritability, confusion, seizures, and coma. In the perioperative period, ADH is
secreted in response to intravascular depletion, which leads
to the development of hyponatremia. In addition, intravascular depletion leads to a decreased GFR, which limits the
kidneys ability to excrete free water, causing hyponatremia.
Hyponatremia causes the overall osmolality to decrease, and
water moves along the osmotic gradient into cells, swelling
them. If this deficit is replaced too rapidly, brain cells are
put at risk of dehydration and damage resulting in central
pontine myolysis. For this reason, hyponatremia needs to be
corrected slowly, at a rate no faster than 10 to 20 mEq/day.9
Correction of the underlying problem is imperative in the
treatment of hyponatremia.
Hypervolemic hyponatremia is seen most often in conditions
such as congestive heart failure, renal failure, and liver disease, in which water is retained along with sodium, leading
to significant clinical manifestations, including peripheral
and pulmonary edema. Treatment involves sodium and water
restriction. In patients with renal failure, dialysis may be
needed to remove the excess fluid and correct the sodium
deficit.9
Situations of isovolemic hyponatremia are most often caused
by the syndrome of inappropriate antidiuretic hormone
(SIADH), which leads to excessive water reabsorption. The
most frequent underlying causes of inappropriate ADH
production are tumors, drugs, and central nervous system
disorders. Isovolemic hyponatremia is also occasionally seen
chapter
Hypernatremia
Symptoms associated with hypernatremia include confusion,
lethargy, muscle twitching, hyperreflexia, and convulsions.18
Patients with hypernatremia are typically dehydrated, with
more water being lost than sodium. Hypernatremia can be the
result of excessive peripheral losses or diabetes insipidus. It
can also occur with the ingestion of such drugs as lithium,
cyclophosphamide, and cisplatin. Premature infants are
predisposed to hypernatremia because of their inability to
properly regulate water and sodium levels. The risk of hypernatremia is that it can cause cerebral dehydration, which can
in turn lead to tearing of arachnoid tissues and intracerebral
bleeds.9
Hypervolemic hypernatremia is usually attributed to the
excess secretion of aldosterone, which causes increased sodium
reabsorption and potassium loss. Treatment of hyperaldosteronism includes the use of diuretics along with administration
of hypotonic fluids.9
Isovolemic hypernatremia may be the result of diabetes
insipidus (central or peripheral) or excessive insensible losses.
Diabetes insipidus results in the collecting tubules becoming impermeable to water. This can be caused by a defect in
central ADH release or by inability of the kidney receptors to
respond to ADH. Treatment includes correction of the sodium
concentration through the administration of hypotonic saline
solution. If central diabetes insipidus is the cause, exogenous
ADH can correct the imbalance.9
Hypovolemic hypernatremia occurs when water losses are
greater than sodium losses. This can result from diarrhea,
vomiting, or diabetes insipidus. Treatment should begin with
the administration of normal saline or lactated Ringer solution to restore the plasma volume. The elevated sodium level
should be lowered slowly, by no more than 10 mEq/day, to
prevent cerebral edema and fatal complications.9
Potassium Abnormalities
Potassium is the major intracellular cation; it is present in
low concentration in the ECF. It is this concentration gradient
between the ECF and the intracellular fluid that allows muscular, cardiac, and neuronal tissues to function appropriately.
Therefore, potassium abnormalities can be life-threatening.10
27
Hypokalemia
Symptoms of hypokalemia include arrhythmias, neuromuscular excitability, hyporeflexia, decreased peristalsis, and
rhabdomyolysis. Hypokalemia (defined as a serum potassium
level <3 mEq/dL) is most often the result of excessive renal
and gastrointestinal losses. Renal causes include both diuretic
and mineralocorticoid use, as well as renal tubular diseases
such as Bartter syndrome.9 Gastrointestinal causes include
excessive vomiting or nasogastric suctioning.
Cardiac arrhythmias, respiratory distress, and muscle
weakness require immediate replacement with KCl intravenously. This is typically done in boluses of 10 mEq in 100 mL
normal saline solution over a 1-hour period; once serum levels
are repleted, the therapy may be changed to oral replacement.
KCl is typically used in patients with metabolic acidosis,
whereas citrate or bicarbonate preparations are more often
employed in cases of renal tubular acidosis.9,19 Patients with
renal tubular diseases such as Bartter syndrome require KCl
replacement, potassium-sparing diuretics, and prostaglandin
synthase inhibitors.
Hyperkalemia
Symptoms of hyperkalemia can include cardiac arrhythmias,
paresthesias, muscle weakness, and paralysis. Hyperkalemia
(defined as a serum potassium level >5.5 mEq/dL) is most
often the result of a hemolyzed blood specimen with liberation of high concentrations of potassium or a specimen drawn
above the potassium-containing fluid line. If such causes are
suspected, another specimen should be drawn. True causes of
hyperkalemia include transcellular shifts, as seen in metabolic
acidosis and tissue catabolism. Chronic or acute renal failure
and hypoaldosteronism can cause serum potassium levels to
be increased. Chronic use of nonsteroidal anti-inflammatory
drugs or diuretics may also cause hyperkalemia.9
Patients with hyperkalemia require cardiac monitoring
during treatment. Calcium gluconate may be given intravenously to stabilize the myocardium, with each dose lasting
approximately 30 minutes. Glucose with insulin or NaHCO3
may also be given intravenously to drive potassium into the
intracellular space. To remove potassium from the body, ion
exchange resins such as Kayexalate may be used, either orally
or as enemas. These bind potassium to the resin in the gastrointestinal tract, which is then excreted. In situations of severe
hyperkalemia or unstable cardiac status, hemodialysis may be
employed to remove potassium quickly.
Hypocalcemia
Calcium is mostly concentrated within the bone matrix; only
0.1% of body calcium is in the ECF. Calcium exists in three forms:
40% is protein bound, 10% is complexed to phosphate and other
anions, and 50% is ionized. Metabolic acidosis decreases protein
binding, primarily to albumin, and increases ionized calcium;
metabolic alkalosis has the opposite affect. Hypocalcemia is the
reduction of the ionized portion. Clinical hypocalcemia manifests with perioral paresthesias, carpal pedal spasm, tetany, and
generalized seizure. Neuromuscular manifestations include
Chvostek sign, which is twitching of the corner of the mouth
produced by tapping over the facial nerve, and Trousseau sign,
which is spasm of the fingers produced by inflating a blood pressure cuff above systolic pressure. Electrocardiographic changes
include prolonged QT and ST intervals and peaked T waves.
Perioperative hypocalcemia may be the result of hypomagnesemia, acute renal failure, septic shock, rhabdomyolysis, or
acute pancreatitis. However, these conditions rarely produce
28
part
I: Basics
Hypomagnesemia
Hypomagnesemia occurs from dietary deficiency, excessive
alcohol consumption, and chronic diuretic use. Persistent
hypomagnesemia can cause hypocalcemia and contributes to
the persistence of hypokalemia by causing renal potassium
wasting. Magnesium should be replaced, either orally or intravenously, to the upper-normal plasma range, especially in the
setting of hypokalemia and hypocalcemia.
ACID-BASE DISTURBANCES
Normal physiologic pH is between 7.35 and 7.45. A normal pH
depends on both renal and pulmonary functions. To evaluate
acid-base disturbance in any patient, an arterial blood gas analysis along with a serum electrolyte panel must be obtained.20
Disturbances in this equilibrium can be the result of changes
in acid production, buffering, or excretion, any of which can
lead to metabolic acidosis or alkalosis. An increase or decrease
in the respiratory expulsion of CO2 can lead to a respiratory
acidosis or alkalosis.10
Metabolic Acidosis
Symptoms of acidosis include cardiac arrhythmias, hypotension, and pulmonary edema. Metabolic acidosis results from
the addition of acid or removal of base from the plasma. The
respiratory system attempts to compensate for this imbalance by blowing off carbon dioxide (CO2) to correct the body
pH. Acids in plasma are buffered in large part by bicarbonate (HCO3) and other unmeasurable anions such as proteins,
phosphates, sulfates, and organic bases.9,20 These unmeasurable bases make up the anion gap. The normal anion gap is
10 to 12 mEq/L.10 The anion gap may be calculated from the
plasma concentrations of certain ions, by the formula
Anion gap = Na+ (Cl + HCO3)
hypovolemia; it may also be caused by inborn errors of metabolism. Treatment hinges on correcting the underlying problem.
With sepsis and hypovolemia, antibiotics and fluid resuscitation may be all that is required. In more severe situations, the
administration of bicarbonate may temporarily stabilize the
pH while systemic treatment takes effect.
Diabetic ketoacidosis is the result of anaerobic metabolism
of glucose to -hydroxybutyrate and acetoacetate. Treatment
requires volume resuscitation and the administration of insulin, which helps metabolize ketoacids. Most situations do not
necessitate the use of bicarbonate.
Poisoning with salicylates or ethylene glycol leads to ketosis and lactic acidosis with the compensatory loss of HCO3.
These conditions are best corrected by removing the drug via
gastric lavage, charcoal, or, in severe situations, dialysis.9,20
Metabolic Alkalosis
Symptoms of metabolic alkalosis include central nervous system changes, muscular irritability, cardiac arrhythmias, and
seizures. Lethargy and confusion are often also seen when the
body decreases the breathing rate in order to retain CO2. Metabolic alkalosis occurs as a result of losing acid or gaining base.
Causes include alkali ingestion, vomiting, nasogastric tube
losses, and hyperaldosteronism.
In mild alkalosis, chloride replacement is needed to allow
the renal excretion of bicarbonate. In severe alkalosis, hydrochloride or ammonium chloride may be given to correct the
balance. If the alkalosis was caused by vomiting, potassium
may also need to be supplemented along with chloride. If the
underlying alkalosis was caused by hyperaldosteronism, the
antagonist spironolactone is given to correct the situation.9,20
Respiratory Acidosis
Respiratory acidosis is caused by an increase in the partial
pressure of carbon dioxide, Pco2 (decrease in respiration), which
drives down the body pH. Causes include airway obstruction,
central nervous system depression, immaturity, and neuromuscular problems. Treatment is aimed at correcting the underlying
problem, and bicarbonate usually is not given.9,20
Respiratory Alkalosis
NUTRITIONAL CONSIDERATIONS
Developing children have a high metabolic rate and low body
stores of fat and nutrients. This makes them more susceptible
to metabolic disturbances in the perioperative period. Prolonged fasting, stress, and trauma lead to a depletion of body
stores, primarily protein, which decreases immunocompetence and increases morbidity and mortality.21 Several issues
must be taken into consideration when developing a plan
for nutritional support in children: (1) the nutritional status
(nutritional assessment), (2) the metabolic status (total urinary
chapter
29
of these commercially prepared diets vary widely, and specific formulations are used for specific patients needs.
Problems of nausea, vomiting, and diarrhea can be overcome by the use of smaller Silastic feeding tubes and by incrementally increasing the feeding rate slowly over time. Typically,
infusion rates begin at 10 mL/hr and may be increased to a
maximum of 90 mL/hr. A minimal infusion rate of 20 mL/hr is
needed for gut preservation and immune stimulation.
Great success has been achieved with enteral alimentation in support of the nondepleted, noncachectic patient.30
However, the enteral route is not always adequate to deliver
enough nourishment rapidly and efficiently in the malnourished patient. In addition, malnutrition can lead to anatomic
changes in the gastrointestinal tract that can exacerbate malabsorption. A more aggressive approach to nutritional restoration in the depleted patient is often warranted because of time
constraints or the degree of nutritional depletion.
Enteral Alimentation
Calories/mL
Protein (g/L)
Fat (g/L)
Carbohydrate (g/L)
kcal/N Ratio
Osmolite HN
1.06
44
37
141
150:1
Osmolite
1.06
37
39
145
178:1
Ensure
1.06
37
37
145
178:1
Vitaneed
1.0
40
40
128
156:1
Nutren Fiber
1.0
40
38
127
156:1
Peptamen
1.0
40
39
127
156:1
Vivonex T.E.N.
1.0
38
206
175:1
Ensure Plus
1.5
55
53
200
170:1
TraumaCal
1.5
83
68
142
116:1
Pulmocare
1.5
63
92
106
150:1
Isocal HCN
2.0
75
102
200
170:1
Suplena
2.0
30
96
255
427:1
Amin-Aid
2.0
19.4
46
366
830:1
PediaSure
1.0
30
50
110
209:1
Adapted from Hensle TW, Kennedy WA. An update on nutrition in the surgical patient. AUA Update Series. Linthicum, MD: American Urological Association
Education and Research, Inc; 1995; Vol. XIV:Lesson 3.
30
part
I: Basics
yperalimentation Solution
H
(per 2618 mL)
Component
Amount
Amino acids
100 g
Dextrose
200 g
Fat
100 g
Sodium
150 mEq
Potassium
82 mEq
Calcium
9 mEq
Magnesium
10 mEq
Chloride
150 mEq
Acetate
187 mEq
Zinc
3.5 mg
Copper
1.4 mg
Manganese
0.35 mg
Chromium
14 g
Multivitamin 12
10 ml
Phosphorus
15 mM
REFERENCES
For complete list of references log onto www.expertconsult.com
S E C T I O N
MORPHOLOGIC INVESTIGATIONS
chapter
32
part
I: Basics
Bilateral Dysplasia
>24
ND
<24
>24
<24
>24
56
18
11
19923
32
13
Levi et al,
<24
Renal Agenesis
ND
ND
19914
10
16
Chitty et al,
Smith et al,
19996
Total (%)
21
30
28 (17)
104 (63)
32 (20)
35 (37)
41 (43)
14
19 (20)
19 (50)
14 (37)
5 (13)
RenalTract
Echogenic kidneys
Dilated bladder
Can you see the ureters? (Ureters should not normally be seen.)
echogenic. With increasing gestation, corticomedullary differentiation takes place, and by 18 to 22 weeks, the renal pelvis
and calyceal pattern can be identified. Fetal kidneys continue
to grow throughout pregnancy, and several charts of fetal
renal size are available.13 Measurements have been made in
both longitudinal and cross-sectional planes using both TVUS
in early pregnancy14 and transabdominal ultrasound from
12 weeks onward.13
The fetal bladder can be identified from 11 to 12 weeks
postmenstrual age, and persistent absence of the bladder
should be considered as abnormal from approximately
15weeks gestation onward.11,12 Normal fetal ureters are not
visualized with ultrasound. Fetal urine production begins at
10 weeks gestation, although tubular function does not begin
until about 14 weeks. Before that time, the amniotic fluid is
thought to be primarily a dialysate of fetal blood across the
skin, which is permeable. By the middle of the second trimester, the fetal kidneys account for most of the amniotic fluid
production; any impairment in production will be manifested
as oligohydramnios, and assessment of volume will provide
some reflection of overall renal function. An adequate amount
of amniotic fluid is required to allow development of the fetal
lungs and to enable movement of the fetus within the amniotic cavity. Oligohydramnios may be caused by mechanical
chapter
33
Renal Agenesis
Renal agenesis occurs when there is complete absence of one
or both kidneys. The underlying pathology is not certain but
probably involves failure of early development of the ureteric
bud. Agenesis may also result as an end stage of dysplastic
change and regression of a multicystic kidney; this can occasionally occur early in gestation, before the first scan, so a
definitive determination of the cause may not always be possible prenatally.
Unilateral agenesis is thought to occur in approximately
1of every 1400 births. If it is an isolated condition, there is usually a normal volume of amniotic fluid, and the contralateral
kidney becomes enlarged through compensatory hypertrophy. Overall prognosis is good if the finding is isolated; however, unilateral renal agenesis may also be associated with
extrarenal abnormalities, particularly of the spine and heart.
In males, unilateral renal agenesis is frequently associated
with dysplasia of the testis, which must be therefore excluded
by ultrasonography after birth.17 In the postnatal period,
renal ultrasound scans should be performed to confirm the
prenatal diagnosis and to examine the contralateral kidney,
because there is a significant incidence of reflux and other
abnormalities. Neonates should also be carefully examined for
other subtle abnormalities, such as hemivertebrae, which may
not have been detected prenatally and which may be seen in
the VATER or VACTERL spectra (discussed later).18
The incidence of bilateral renal agenesis is approximately 1
in 4000,19 with a male-to-female ratio of 2.5:1. Classically, the
findings include failure to identify either kidney, a persistently
absent bladder, and oligohydramnios. Visualization of the fetus
can be difficult, but the use of color Doppler ultrasonography
can enhance the diagnosis, because failure to demonstrate
renal artery flow is evident even in the presence of severe
An ectopic kidney occurs as a result of failure of normal migration of the kidneys during early embryologic development
along the cranial-caudal axis. Most commonly, the kidney is
located in a pelvic position, although iliac, abdominal, and thoracic locations have been reported.21,22 The incidence of simple
renal ectopia based on postmortem data varies between 1 in
500 and 1 in 1200.23-25 There is an equal sex incidence and a
slight preponderance to the left side; 10% of cases are bilateral.26 The ectopic renal mass is often smaller than expected
and has an unusual shape because of the presence of fetal
lobulations. The vascular supply is usually anomalous and
depends on the final position of the kidney.
During the routine second-trimester scan, an empty renal
fossa should raise the suspicion of an ectopic kidney and initiate a search within the pelvis (Fig. 4-2). The diagnosis is not
always easy to make; the adrenal gland may be mistaken for
a hypoplastic kidney, or bowel in the renal bed for a cystic
renal mass. The diagnosis can usually be made with the use
of transabdominal ultrasound,27 but it may sometimes be necessary to perform TVUS to fully assess a kidney positioned
deep within the pelvis. Pelvic kidneys are often smaller than
expected for the gestational age, and they may have an abnormal shape as a result of malrotation.28 Color Doppler assessment may be a useful aid to diagnosis and will demonstrate
the blood supply to the ectopic kidney, which may arise from
the lower aorta or from the common iliac, middle sacral, or
inferior mesenteric vessel.28 Both kidneys should be assessed
for size, echogenicity, and renal pelvis dilatation (RPD); the
bladder and external genitalia should be examined for associated urogenital anomalies; and a detailed examination of the
fetus should be carried out to search for associated extrarenal
anomalies. Coexisting urogenital abnormalities occur in 15%
to 45% of these cases, including contralateral renal anomalies
such as agenesis or upper tract dilatation; hypospadias, cryp
torchidism, and urethral duplication in males; and uterine
and vaginal anomalies in females.29,30 Extrarenal anomalies in
the cardiovascular, skeletal, and gastrointestinal systems can
occasionally be found in association with ectopic kidneys,26
which have also been described in association with a number
of genetic syndromes, including Beckwith-Wiedemann syndrome (BWS), branchio-oto-renal dysplasia, and abnormalities in chromosomes 19 and 22.
There are limited data regarding the long-term implications
of a prenatal diagnosis of pelvic kidney. In two series, prenatally diagnosed pelvic kidneys were found mainly in isolation
and without obvious significant consequence.27,28 Masnata
and colleagues31 reported on 32 cases, 15 of which were accurately diagnosed before birth. Surgery was required for four
children with a contralateral anomaly, and four underwent
nephrectomy for a large pelvic multicystic dysplastic kidney.
Overall renal function was normal in all of these cases. In a
study of 12 pelvic kidneys seen in our unit, all either were
34
part
I: Basics
Normal kidney
A
Normal kidney
Pelvic kidney
C
Figure 4-2 Sonographic images showing a normal kidney with an
empty renal fossa (A), a pelvic kidney located anterior and inferior to
the normal kidney (B), and an absence of normal renal artery flow to
the pelvic kidney (C). The pelvic kidney in C was subsequently identified as arising from the iliac vessels.
small at initial diagnosis or decreased in size during pregnancy. Amniotic fluid volume remained within the normal
range, although it approached the 5th percentile in one case
later in pregnancy. The contralateral kidney appeared normal
during pregnancy in seven cases, and in five cases there was
compensatory hypertrophy. The remaining five cases had contralateral renal anomalies. Overall postnatal renal function,
as determined either by uptake and drainage of radioactive
chapter
35
Figure 4-3 Enlarged echogenic kidneys seen in the axial (A) and coronal (B) planes with associated absence of amniotic fluid. After birth, the
cause was identified histologically as autosomal recessive polycystic kidney disease.
Figure 4-4 Enlarged echogenic kidneys seen in the axial (A) and coronal (B) planes in a fetus with Beckwith-Wiedemann syndrome. Note the
presence of normal liquor in this case.
Dysplastic Kidneys
Renal dysplasia is a histologic diagnosis, but the diagnosis
may be inferred prenatally from increased echogenicity of the
renal cortex, which results from the lack of normal renal parenchyma and structurally abnormal kidneys. Dysplastic kidneys
can be any size, ranging from massive kidneys distended with
multiple large cysts up to 9 cm in diameter, commonly termed
multicystic dysplastic kidneys (MCDK), to normal-sized or
small kidneys with or without cysts. Dysplasia can be unilateral or bilateral, and MCDK is one of the most common causes
of abdominal masses in the newborn. The incidence of unilateral MCDK is between 1 in 3000 and 1 in 5000 births, compared to 1 in 10,000 for bilateral dysplasia.35
MCDK confined to one kidney is often an incidental finding, but bilateral dysplasia should lead to consideration of
36
part
I: Basics
of Hyperechogenic Kidneys
color flow Doppler may be useful, as in bilateral renal agenesis (see Fig. 4-1).
aneuploidy or inherited conditions. There is a strong association between dysplasia and obstruction: MCDKs are classically attached to atretic ureters; renal dysplasia frequently
develops in conjunction with lower urinary tract malformations that impair urine flow; and many features of dysplasia
can be generated in animals by experimental obstruction
of the urinary tract during development.36,37 Therefore, the
lower urinary tract should be carefully assessed in all cases of
presumed renal dysplasia.
Sonographic Findings
The classic presentation of MCDK is a multiloculated abdominal mass consisting of multiple thin-walled cysts which do not
appear to connect (Fig. 4-5). The cysts are distributed randomly;
the kidney is usually enlarged with an irregular outline, and no
renal pelvis can be demonstrated. Circumferential cysts may
occasionally be detected in kidneys of more normal size, particularly in association with lower urinary tract obstruction.
Parenchymal tissue between the cysts is often hyperechogenic.
In the unilateral form liquor volume is usually normal, but oligohydramnios or anhydramnios is likely to be present with
bilateral MCDK. Differential diagnosis of multicystic dysplasia includes upper tract dilatation and other intra-abdominal
cystic masses. Color Doppler ultrasonography may be useful in determining the diagnosis, because the renal artery is
always small or absent in MCDK, and the Doppler waveform,
when present, is markedly abnormal, with a reduced systolic
peak and absent diastolic flow. The appearance of MCDKs
may change during pregnancy; frequently there is an initial
increase in size, often surpassing normal expected growth, followed by decrease in size as gestation progresses. Dysplastic
kidneys may even disappear completely, either before or after
birth,38-40 suggesting that many patients diagnosed with renal
agenesis may have originally had dysplasia.
Bilateral severe dysplasia without associated cystic change
may be difficult to distinguish from renal agenesis, especially
because detailed examination of the fetal anatomy is difficult in the presence of oligohydramnios or anhydramnios.
Unilateral small dysplastic kidneys are much more difficult
to detect in utero, unless they are specifically sought after
diagnosis of other abnormalities in the urinary tract or other
organ systems (Fig. 4-6). The bladder is usually normal in
unilateral dysplasia unless there is lower tract pathology; in
bilateral disease, the bladder may be difficult to detect, and
chapter
37
A
B
Figure 4-5 Sagittal (A) and axial (B) views through the abdomen of
a fetus with a typical unilateral multicystic kidney. There are large irregular cysts that do not communicate. A sagittal view of a fetus with
a multicystic kidney with cysts confined to the cortical region is also
shown (C). Multicystic kidneys can easily be confused with upper
tract dilatation, as demonstrated in the axial (D) and sagittal (E) views
of a fetus in which the multicystic dysplastic kidney had one major
cyst and a few scattered smaller ones visible only in the axial view.
38
part
I: Basics
DK
NK
B
Figure 4-6 Sagittal (A) and axial (B) views of a unilateral small dysplastic kidney (DK) with the normal contralateral kidney (NK) showing
compensatory hypertrophy.
Prognosis
for
chapter
respiratory failure rather than renal problems, although aggressive ventilatory support and emergency nephrectomy may
improve the outcome.54 Genetically, the severe cases map to
the same region as the milder forms, and therefore they cannot
be distinguished by currently available molecular genetic techniques.55 Survivors beyond the neonatal period have a much
better prognosis56,57 than that reported in most textbooks (progressive renal and hepatic failure, with death during childhood in most cases). The 1-year survival probability after the
first month was reported as 94% for male patients and 82% for
female patients in a large study of more than 100 children,56
and actuarial renal survival rates of 86% at 1 year and 67% at
15 years was described by another group.57 Aside from declining
renal function, the major problems reported were urinary tract
infections, severe systemic hypertension requiring multipledrug therapy, and hepatic fibrosis with portal hypertension
leading to hypersplenism and gastroesophageal varices.
Sonographic Findings
The sonographic presentation of ADPKD is usually as large,
hyperechogenic kidneys; in contrast to ARPKD, individual
cysts may also be detected.62 The size of the cysts in ADPKD is
variable, and a mixture of small and large cysts can be observed.
Liquor volume is usually preserved. Definitive diagnosis may
be possible prenatally if a family history of ADPKD can be established or if one parent is found to have renal cysts on ultrasound,
because new mutations occur in fewer than 10% of cases, and
almost all affected individuals have at least one cyst by the age
of 30 years.63 In families at known prior risk who request it, prenatal diagnosis is best done by molecular analysis of chorionic
villi if linkage has been established before pregnancy. It is particularly important to establish the diagnosis of ADPKD if it has
been inherited from the mother, because hypertensive mothers
with ADPKD have a high risk for fetal and maternal complications and require close monitoring to prevent the development
of preeclampsia.64 In one case, the appearances were reported
to change during pregnancy, with large bright kidneys seen at
21, 23, and 34 weeks of gestation but normal-sized kidneys and
corticomedullary differentiation after birth.65 ADPKD was confirmed in that infant when cysts developed at 11 months of age
in one kidney and at 20 months in the other.
Prognosis
for
39
Overgrowth Syndromes
The presence of large echogenic kidneys in a fetus with generalized macrosomia and normal or increased liquor points
toward the diagnosis of an overgrowth syndrome. All are rare,
the most common being BWS and Simpson-Golabi-Behmel
syndrome. Prenatally, differentiation among these syndromes
can be extremely difficult unless there is a positive family
history, a distinctive pattern of structural abnormalities, or a
positive molecular or cytogenetic diagnosis. In low-risk cases,
distinction usually must await the results of postnatal investigations, and even then there is considerable clinical overlap
among the syndromes (Table 4-5).33,69
Beckwith-Wiedemann Syndrome
BWS is characterized by gigantism (which is often, but not
always, present at birth), macroglossia, visceromegaly (liver,
spleen, kidneys, adrenals), abdominal wall defects (omphalocele and umbilical hernia), and predisposition to embryonal tumors, particularly Wilms tumor.71 The features can be
extremely variable, and specific dysmorphic features such
as ear creases, nevus flammeus, and hemihypertrophy may
be useful distinguishing features postnatally.72 BWS is the
result of abnormal expression of imprinted genes involved in
growth and cell cycle control lying in the region of chromosome 11p15.73 It seems that the syndrome is caused by paternal disomy for 11p15.5, which contains the insulin-like growth
factor 2 (IGF2) gene. In some cases there is a cytogenetic deletion of this region, and in others paternal disomy can be demonstrated; however, in many cases no molecular or cytogenetic
abnormality is demonstrable.72
Sonographic Findings. Polyhydramnios is often reported in association with bilateral enlarged echogenic kidneys
due to BWS (see Fig. 4-4).33,74 Other features reported include
hepatomegaly, macroglossia, generalized macrosomia, and
omphalocele. Mild hydronephrosis,75 placental enlargement,76
and elevated maternal serum beta-human chorionic gonadotrophin have also been reported.77 The prognosis for BWS is
now recognized to be much better than previously thought,72
40
part
I: Basics
Liquor
Renal Cyst
RPD
Macrosomy
Other
Abnormalities
Cardiac
Abnormalities
ARPKD
N/oligo
AR
ADPKD
N/oligo
(+)
AD
BWS
N/poly
Perlman
N/oligo
AR
SGB
X-linked
Inheritance
Trisomy 13
Oligo
Sporadic
Meckel-Gruber
Oligo
AR
Sporadic
Obstructions
N/oligo
Nephrocalcinosis
Bardet-Biedel
N/poly
AR
AD, autosomal dominant; ADPKD, autosomal dominant polycystic kidney disease; AR, autosomal recessive; ARPKD, autosomal recessive polycystic
idney disease; BWS, Beckwith-Wiedemann syndrome; N, normal; oligo, oligohydramnios; poly, polyhydramnios; RPD, renal pelvic dilatation; SGB, Simpson-
k
Golabi-Behmel syndrome.
Simpson-Golabi-Behmel Syndrome
Simpson-Golabi-Behmel syndrome is an X-linked neonatal
overgrowth syndrome that is characterized by a large head
with coarse features, hepatosplenomegaly, cryptorchidism,
and variable degrees of developmental delay, with some
affected individuals having normal intelligence.78 Associated structural abnormalities amenable to prenatal diagnosis
include polydactyly, cardiac abnormalities, vertebral anomalies, and umbilical hernia. Because the condition is X-linked,
this diagnosis should be considered only in a male fetus. It has
been mapped to Xq25-q27.79
Sonographic Findings. The diagnosis should be considered in all cases of large hyperechogenic kidneys in a male
fetus with all other measurements lying above the 95th percentile. A finding of polydactyly may be a useful adjunct to
diagnosis, as may a diaphragmatic hernia or cardiac anomaly.
Referral to a clinical geneticist may be of value, because there
is often a family history of X-linked problems, and female carriers may have distinctive facial features.
Perlman Syndrome
Perlman syndrome is a rare, autosomal recessively inherited
overgrowth syndrome characterized by general organomegaly, facial dysmorphisms, and renal hamartomas with a tendency to hepatoblastomatosis. Fetal and neonatal mortality
rates are high.74
Sonographic Findings. The main sonographic features
of Perlman syndrome are generalized fetal macrosomia and
large echogenic kidneys, secondary to renal hamartomas with
or without nephroblastomatosis.69 Hydronephrosis and hydroureter have been reported, as has a large cisterna magna
with skeletal abnormalities.80 Diaphragmatic hernia and cardiac defects have also been reported.81 Polyhydramnios is often
associated with this syndrome, but oligohydramnios has also
been described together with fetal ascites.69 The prognosis is
poor, with neonatal death occurring in many cases, often secondary to pulmonary hypoplasia and prematurity. The survivors have a high incidence of developmental delay and Wilms
tumors.82
Meckel-Gruber Syndrome
Meckel-Gruber syndrome is a lethal autosomal recessive syndrome that is characterized by bilateral enlarged echogenic
kidneys (100%), encephalocele or other major intracranial
abnormality (90%), and postaxial polydactyly (90%).85 The
syndrome has been mapped to chromosome 17q21-24 in Finnish families,86 and, more recently, a second locus on chromosome 11 has also been identified.87
Sonographic Findings. The in utero presentation of MeckelGruber syndrome is that of large, echogenic kidneys in association with anhydramnios and an encephalocele or other major
chapter
intracranial abnormalities such as anencephaly, severe hydrocephalus, or Dandy-Walker malformation. Polydactyly may
not be detected prenatally if visualization is poor with oligohydramnios, which may be present from as early as 14weeks gestation.88 Diagnosis early in gestation, between 11 and 14 weeks,
may be easier, because the liquor volume should be normal at
this stage, examination of the fetal brain is easier, and kidneys
are usually enlarged early in pregnancy.89,90 Prenatally, the major differential diagnosis is that of trisomy 13, which may also
manifest with intracranial abnormalities in the presence of large
bright kidneys, cardiac anomalies, and polydactyly.
The prognosis is awful for a fetus with Meckel-Gruber syndrome. Neonatal death occurs within a few hours of life as a
result of renal failure and pulmonary hypoplasia.
Bardet-Biedl Syndrome
Bardet-Biedl syndrome, also called Laurence-Moon-BardetBiedl syndrome (LMBBS), is a genetically heterogeneous disorder characterized by polydactyly, obesity, developmental
delay, hypogonadism, and a rod-cone dystrophy (atypical
retinitis pigmentosa).91 Renal abnormalities are present in up
to 90% of cases, and renal failure occurs in up to 60%.92,93 Polydactyly may be the only feature that is obvious at birth. The
retinal dystrophy is progressive and often is not detected until
the child is at school, and, although the renal changes may be
detected earlier, they rarely cause early symptoms. Prenatally,
large, echogenic kidneys are the most common presenting
feature. This finding should prompt a search for polydactyly,
which is present in 70% of cases, and cryptorchidism in a male
fetus. To date, 12 loci have been identified (BBS1 through
BBS12), with at least 50% of the families tested mapping to
11q13 (BBS1).94 Although BBS is considered an autosomal
recessive syndrome, it has been further delineated to suggest a
triallelic mode of inheritance, in which three mutant alleles
are required to manifest the phenotype.95 In sporadic cases,
definitive diagnosis must await postnatal investigations. In
families with a previously affected child, detection of large,
bright kidneys and polydactyly can be used diagnostically.
Elejalde Syndrome
In 1977, Elejalde and coworkers described a spectacular overgrowth syndrome in two siblings with birth weights approximately twice that expected, 7500 g at term and 4300 g at
34 weeks.98 Subsequent reports showed similar overgrowth,
with the placenta included in the size discrepancy. The
41
Fraser Syndrome
Fraser syndrome is a rare, autosomal recessive disorder characterized by cryptophthalmos, syndactyly, and renal agenesis
or obstructive uropathy.100 The cryptophthalmos is present in
85% and is bilateral in 70% of these cases. Syndactyly occurs
in approximately 80% of cases and may be partial or complete.
Renal agenesis is present in 85%; it is unilateral in 37% and
bilateral in 47% of cases. Developmental delay occurs in about
80% of survivors, although this condition is usually lethal.
Cleft lip and palate occur in 10% and may be detectable on
an anomaly scan.101 The gene for this disorder has not been
located, but suspicion may be raised at the time of a 20-week
anomaly scan if the renal lesion is unilateral and the associated
eye and hand abnormalities are suspected. If renal agenesis is
bilateral, oligohydramnios may preclude further assessment,
and a full postmortem examination would be required for the
correct diagnosis.
Branchio-oto-renal Syndrome
The autosomal dominant disorder known as branchio-otorenal (BOR) syndrome comprises conductive and sensorineural deafness, branchial fistulas, and renal anomalies that
include duplication of the collecting system, hydronephrosis,
cystic kidneys, and unilateral or bilateral renal agenesis. There
is considerable variation in expression and penetrance in this
disorder, so a detailed family history is important. Without a
family history, the diagnosis would be difficult to make prenatally. Mutations in the gene EYA1, located at 8q13.3, have been
shown to be responsible in some cases.102 A definitive prenatal
diagnosis is unlikely in low-risk cases, because the associated
findings can be very subtle.103
and
Clefting Syndrome
Schinzel-Giedion Syndrome
The autosomal recessive condition termed Schinzel-Giedion
syndrome comprises severe midface retraction, skull anomalies, talipes, and cardiac and renal malformations. There is
frontal bossing, which, together with midface retraction and
chubby cheeks, gives the face a figure 8 shape. Death usually occurs before 18 months. Gross congenital hydronephrosis (>80mm) may be the presenting feature, usually late in the
second trimester.107 This is often the main prenatal feature,
42
part
I: Basics
Renal Cysts
and
detailed assessment of the rest of the fetal renal tract and extrarenal structures.
chapter
43
A
B
Figure 4-7 Mild bilateral renal pelvic dilatation seen in the second
trimester in the coronal (A) and axial (B) planes and in the third trimester (C).
RPD and adjust the prior risk by this factor. Pilu and Nicolaides
used this approach to suggest that isolated RPD confers a risk
of trisomy 21 that is 1.5 times the background risk.128 However,
not all authors concur with this view. In a series of 1177 fetuses
with mild RPD recruited between 16 and 26 weeks of gestation,
5 fetuses from a total of 805 with apparently isolated RPD had
trisomy 21. The expected frequency of trisomy 21 in the population was estimated as 0.40%, which was not significantly different from the observed frequency of 0.62%.8
The widespread incorporation of first-trimester and early
second-trimester Down syndrome screening into routine
prenatal care has implications for the role of second-trimester
minor markers of aneuploidy such as RPD in
assessing the
risk for aneuploidy
. In 1998, Thompson and Thilaganathan
reported on a prospective study evaluating the significance
of isolated RPD in an unselected population in which firsttrimester nuchal translucency measurement, second-trimester
maternal serum biochemistry, and second-trimester ultrasound screening were offered.129 A total of 20 cases of trisomy 21 were detected. Of these, 14 were identified through
44
part
I: Basics
Extrarenal Causes
Sacrococcygeal teratoma
Hydrometacolpos
Duplex systems
Ureterocele/ectopic ureter
Urethral atresia
Cloacal anomaly
Vesicoureteric reflux
Megaureter
Megacystis microcolon
hypoperistalsis syndrome
chapter
45
Figure 4-8 Images of a fetus with bilateral pelviureteric junction obstruction, with asymmetric dilatation demonstrated in the axial plane (A).
The sagittal view (B) demonstrates the dilatation of the pelvis, which ends abruptly at the junction with the ureters, giving the classic Mickey
Mouse ears appearance.
infants, because spontaneous improvement or resolution is
the most common outcome. However, regular follow-up with
repeated ultrasound scans and isotope studies is needed during the first 2 years of life to ensure that the spontaneous evolution is satisfactory. Fewer than 20% of children presenting
with significant prenatal dilatation of the upper urinary tracts
will require surgery. The incidence among those presenting
with mild pyelectasis is much lower, and surgery is usually
confined to those in whom dilatation increased to greater than
10 mm.131,138
Sonographic Diagnosis
and
Management
Outcome is generally good for both unilateral and bilateral disease, but occasionally oligohydramnios develops in
association with bilateral disease and worsens the prognosis,
so careful monitoring is required. Prenatal intervention (e.g.,
shunting an extremely dilated renal pelvis) is very rarely
required. Serial sonography during pregnancy may help to
inform both parents and pediatricians as to the likelihood
of requirement for surgical intervention, but ultimately this
decision will be undertaken after postnatal investigation.
The infant should be placed on prophylactic antibiotics while
these tests are carried out, to minimize the risk of urinary tract
sepsis.
It is important to define whether the PUJ anomaly is an
isolated condition or is associated with other anomalies.
Twenty-five percent of cases are associated with other renal
abnormalities, including renal agenesis, multicystic renal
dysplasia, VUR, ureteric hypoplasia, partial or complete
ureteric duplication, and horseshoe kidney, and some have
other, extrarenal abnormalities, such as anorectal anomalies,
congenital heart disease, or VATER syndrome.
Diagnosis
Prenatal sonography shows a dilated ureter, which may be
seen communicating with the dilated renal pelvis (Fig. 4-9).
The bladder appearance and liquor volume are normal. The
main differential diagnoses are VUR and ureteric obstruction
due to ureterocele associated with a duplex kidney (Fig. 4-10).
Coexisting abnormalities occur in 16% of cases and include
PUJO, multicystic renal dysplasia, pelvic kidney, renal agenesis, and VUR.144
Vesicoureteric Reflux
VUR is a permanent or intermittent retrograde flow of bladder urine into the upper urinary tract; it occurs either as a
primary abnormality in an anatomically normal bladder or
46
part
I: Basics
Duplex Kidneys
secondary to another cause of urine flow impairment or bladder neuropathy. The incidence in the general pediatric population is 1% to 2%, and it is usually diagnosed in infants being
investigated for urinary tract infection.145 The associated predisposition to infection can lead to significant morbidity due
to scarring and chronic renal dysfunction. VUR accounts for
approximately 10% of all instances of prenatally diagnosed
RPD, and the sonographic findings may be limited to RPD,
although bilaterally dilated ureters and bladder may be seen
in severe cases (Fig. 4-11). It is not possible to make a definitive
diagnosis in utero. More than 80% of children with prenatally
diagnosed reflux are boys.135,146,147 In contrast, the postnatal
incidence of reflux has a female-to-male ratio of 5:1.148 The
increased voiding pressure required in boys, which in utero
may distort the ureterovesical junction, is a possible explanation for this.
VUR may be associated with other renal abnormalities,
in particular ureteroceles in duplex kidneys, PUJ anomalies,
multicystic renal dysplasia, and unilateral renal agenesis.149
Prenatal sonography may not be able to assess these definitively, so all infants should be carefully assessed in the postnatal period. For prenatally diagnosed VUR, the dilatation
Sonographic Diagnosis
Prenatal ultrasound has not always proved reliable in accurately distinguishing duplex kidneys from a range of other disorders causing renal dilatation. Differential diagnoses include
hydronephrosis, polycystic kidneys, solitary renal cysts,
and PUJO.153 Abuhamad and colleagues described features
that were more accurately associated with a duplex kidney,
including two separate, noncommunicating renal pelves (see
Fig. 4-12A), dilated ureters (see Fig. 4-12B), cystic structures
within one pole (see Fig. 4-12F), and one or more echogenic
cysts in the bladder, representing ureterocele (see Fig. 4-10).154
chapter
47
Ureterocele
Ureteroceles consist of cystic dilatations of the submucosal
segment of the intravesical ureter with consequent narrowing of the ureteral orifice. They are associated with the upper
pole of a duplex kidney in 80% of cases (see earlier discussion)
but may be isolated. Ureteroceles may be identified prenatally
by the detection of an echolucent circular rim within the fetal
bladder (see Fig. 4-10).
BLADDER ABNORMALITIES
Normal Sonography of the Fetal Bladder
The normal fetal bladder can be visualized from the onset
of urine production, which occurs by about 10 weeks. By 12
weeks, the fetal bladder can be visualized in 100% of normal
fetuses on TVUS. The diameter of the bladder at 12 weeks
should be no more than 6 to 8 mm.160 By the time of the 18- to
20-week routine anomaly scan, the bladder should be identified in 100% of cases. The normal fetus voids regularly, but
the bladder is never completely empty and always contains
a small residual volume. The observation of cyclic filling and
emptying of the bladder forms an important part of the ultrasound assessment. In the normal bladder, the mucosa and
musculature are of similar echogenicity to other structures
in the pelvis, and there is little discernible space between the
fluid in the bladder and, for example, paravesical arteries. The
bladder wall itself should be no thicker than 3 mm.
As the pregnancy progresses, the normal bladder is imaged
as an elliptical, fluid-filled structure within the fetal pelvis; it
is bordered laterally by the umbilical arteries, which in the
adult become the superior vesical arteries. Anterior to the
bladder are the ossified pubic bones, and posterior to it is
the normal rectosigmoid colon, which can be seen anterior to
the sacral segment of the spine. The paravesical arteries may
be used to differentiate the bladder from other cystic structures within the pelvis.
Megacystis
A distended bladder may arise for two main reasons. First,
there may be obstruction to the flow of urine out of the bladder. This occurs most commonly in male fetuses, usually as a
result of maldevelopment of the urethra. A spectrum of abnormalities occurs, from complete urethral atresia through to the
formation of urethral valves that form around the membranous/prostatic urethra. In the female, bladder obstruction is
usually the result of rather more complex defects in the development of the urogenital system, often grouped under the
term cloacal plate abnormalities (discussed later). The second group has an enlarged bladder secondary to nonobstructive causes. This is a heterogeneous group, often with complex
underlying pathology.
A distended, thick-walled bladder associated with a dilated
posterior urethra and oligohydramnios is pathognomonic of
PUV (Fig. 4-13), but without this combination of ultrasound
signs, the underlying pathology is less certain. Prediction of
other etiologies for the megacystis is less accurate, but primary reflux, cloacal plate anomalies, urethral duplication,
48
part
I: Basics
C
D
Figure 4-12 Ultrasound images of duplex systems showing a simple duplex (A), a duplex with one dilated pole at 20 weeks gestation (B), and
progressive dilatation at 32 weeks (C). A dilated upper pole with a dilated tortuous ureter is shown in D (B, bladder; LP, lower pole; U, ureter; UP,
upper pole). A bilateral duplex system with both poles dilated is shown in E. A duplex with a dilated upper pole and cystic lower pole is shown
in the axial view (F),
chapter
G
Figure 4-12, contd, and in the sagittal plane (G).
and megacystis microcolon are included in the differential
diagnosis.
In a review carried out in our own unit of 115 fetuses with
persistent bladder dilatation seen over a 10-year period, 47 (41%)
underwent termination of pregnancy, 61 (53%) were liveborn, and 7 (6%) died in utero.161 Of the 47 fetuses undergoing termination, 3 had aneuploidy (trisomy 13, trisomy 21,
XXYY). Sixteen of these fetuses had oligohydramnios by 20
weeks gestation (Fig. 4-14; see Fig. 4-13), the presence of
which contributed to a decision to terminate the pregnancy.
A definitive postnatal diagnosis was available in 93 cases,
from either postmortem data or postnatal investigations.
Just over half (48/93) were caused by PUV, and almost one
quarter (21/93) were associated with megaureter, VUR, or
PUJO. Other causes included cloacal anomalies, complex
renal abnormalities, urethral stenosis, and complex genetic
syndromes including hollow visceral myopathy, oculodental
digital syndrome, VACTERL association, and the CHARGE
association (coloboma, heart disease, choanal atresia, retardation, genital hyperplasia, and ear anomalies). Of the 61
live births, there were 7 neonatal deaths. Four of these were
associated with pulmonary hypoplasia and renal failure with
prenatal anhydramnios. Three infants died from complications related to other congenital abnormalities, including
short-ribbed polydactyly syndrome, congenital cardiac abnormality, and megacystis-microcolon-intestinal hypoperistalsis
syndrome. In addition, four died before the age of 4 years
from other complications of renal failure, including sepsis and
end-stage renal failure. Long-term follow-up in the surviving
infants revealed impaired renal function in 32% (defined by
a GFR of less than 75 mL/min/1.73 m2); a further 44% have
normal renal function but have undergone repeated surgery.
Of 11 survivors older than 5 years of age, 6 have abnormal
bladder function.161
First-Trimester Megacystis
Early-onset megacystis frequently regresses spontaneously.160
The presence of other structural abnormalities increases the risk
of aneuploidy up to 40% in some series. Sebires series defined
a distended bladder one having a diameter greater than 8 mm
49
50
part
I: Basics
Ut
B
Ut
U
Ut
Ut
A
B
Cloacal Anomalies
Cloacal dysgenesis sequence is a rare cause of fetal obstructive uropathy; it usually, but not always, occurs in females.164
In the female fetus, cloacal plate problems are associated with
complex abnormalities of the genital tract and bowel abnormalities, with significant morbidity resulting. The sequence
has complex pathology and characteristic features, including
chapter
Right
51
Left
Figure 4-14 A fetus with posterior urethral valves, demonstrating the variety of cystic change seen at 29 weeks gestation. Both kidneys are
demonstrated in the sagittal plane. Both kidneys are echogenic; the right is developing small cortical cysts, and larger cysts are seen in the left
kidney.
study of 11 males with in utero megacystis, hydronephrosis,
and dilated ureters, who were found to have the megacystismegaureter association after birth, supported these conclusions.167 In all of the latter cases, a large bladder with severe
reflux into dilated, tortuous ureters and dilated pelvicalyceal
systems was found postnatally, leading to the conclusion that
the megacystis-megaureter association can be suspected with
reasonable accuracy if a large, thin-walled bladder is found
together with dilated ureters and bilateral hydronephrosis but
normal renal parenchyma and normal amniotic fluid volume.
Megacystic microcolon intestinal hyperperistalsis syndrome is
considered to be caused by degenerative disease of smooth
muscle, which causes small-intestinal obstruction, microcolon, and a large bladder. The syndrome is lethal, but, in spite
of a distended bladder, it is associated with normal amniotic
fluid volume and nondysplastic kidneys.
Another nonobstructive cause of bladder distention is
prune-belly syndrome. This is a rare condition associated
with congenital deficiency of the abdominal musculature and
associated urinary tract abnormalities. The sonographic appearances of the fetal bladder help differentiate this syndrome from
obstructive uropathies. The bladder appears thick-walled and
tense in cases of obstruction, whereas in prune-belly syndrome
it often appears floppy. However, it may be very difficult to
differentiate sonographically between urethral atresia and
PUV. Increased renal echogenicity, loss of corticomedullary
differentiation, and the presence of subcortical cysts indicate
renal dysplasia and are poor prognostic signs.
Evaluation
of
Renal Function
52
part
I: Basics
Vesico-amniotic Shunting
Consideration of bladder shunting relates to the likelihood of
such a procedures preventing the renal dysfunction and pulmonary hypoplasia that would result if persistent significant
outflow obstruction persists. However, like all invasive procedures, it is not without risk, and is not guaranteed to confer an
advantage to the long-term outcome. If renal dysplasia persists
despite relief of the anatomic obstruction, then oligohydramnios will not be corrected and pulmonary hypoplasia will still
develop. The timing of intervention is important, because
long-term renal outcome will not be influenced by shunting if
renal damage has already occurred in early pregnancy. Before
discussion of shunting, renal function should be evaluated, as
described earlier.
Vesico-amniotic shunting is performed with ultrasound
guidance using a pigtail shunt. It is important that the shunt
be placed as low as possible in the bladder to prevent displacement after bladder decompression; the optimal site for trocar
entry is midway between the pubic ramus and the insertion of
the umbilical cord. If oligohydramnios is present, an amnioinfusion may be required to provide a potential space into
which to deposit the intra-amniotic end of the catheter. It may
be necessary to wait for the fetus to move into an appropriate
plane for an anterior approach to the abdomen, or the operator
may have to manipulate the fetal trunk into position.
In 1997, Coplen reviewed the five largest series of prenatal
intervention, comprising 169 cases of successful percutaneous shunt placement over 14 years. The overall perinatal
survival rate after intervention was only 47%, and shuntrelated complications occurred in 45% of the cases. Forty
percent of survivors had end-stage renal disease.176 Not
all pregnancies exhibited pretherapy oligohydramnios, but
among those that did, 56% of babies died despite intervention. Failure to restore amniotic fluid volume was associated
with 100% mortality. Limiting intervention to fetuses with
good prognosis appeared to improve survival and resulted
in a lower incidence of renal failure among survivors. Within
Coplens review, Crombleholme177 and Freedman178 and their
colleagues evaluated outcomes based on prognosis, as determined by fetal urine biochemistry. Fetuses with oligohydramnios were further separated into those with dysplasia and
those with normal neonatal renal function. Among 45fetuses
Fetal Cystoscopy
Fetal cystoscopy has been introduced as an alternative to
shunting as a therapeutic and diagnostic procedure. In utero
percutaneous cystoscopy was first described by Quintero and
colleagues184 in the management of fetal obstructive uropathy
under maternal general anesthesia185 and more recently was
reported by others using local anesthesia.186 The indications
chapter
Outcome
of
Quintero and colleagues185 treated nine fetuses with lower urinary tract obstruction by fetal cystoscopy and laser ablation
of the valves. Four of the nine fetuses did not have a patent
urethra at birth (one had urethral atresia). Of the remaining
five with a patent urethra, two were viable at birth, one had
progressive renal damage and was aborted, and two were lost
to chorioamnionitis. Of the two fetuses with patent urethras
that survived the neonatal period, one had renal impairment
and died at 4 months of age from bronchopneumonia, and the
second died at 3 months from necrotizing enterocolitis. There
were thus no survivors in this study, although this may have
reflected the fact that entry was restricted to fetuses with poor
prognostic factors.
Welsh and coworkers188 undertook fetal cystoscopy on 11
fetuses between 16 and 24 weeks gestation. There were no
immediate or long-term iatrogenic complications from the
procedure (such as membrane rupture, abruption, or preterm
labor before 34 weeks). Five of the 11 cases were complicated
by postprocedural urinary ascites, which was managed conservatively. Cystoscopy was performed for diagnosis in only
seven cases. Among the remainder, therapeutic procedures
were attempted in four cases with PUV (one with hydroablation and three with guidewire technique). The valves were
completely destroyed in one fetus, a result that was confirmed
radiologically as well as cystoscopically in the postnatal
period. Two were judged to have partial success (increase in
amniotic fluid volume and decrease in bilateral hydroureteronephrosis during pregnancy) but required treatment in
the postnatal period. Three of the four had acceptable renal
function in infancy.
The main challenge to fetal cystoscopy is technical difficulty,
either in the ability to enter the posterior urethra with the
cystoscope or in visualization of the valves. Further research
and development are needed before this therapy can be more
widely adopted.
Decision Making
in the
Assessment
of the
Enlarged Bladder
53
Bladder
Absent Bladder
Persistent absence of the bladder should be considered as
abnormal from 15 weeks gestation. If the bladder is difficult to
identify, color Doppler examination of the paravesical vessels
should be undertaken, together with a detailed examination of
the rest of the fetal anatomy. The causes of an absent bladder
on fetal ultrasound can be divided into lack of fetal urine production or inability of the bladder to store urine.189
54
part
I: Basics
Tract Abnormality
the fetus, with poor renal umbilical artery flow and an increase
in flow to the brain, as evidenced by an increase in middle
cerebral artery flow. In this situation, uterine artery Doppler
values are usually abnormal. The finding of oligohydramnios
and a poorly filled bladder with abnormal fetal and uterine
artery Doppler results makes intrauterine growth retardation
(IUGR) secondary to placental insufficiency the most likely etiology. Abnormal fetal biometry may also be present. Careful
examination of the fetus should reveal the presence of normal
kidneys; often, a small amount of fluid may be seen within the
bladder.
Renal causes for lack of fetal urine production relate to
bilateral pathologies: bilateral renal agenesis, in which there
is no evidence of kidneys in the renal beds; bilateral MCDK,
in which the dysplastic kidneys are nonfunctioning, have an
atretic ureter, and consequently do not produce urine; and
bilateral renal dysplasia. If both kidneys are dysplastic and
have no function, absence of urine production will result in
failure to visualize a fetal bladder in association with anhydramnios. As discussed earlier, absence of both kidneys or
absence of any renal function will eventually be fatal.
CONCLUSION
Renal tract abnormalities are commonly found on prenatal
ultrasound studies. Isolated abnormalities such as mild RPD
often resolve during pregnancy or early neonatal life, and the
potential benefit of detection in terms of monitoring progression and need for postnatal intervention should be balanced
against the potential anxiety that is often induced in the parents on detection of an apparent abnormality. The identification of a renal tract abnormality should initiate a detailed
examination of the remainder of the renal tract, to assess the
likely effect on overall renal function both during gestation
and after birth. In addition, the remainder of the fetal anatomy should be examined for other structural abnormalities
and markers of aneuploidy. The results of any prior screening tests for Down syndrome should be taken into consideration, and enquiry about family history should be undertaken.
It is not always possible to establish the specific underlying
pathology during the pregnancy. Therefore, it is important in
the event of fetal demise that a detailed postmortem examination be undertaken, together with retention of tissue or fluid
for DNA analysis either then or in the future, so as to reach a
specific diagnosis and thereby accurately inform the parents
regarding risks to future pregnancies and to the wider family.
Consideration should be given to parental and sibling renal
scanning. In many cases, accurate prediction of outcome is not
possible, and the establishment of multidisciplinary prenatal
renal clinicswhere parents can be seen and counseled by a
fetal medicine specialist together with pediatric urologists,
nephrologists, and, if appropriate, geneticistscan provide a
joint approach to care and optimal counseling of parents both
during the pregnancy and after delivery (Table 4-8).
REFERENCES
For complete list of references, log onto www.expertconsult.com
CHAPTER
J. Michael Zerin
ULTRASONOGRAPHY
Ultrasound (US) is the primary modality that is used for
screening children with suspected urinary tract disease, and
it has largely, if not completely, replaced the intravenous urogram (IVU). Dramatic growth in the use of US has in great
measure resulted from the perception of US as a noninvasive, safe, and reliable screening modality requiring neither
intravenous administration of contrast material nor exposure
of the patient to ionizing radiation.1,2 The absence of a need
for shielding against ionizing radiation allows for a degree of
portability that is unattainable with other imaging modalities. Affordability has also played an important role, given
that even the most sophisticated US equipment is relatively
inexpensive. Introduction of highly sophisticated, inexpensive, portable, laptop-based ultrasound units has promoted
further expansion in the use of US. Continuing technologic
innovation in transducer and software design, such as in tissue harmonic imaging, three-dimensional imaging, and the
clinical application of sonographic contrast media, will continue to enhance the flexibility and ease of use of this modality, with associated improvements in image quality and
diagnostic accuracy.
chapter
57
Figure 5-1 Normal gray-scale ultrasound image of the right kidney in a 5-year-old girl with previous urinary tract infections. Longitudinal coro-
nal (A) and transverse (B) images of the right kidney show normal renal contours and parenchymal echogenicity. The prominently hypoechoic
appearance of a medullary pyramid in the lower third of the kidney is a normal finding.
58
part
I: Basics
Figure 5-2 Normal power Doppler study of the right kidney in a 6-year-old girl with urinary tract infection. Longitudinal coronal view of the
right kidney (A) and transverse image through the midpolar region of the right kidney (B) show perfusion diffusely throughout the kidney with
no visible defects.
and infants, compared with older children and adults. The
medullary rays are characteristically triangular or pyramidal
in cross section, although compound pyramids in the renal
poles can be quite large and irregular in contour. Familiarity
with these normal differences in the sonographic appearance
of the neonatal kidney is very important, because the less
wary observer could occasionally mistake very hypoechoic
medullary pyramids for dilated calyces or renal cysts. The
absence of posterior acoustic enhancement and lack of dilatation of the renal pelvis and infundibula differentiate echolucent pyramids from hydronephrosis. Medullary pyramids
are also generally more angular and irregular in shape than
dilated calyces and cysts, which tend to be more smoothly
rounded. Visualization of the echogenic margin of the arcuate
artery at the outer perimeter of the papilla and the absence of
any visible compression of the overlying cortex or distortion
of the renal contour are additional clues to its normality.
Some normal variations in the contour of the neonatal and
infant kidney occasionally cause confusion. Persistent fetal
lobation is manifested by a smoothly undulating renal outline
with superficial clefts between the incompletely fused fetal
renal lobes. Although persistent fetal lobation is most commonly seen in neonates and young infants, this appearance
can persist throughout life in some individuals and can be
mistaken for renal masses or cortical scarring.12 In fetal lobation, the clefts characteristically lie between the medullary
pyramids, rather than overlying them as in reflux nephropathy, and the echo texture of the underlying renal parenchyma
is normal. The junctional parenchymal defect appears as a
triangular, echogenic, cortical indentation along the anterolateral aspect of the junction of the middle and upper thirds of
the kidney.13 The defect extends inferomedially for a variable
distance into the renal sinus and represents the anterior site of
fusion of the superior and inferior renunculi, the two primitive nephrogenic masses that combine to form the kidney.
Differentiation from a cortical scar or peripheral echogenic
tumor is based on the triangular shape of the defect and its
characteristic location. Prominent cortical infolding occurring
at the interfaces between the renal lobes is referred to columns
of Bertin and is most commonly visible on transverse images
through the midsections of the kidneys; it should not be mistaken for an area of parenchymal edema or a renal mass.
Visualization of a small amount of urine separating the walls
of the collecting system in the renal sinus is a frequent sonographic observation in neonates and young infants.1,2,7,8,14,15
Whereas such dilatation of the renal pelvis would generally
be considered to be abnormal in an older child or adult, the
situation is quite different in neonates and young infants. In
the absence of infundibular or calyceal dilatation, isolated
mild distention of the renal pelvis, so-called pelviectasis, is
rarely progressive. This appearance in a neonate or young
infant is probably physiologic in most cases and is related to
the highly compliant nature of the renal collecting system in
this age group.7,8,14-16 If the renal pelvis is extrarenal, the
dilatation can be even more pronounced. Acute or chronic
distention of the urinary bladder can augment such physiologic pelviectasis. Concurrent diuresis can further augment
the dilatation.17,18 Therefore, US examinations that are performed after diuretic renal scintiscansor, in the past, after
IVU with ionic contrast mediamay show greater distention of the renal pelvis than do scans performed before these
procedures. If upper tract dilatation is secondary to bladder
distention, catheterization of the urinary bladder and complete decompression of the lower urinary tractby aspiration
of the bladder urine into a syringe, if necessarycan lead to
rapid improvement in the appearance of the kidneys. If the
ureters and collecting systems are severely distended, the
bladder will again become distended as urine drains into it
from above. In this situation, it may be necessary to repeat the
aspiration of the bladder contents in order to decompress the
entire urinary tract.
There is no single measurement that can be used reliably
as a threshold value to differentiate physiologic renal pelvic
distention from mild obstructive hydronephrosis that will
progress in the future. It is widely accepted, however, that
assessment of the anteroposterior dimension of the renal
pelvis, as visualized on transverse views through the renal
hilum, is much more useful than measurements of renal pelvic size in the coronal or sagittal planes. Frequently, although
the coronal or sagittal dimensions of the renal pelvis appear
chapter
59
BLADDER
Careful examination of the distended urinary bladder is an
essential part of any sonographic study of the urinary tract in
a child of any age (Fig. 5-3).1,2 In neonates and infants, and
in older children who are incontinent, the bladder should be
interrogated first, to avoid the possibility that the child might
empty the bladder while the kidneys are being examined. If
the bladder is empty at this time, it can be re-evaluated after
the kidneys have been imaged, at which point it will usually
be more distended. In children who are potty-trained, the bladder can be routinely evaluated at the end of the examination,
when it will be maximally distended. In some cases, catheterization and infusion of sterile saline or contrast material may
be necessary to provide sufficient distention of the urinary
bladder to allow a satisfactory examination. In the transverse
plane, the normal bladder is rhomboidal in shape, and its distended wall is thin and smooth.34 Longitudinally, the bladder
appears more ovoid, with its apex anteriorly and its base along
the pelvic floor posteriorly.
The bladder wall normally has a smooth contour and
measures up to 3 mm in thickness when the bladder is well
distended.34 The bladder wall often appears somewhat thicker
and may appear mildly irregular if the bladder is not well
distended. Diffuse thickening of the bladder wall frequently
evokes the possibility of bladder outlet or urethral obstruction or neurogenic dysfunction.35 However, it is also seen
in children with recent or recurrent urinary infection and in
those with dysfunctional voiding. In cystitis, the thickening
is caused by inflammatory infiltration and edema of the bladder wall (Fig. 5-4). The bladder may also be more echogenic
than normal, with increased flow to the bladder wall and
perivesical tissues visible on Doppler imaging. Common
causes of focal thickening of the bladder wall include focal
bacterial or viral cystitis, collapsed ureterocele, and postoperative thickening. Nodular thickening at the site of ureteral
60
part
I: Basics
Figure 5-3 Normal gray-scale ultrasound image of the urinary bladder in a 5-year-old girl with previous bilateral vesicoureteral reflux. Midline
longitudinal (A) and transverse (B) views of the distended urinary bladder demonstrate the normal rhomboidal shape of the bladder, which is
filled with anechoic urine and has a smooth and uniformly thin wall.
Figure 5-4 A 4-year-old girl with fever, pelvic discomfort, and gross
hematuria secondary to Escherichia coli hemorrhagic cystitis. Transverse (A) and longitudinal (B) sonographic images of the pelvis show
that the bladder wall is markedly thickened diffusely and irregular,
with mildly increased echogenicity, consistent with inflammatory
infiltration and edema. C, Power Doppler ultrasound image shows
that the posterior bladder wall and adjacent perivesical tissues are
also hyperemic.
chapter
61
A
A
LEFT KIDNEY CURVE
CTS/sec
1071
803
536
Lt. kidney
Lt. lasix
268
0
630
1260
Time in seconds
1890
2520
B
Figure 5-5 Sonographic evaluation of the bladder after right Deflux
62
part
I: Basics
Figure 5-7 Classic multicystic dysplastic kidney with progressive involution (longitudinal sonographic images). A, View of the left kidney on
the second day of life. The kidney measures 7.6 cm and is entirely replaced by noncommunicating cysts (C) of various sizes. The cysts are separated by thin strands of dysplastic, echogenic parenchyma. No normal parenchyma is visible. B, The left kidney of the same patient at 6 months
of age. The multicystic kidney measures 5.6 cm in length. Three small cysts (C) and some echogenic dysplastic parenchyma are still visible.
C, The left kidney at 21 months of age. The kidney measures 2.4 cm in length. No cysts are visible. D, The left renal fossa at 9 years of age. The left
kidney is no longer identifiable.
hips, and soft tissues should be carefully inspected for any evidence of an underlying neuromuscular disorder or anomaly
that might be associated with neurogenic bladder dysfunction.
Similarly, the bowel gas pattern may yield important information in regard to constipation, whether functional or neuropathic. Displacement of the bowel loops can be an important
clue to the presence of a renal or retroperitoneal mass. Vertebral
segmentation anomalies (Fig. 5-12) are frequently associated with renal anomalies, particularly renal agenesis, renal
ectopia, and multicystic dysplastic kidney, and anomalies of
the sacrum are more specifically associated with anorectal
malformations. Widening of the pubic symphysis is almost
always present in children with the epispadias-exstrophy
complex and cloacal anomalies. The radiographic conspicuity
of renal, ureteral, and bladder calculi (Fig. 5-13) varies greatly
depending on the composition of the stones, their size and
location, and interference of overlying structures with their
visualization.
chapter
nate (estimated gestational age, 28 weeks) with very poor renal function. Longitudinal sonographic view of the right kidney on the first
day of life. The parenchyma of the kidney is diffusely echogenic with
no corticomedullary differentiation. The collecting system is dilated
and somewhat dysmorphic in shape. Ascites (A) is visible anterior to
the kidney in Morison pouch.
Intravenous Urography
IVU has been all but replaced in pediatric imaging by other
modalities, including US, renal scintigraphy, computed tomography (CT), and magnetic resonance urography, with few indications for the examination remaining. In fact, because of the
widespread availability of CT, few pediatric radiology departments in the United States have even retained the ability to
perform linear tomography. As a result, even if IVU is to be
done, its performance is usually limited to a series of plain
radiographs alone. In our own department, we perform at
most two to three IVUs a year, in each case at the insistence of
the referring physician and despite our own recommendation
that another modality be performed in its place. Nonetheless,
images simulating those obtained with the conventional IVU
are at times obtained after administration of intravenous iodinated contrast media for other examinations (e.g., computed
tomography, abdominal or cardiac angiography). Although the
diagnostic value of such images may be more limited than with
formal IVU, the principles of interpretation are the same.42
The minimum approach to the pediatric IVU includes a
scout view of the abdomen and pelvis before contrast material
is administered and two anteroposterior radiographs of the
abdomen and pelvis at 5 and 10 minutes. Additional oblique or
lateral views and delayed images can be obtained as required.
Serious allergic and other adverse reactions to intravenous
contrast media are relatively rare in children, particularly when
non-ionic, low-osmolarity urographic contrast media are used.43
Appropriate preparation of the patient for the examination by
fasting is important, both to improve visualization of contrast
material in the kidneys and ureters and to reduce the frequency
and severity of contrast-induced nausea and vomiting.
Voiding Cystourethrography
The fluoroscopic voiding cystourethrogram (VCUG) is the
most reliable examination for diagnosing and characterizing
vesicoureteral reflux in children.44,45 It also provides excellent
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Figure 5-9 Prominent neonatal adrenal glands mimic hypoplastic kidneys in an anuric newborn boy with bilateral renal agenesis and Potters
syndrome. A, Longitudinal sonographic view of the right renal fossa on
the first day of life. The right adrenal gland (arrow) is elongated and overlies the right psoas muscle, partially filling the renal fossa. The relatively
hypoechoic adrenal cortex surrounds the centrally located, more hyperechoic adrenal medulla. No right kidney is visible. B, Longitudinal sonographic view of the left renal fossa on the first day of life. The left adrenal
gland (arrow) is elongated and overlies the left psoas muscle, partially filling the renal fossa. The relatively hypoechoic adrenal cortex surrounds the
centrally located, more hyperechoic adrenal medulla. No left kidney is visible. C, Technetium 99m MAG3 renal scan, showing a posterior view of the
abdomen obtained 20 to 21 minutes after injection. Background activity is
markedly increased. There is no visible functioning renal parenchyma and
no activity in the urinary bladder.
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Figure 5-10 Right duplex kidney and right upper pole ure-
Figure 5-11 Use of power Doppler ultrasound in the identification of a small Wilms tumor in a 2-year-old girl with sporadic aniridia. A, Longitudinal posterior gray-scale ultrasound image of the left kidney with the patient prone shows a subtle echogenic lesion (arrow) in the posterior
cortex of the interpolar region of the kidney which does not appear to alter the renal contour. B, Longitudinal posterior power Doppler image of
the left kidney confirms the presence of the lesion in the posterior interpolar region of the kidney and more clearly delineates its margins and size
based on the distortion of the parenchymal flow.
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B
Figure 5-12 Association of renal ectopia with vertebral anomalies in
a 6-year-old girl with VACTERL association and congenital scoliosis.
A, Intravenous urogram, frontal radiograph of the abdomen shows
multiple lumbosacral vertebral anomalies with congenital scoliosis.
The left, nondilated collecting system of the left kidney (arrow) is visible in the upper pelvis. The right kidney appears normal. Note the
abnormally caudal and medial position of the splenic flexure (arrowheads), related to the ectopic position of the left kidney. B, Linear tomogram of the pelvis shows the left pelvic kidney to better advantage.
chapter
Postcystography Symptoms
Young children are frequently very concerned about the presence of the catheter and any discomfort that is associated with
its placement or removal. Symptoms resulting from the catheterization are common in children after cystography.52 Dysuria is most frequent, although enuresis, hematuria, urinary
retention, and toileting anxiety also occur. These symptoms
are usually transient, lasting in most patients for less than
24 hours. In exceptional cases, they may remain for up to
10 days or longer. Serious urethral or vesical trauma is quite
rare during catheterization for cystography, although urethral
stricture and perforation of the urethra or bladder can occur.
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B
Figure 5-14 Normal appearance of the urinary bladder on voiding
cystourethrogram in a 5-year-old girl with bilateral low-grade vesicoureteral reflux. Frontal (A) and lateral (B) views of the filled urinary
bladder. The bladder shape and position are normal, and the bladder
wall is smooth.
compartment expands anteriorly and upward into the abdomen.39,68,69 A small portion of the anterior compartment also
projects inferiorly, just anterior to the bladder neck, and is best
appreciated on VCUG in the lateral projection. Occasionally,
two anterolateral recesses can also be identified, which are
often referred to as bladder ears. When the bladder neck
opens during voiding, the posterior compartment becomes
funnel-shaped, and the anterior compartment collapses uniformly in all directions. The bladder wall normally has a
smooth contour on cystography when distended, although it
can be slightly irregular, particularly posteroinferiorly, when
not distended.
In neurogenic dysfunction, the bladder often appears
elongated vertically and can be thickened and trabeculated
with numerous diverticula (Fig. 5-15).39,69,70 Discoordination
between the bladder-trigone and bladder neckexternal
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12-year-old girl with myelomeningocele. Frontal image of the abdomen and pelvis with the bladder distended shows that the bladder
has a vertically elongated configuration with a markedly irregular and
thickened wall and numerous diverticula. The sacrum is markedly
dysraphic, and the distal end of a ventriculoperitoneal shunt is visible
in the pelvis on the right side.
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Figure 5-17 Very large single-system ureterocele. Voiding cystourethrogram in a newborn boy with severe right hydroureteronephrosis. Frontal
(A) and lateral (B) views of the partially filled urinary bladder show a very large, smoothly rounded filling defect posteriorly along the floor of
the bladder, typical of a large ureterocele.
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Figure 5-18 Everting left upper-pole ureterocele mimicking a left paraureteral diverticulum on voiding cystourethrography in a newborn boy
with antenatally detected left duplex kidney and upper-pole hydronephrosis. The series of five right posterior oblique images of the left side of the
bladder during bladder filling shows a left ureterocele that initially appears as a filling defect (top row). As the bladder is distended, the ureterocele
is initially effaced and then everts, projecting outside of the bladder and mimicking a paraureteral diverticulum (bottom row).
of the verumontanum, near the junction of the prostatic and
membranous portions of the urethra. The penile and bulbous
segments of the anterior urethra are separated by the suspensory ligament (Fig. 5-25).
Posterior urethral valves are the most common cause
of urethral obstruction in the male infant and child (Fig.
5-26).39,83 The degree of obstruction is variable but is frequen
tly severe, with the urinary stream emerging from between
the valves along the ventral surface of the base of the verumontanum. During attempts at voiding, the posterior urethra
dilates and the valves balloon outwardly. Reflux into prostatic
or ejaculatory ducts, or both, is also common. The bladder
neck is usually hypertrophied and the bladder wall thickened
and trabeculated, with numerous bladder diverticula. The
diagnosis of posterior urethral valves by cystography requires
visualization of the urethra in a steep oblique projection during attempted micturition after the catheter has been removed.
However, if bladder wall contractility is severely impaired,
the child may be unable to generate sufficient forward force
during voiding to distend the posterior urethra and visualize
the valves. Aberrant micturition secondary to associated
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Figure 5-20 Bilateral complete duplex kidneys with bilateral lowerpole vesicoureteral reflux. Voiding cystourethrogram in a 1-monthold girl with mild right antenatal hydronephrosis. Note that the most
superior visible calyx in each kidney is very far from the ipsilateral
pedicle and the renal axes (hatched lines) are reversed bilaterally, suggesting that only the lower pole is opacified on each side.
Figure 5-19 Bilateral grade III vesicoureteral reflux. Voiding cystourethrogram in a 10-month-old girl with multiple urinary tract infections. The renal pelves and calyces are distended but not distorted,
and the renal axes are normal.
The past several decades have seen rapid growth in the application of both CT and magnetic resonance imaging (MRI) in
the evaluation of a widening spectrum of pediatric genitourinary disorders. CT has the advantages of speed, simplicity,
and widespread availability. However, CT is also the primary
source of medical radiation exposure in children and the
largest source other than background.87 Although CT accounts
for less than 5% of all imaging studies, more than 60% of all
medical radiation exposure results from CT. Evidence for
an increased risk of cancer and other disease secondary to
exposure to low-dose radiation is derived from long-term
follow-up of atomic bomb survivors and from data on medical and occupational exposures. The estimated lifetime risk of
radiation-induced fatal cancer is 1:1000 from a single pediatric CT examination, and the risk is cumulative when multiple
examinations are performed. Less is known about the potential health and economic consequences of nonfatal cancer and
other disorders resulting from low-level radiation. Evidence
for greater vulnerability of organs and tissues in growing
children to radiation-induced cancer should raise particular
concern in pediatrics. Because most radiation-induced cancers do not manifest until decades after exposure, and because
children generally have a longer residual life expectancy than
adults, they also have a longer period of time in which to
manifest radiation-related disease. The first step in limiting
medical radiation exposure is to consider whether CT is the
most appropriate modality. When provided with adequate
clinical information, the pediatric radiologist might in some
cases suggest an alternative modality that does not involve
ionizing radiation, such as US or MRI. However, even when
CT is appropriate, access to clinical information can help the
pediatric radiologist customize the study so as to best address
the important clinical issues while at the same time minimizing the radiation dose to the patient.
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Figure 5-21 Bilateral vesicoureteral reflux. Radionuclide cystogram in a 2-year-old girl with multiple previous urinary tract infections. The series
of 18 30-second posterior images obtained during bladder filling and emptying show persistent reflux to the left collecting system (arrow) and
subtle, transient reflux into the distal right ureter that is visible only on a single image (arrowhead).
Figure 5-22 Spinning top appearance of the female urethra. Voiding cystourethrogram (VCUG) in a 10-year-old girl with recurrent urinary tract infections. Dramatic distention of the female urethra at peak
flow during voiding is a common, normal finding on VCUG and does
not necessarily indicate dyssynergy.
old girl. Although vaginal filling during cystography has been attributed to voiding in the supine position, it can also occur in some girls
when they are seated or even standing upright, and it can be a cause
of postmicturition incontinence.
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External sphincter
Exquisite soft tissue contrast and direct multiplanar capabilities are important advantages of MRI. Moreover, MRI
does not require intravenous administration of iodinated
contrast material, nor is the patient exposed to ionizing radiation. The excellent safety profile of gadolinium-based MRI
contrast agents, compared with the iodinated media used for
conventional urography and CT, are other significant advantages of MRI. Although the administration of gadoliniumbased contrast agents is contraindicated in patients with
renal insufficiency because of the risk of nephrogenic systemic fibrosis, non-enhanced MRI can still be performed in
these patients.88 MRU provides higher temporal, spatial, and
c ontrast resolution than traditional IVU, and it combines anatomic and functional evaluations of the urinary tract into a
single test that does not use ionizing radiation.
The need for procedural sedation, and occasionally general anesthesia, to eliminate motion-related degradation in
image quality and associated motion-related artifacts remains
an important limitation of MRI, particularly in infants and
younger children and in the developmentally challenged.
Although procedural sedation and anesthesia services are
routinely provided in pediatric centers and are highly efficacious and safe, the availability of such services outside the
dedicated pediatric medical imaging environment is more
limited. Continuing improvements in MRI technology and
faster imaging protocols that reduce acquisition times should
diminish the necessity, or at least the duration, of sedation in
some children in the future.
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Figure 5-27 Anterior urethral valves with high-pressure left vesicoureteral reflux in a 4-year-old boy. A, Steep right posterior oblique view of the
bladder and urethra during voiding shows that the posterior and proximal anterior urethra are dilated, with an abrupt transition in caliber at the
middle anterior urethra (arrowhead). At the site of the obstruction, the urethra is ballooned distally, with a wind-sock appearance, characteristic of anterior urethral valves. B, Image obtained during voiding shows dilating, high-pressure left vesicoureteral reflux with calyceal blunting and distortion.
old boy with dysuria and microhematuria. Steep right posterior oblique
view of the urethra during voiding shows opacification of a narrow
tubular structure extending proximally from the ventral surface of the
middle anterior urethra toward the urogenital diaphragm (arrowheads).
medulla and cortex (Fig. 5-29).89-91 The renal hilum and pelvis
are readily identified, but nondilated calyces and infundibula
usually are not visible on precontrast images, except occasionally as faint, irregular areas of fluid attenuation within
the parenchyma. In older children and adults, the main renal
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A
Figure 5-29 Normal noncontrast axial computed tomographic scan
through the kidneys at the level of the left renal vein in a young child.
The renal hilum and pelvis are readily identified. However, the renal
parenchyma is very homogeneous in attenuation, with no differentiation between the renal medulla and cortex.
B
Figure 5-31 Normal T1-weighted (fat-suppressed) noncontrast-en-
hanced axial (A) and coronal (B) magnetic resonance images of the
kidneys in a young child show some corticomedullary differentiation,
with the cortex having slightly greater signal intensity than the medullary pyramids.
through the kidneys at the level of the left renal vein in a young child
during the early excretory phase. The renal cortex is still enhanced,
although less so than the medullary pyramids, and a small amount
of contrast material is beginning to appear in the collecting systems.
Note that the aorta and its branches and the inferior vena cava and left
renal vein are also still somewhat opacified.
infants and young children, who have less hilar fat. The renal
collecting system and ureter have low signal intensity on spinecho sequences because of the long T1 relaxation time of urine.
The renal artery and vein also usually have very low signal
intensity, related to rapid flow of blood into and out of the kidney, although an intraluminal signal normally can be identified when flow within the renal vessel is slower. This artifact
can also occur secondary to flow-related enhancement when
images are obtained of the vessel in cross section.
On T2-weighted sequences, the renal cortex and medulla
both have increased signal intensity (Fig. 5-32).91,92 However,
corticomedullary differentiation is less well visualized,
because the cortex is only slightly higher in signal intensity
than the medulla. The perirenal fat also appears bright on
T2-weighted sequences and Gerotas fascia appears as a lowintensity line separating the perirenal and pararenal spaces.
A low-signal-intensity line is occasionally visible along one
side of the kidney, with a symmetric high-signal-intensity
line along the opposite side.93 This represents a chemical shift
misregistration artifact occurring at the interface between the
kidney and the adjacent perirenal fat and should not be attributed to a rim of calcification.
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Figure 5-32 Normal T2-weighted (fat-suppressed) noncontrast-enhanced axial (A) and coronal (B) magnetic resonance images of the kidneys
in a young child show somewhat greater signal intensity of the renal parenchyma than on the T1-weighted images, but with little, if any, corticomedullary differentiation.
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Figure 5-35 Left cross-fused renal ectopia. The left kidney overlies
the spine, near the midline, in the lower abdomen. The left collecting
system is directed toward the right side across the midline, and its
lower pole is fused to the inferior hilar lip of the right kidney.
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Figure 5-36 Complete right duplex kidney with an extravesical ectopic right upper-pole ureter in a 7-year-old girl with persistent incontinence.
A, Non-enhanced axial computed tomographic (CT) image through the upper poles of the kidneys. There is a distended, slitlike, right upper-pole
calyx (arrow). There is minimal surrounding upper-pole parenchyma. B, Contrast-enhanced axial CT image through the upper poles of the kidney.
There is now a contrast agenturine level in the right upper pole calyx, with the contrast material layering dependently (arrow). C, Contrastenhanced axial CT image through the right renal hilum. The lower-pole collecting system and proximal lower-pole ureter are densely opacified. The right upper-pole ureter (arrow), containing nonopacified urine, lies anterior and medial to the lower-pole ureter. D, Contrast-enhanced
delayed axial CT image through the pelvis, obtained 20 minutes after contrast agent administration. The distal upper-pole ureter (arrow) is now
becoming faintly opacified and lies posterior and medial to the lower-pole ureter, which is densely opacified.
kidneys. On the other hand, the site of fusion in horseshoe kidney or crossed-fused ectopia is often better visualized on axial
images (see Fig. 5-35).
In girls, unilateral renal agenesis can be associated with
uterovaginal anomalies, such as agenesis, duplication, and
atresia.105 In boys, unilateral agenesis can be associated with
an ipsilateral seminal vesicle cyst.106 Rarely, the ipsilateral vas
deferens and testis are also absent. CT or MRI occasionally
reveals a tiny, poorly functioning or nonfunctioning kidney
in a child who appears on US, IVU, or renal scintigraphy to
have unilateral renal agenesis. In such cases, the small kidney
most likely represents the remnant of an involuted multicystic
dysplastic kidney, and a single ectopic ureter is frequently
present.107 In the absence of associated lower genitourinary
anomalies, definitive historical information, or previous imaging studies, however, it is not possible to differentiate this from
other causes of severe renal atrophy, such as renal infarction or
reflux nephropathy, on the basis of imaging alone.
The history of incontinence in a girl that is characterized
by persistent and incessant dampness is suggestive of an
extravesical, ectopic ureter that inserts into the urethra or
vagina or onto the perineum. Although the ectopic ureter
usually drains the upper pole of a completely duplicated
collecting system,108 incontinence can also occur with a nonduplicated ureter that drains through an ectopic orifice.109
Boys who have this anomaly are not incontinent, because the
ectopic ureter always inserts proximal to the urethral sphincter.110 Because the upper pole that is drained by an ectopic
ureter is not always dilated, it may not be visible on US, and
the findings can similarly be very subtle on IVU, particularly
if the offending upper pole does not function well enough to
be directly visualized.111 If the ectopic ureter drains a nonduplicated collecting system, the affected kidney is often very
small and dysplastic, with very poor function. CT with thin
sections through the kidneys obtained 10 to 15 minutes after
administration of contrast material (see Fig. 5-36), coronal
T1-weighted MRI, and MRU are the most sensitive modalities
for diagnosing this disorder and should be performed in any
girl who presents with a history of incontinence suggestive of
an occult ectopic ureter.108,109,112
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Figure 5-37 Magnetic resonance urogram (MRU) in a 6-year-old boy with sickle cell disease and a complete right duplex kidney with right
upper-pole hydroureteronephrosis and ureterocele. A, Coronal T1-weighted contrast-enhanced MRU clearly illustrates the duplicated right collecting system and the obstructed upper-pole hydroureter ending in a ureterocele. The signal changes in the lumbar spine are related to the
patients hemoglobinopathy. B, Coronal thick-slab re-projection from noncontrast-enhanced T2-weighted MRU very elegantly displays the
anatomy of the duplicated right kidney and the two intertwined right ureters with the upper-pole ureter ending in a ureterocele.
Figure 5-38 Bilateral acute multifocal pyelonephritis in a 6-monthold girl with fever and bacteriuria. Contrast-enhanced axial CT image through the upper poles of the kidneys. Multiple segmental,
low-attenuation zones of reduced perfusion and enhancement are
visible bilaterally. Some of the affected areas have a faintly striated
appearance.
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B
Figure 5-40 Severe right pyelonephritis with perinephric and multiple intraparenchymal abscesses in a 3-year-old boy with fever and
gross hematuria. A, Axial postcontrast, T1-weighted (fat-suppressed)
magnetic resonance image (MRI) through the upper pole of the right
kidney shows irregular shape and attenuation of the upper pole, with
a multiple, irregular, intraparenchymal abscess with enhancing walls
anteriorly and a larger perinephric abscess surrounding the posterior
aspect of the upper pole of the right kidney, which also has an enhancing wall. B, Coronal postcontrast fast-spin-echo inversion recovery
MRI of the kidneys shows extensive abnormal signal throughout the
right kidney, with multiple very-high-signal-intensity, focal, fluidfilled cavities in the lower pole and a large perinephric collection surrounding the upper pole. Bright signal superior to the right kidney
most likely represents adrenal hemorrhage.
Diffusion-weighted MRI provides information on velocity
and direction of movement of water molecules in tissue under
the influence of a diffusion gradient. Differences in the relative mobility or viscosity of water molecules in tissues create
the contrast in diffusion-weighted imaging.122 Until recently,
application of diffusion-weighted imaging techniques outside the central nervous system has been severely limited by
respiratory and cardiac motion. Recent development of ultrafast, single-shot echo planar imaging techniques now permit
its application elsewhere, including in the urinary tract.
Marked hyperintensity on diffusion-weighted sequences in
pyelonephritis and renal abscess is believed to result primarily from cytotoxic edema and intratubular inspissation of
inflammatory cells.123,124 Because pus is a thick, high-viscosity
fluid consisting of water, inflammatory cells, necrotic tissue,
and proteinaceous exudates, water proton mobility is very
restricted, both in renal abscess and in a pyonephrotic
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Figure 5-41 Computed tomographic (CT) confirmation of a nonshadowing left lower-pole calculus in a 7-year-old boy with oxalosis. A, Ultrasonographic longitudinal coronal view of the left kidney. There is a 5-mm nonshadowing echogenic focus in the lower pole (arrow). B, Non-enhanced
axial CT image through the lower poles of the kidneys. There is a 5-mm brightly echogenic calculus in the left lower pole (arrow).
Nephrolithiasis
Noncontrast-enhanced CT has almost completely replaced
IVU for the investigation of suspected urolithiasis.125-127 Noncontrast CT can be performed rapidly and is relatively easy to
interpret and highly accurate, with excellent interobserver and
intra-observer agreement in interpretation.128 Neither oral nor
intravenous contrast material is given. In fact, the presence of
either type of agent interferes with proper interpretation. Contiguous 4- to 5-mm thick axial images are obtained from the top
of the kidneys to the symphysis pubis during a single breathhold. In very tall individuals, a second acquisition may be
necessary through the patients pelvis. The diagnosis of a ureteral calculus is based principally on direct identification of the
offending calculus within the ureter. Associated findings, such
as edema of ureteral wall (the tissue rim sign) and of the fat
surrounding the ureter at the level of the impacted stone, suggest the presence of a localized inflammatory reaction to the calculus.129-131 Similarly, edema of the ureterovesical junction can
be seen with calculi that are impacted within the submucosal
tunnel. Hydronephrosis and ureteral dilatation proximal to the
stone are highly predictive of an obstructing calculus, particularly when they are associated with other findings, such as perinephric stranding. Transient persistence of any or all of these
findings after passage of a previously impacted stone occasionally provides an indirect clue to the correct diagnosis.
Abdominal radiography and US are generally preferred
for the diagnosis of renal calculi. However, noncontrastenhanced CT can be very helpful in patients whose kidneys
are difficult to examine satisfactorily with US. For example, in
older patients with myelomeningocele or spinal cord injuries,
sonographic visualization of the kidneys can be hampered
by severe scoliosis or interfering bowel gas. Multiple small
calculi in ectopic kidneys, horseshoe kidneys, or severely
Wilms Tumor
US is usually the first imaging study performed in an infant
or young child who presents with a palpable abdominal mass;
it is, therefore, the modality by which the diagnosis of Wilms
tumor is initially made in most cases. On US, Wilms tumor
appears as a predominantly solid, hyperechoic, intrarenal
mass. The remaining normal renal parenchyma is often visible
splayed around the periphery of the mass. The mass is often
large and can contain cystic necrosis and hemorrhage.
On CT, Wilms tumor appears as a low-attenuation renal
mass on non-enhanced scans.132 Calcification is uncommon.
Postcontrast scans show a more inhomogeneous appearance
of the mass, with variable enhancement of the solid components and lack of enhancement in areas of necrosis and
cystic change (Fig. 5-42). On MRI, the signal intensity in the
mass is typically inhomogeneous, with predominantly low
signal intensity on T1-weighted sequences and bright signal
on T2-weighted sequences. Solid areas enhance after administration of gadolinium.133,134 CT and MRI generally provide
comparable information regarding local tumor extent and
regional adenopathy, and both are superior to US with regard
to precisely defining tumor extent and staging. However,
direct multiplanar imaging with MRI occasionally provides
more detailed information in cases where direct invasion of
adjacent structures is difficult to confirm or exclude at CT.
Careful evaluation of the contralateral kidney for tumor or
nephroblastomatosis is essential. Because of the propensity
of Wilms tumor to grow into the renal vein and inferior vena
cava, these structures should be carefully evaluated for evidence of tumor thrombus. Identification of the cranial extent
of the thrombus is critical in presurgical planning.135,136
Renal Trauma
CT is the principal modality used for the evaluation of patients
with suspected renal trauma. CT provides both anatomic and
functional information and is superior to US in the evaluation
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Figure 5-42 Left Wilms tumor with extension into the left renal vein and inferior vena cava and contralateral nephroblastomatosis in a
4-year-old girl. A, Contrast-enhanced axial computed tomographic (CT) image through the kidneys at the left of the left renal vein. There is
a large, low-attenuation, solid left renal mass (M). The left renal vein (V) and inferior vena cava are markedly distended by non-enhancing,
low-attenuation tumor thrombus. B, Contrast-enhanced axial CT image through the upper poles of the kidneys. There is a large, low-attenuation,
solid left renal mass (M). The inferior vena cava (V) is distended by non-enhancing, low-attenuation tumor thrombus. In addition, there are
two small, non-enhancing peripheral nodules (black arrows) in the upper pole of the right kidney, consistent with perilobar nephrogenic rests.
C, Contrast-enhanced axial CT image through the liver. The intrahepatic inferior vena cava (V) is distended with non-enhancing tumor thrombus.
D, Contrast-enhanced axial CT image through the dome of the liver. The tumor thrombus within the inferior vena cava (V) extends to its junction
with the right atrium.
Subcapsular and perirenal hemorrhage frequently accompanies both superficial and deeper parenchymal lacerations.138,139 Subcapsular collections closely conform to the
renal contour and are separated from Gerotas fascia
by the perirenal fat. Perirenal blood extends to Gerotas
fascia. On precontrast images that are performed soon
after the injury, blood surrounding the kidney appears
somewhat higher in attenuation than the adjacent renal
parenchyma. After administration of contrast material,
this relationship is reversed, with the renal parenchyma
enhancing and the adjacent, non-enhancing clot appearing relatively lower in attenuation. With time, as the clot
matures and liquefies, its attenuation decreases. Urinomas
occur as the result of disruption of the collecting system
and appear as masses of fluid attenuation. If the leakage is still active during the study, the mass will contain
opacified urine and the site of the extravasation from the
collecting system occasionally can be directly documented
(Fig. 5-43).
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Complete loss of flow and function in the kidney is suggestive of an injury to the renal vascular pedicle and is one of the
few absolute indications for emergent surgical intervention.
A rim of enhancement at the periphery of the kidney is frequently present secondary to collateral flow through capsular
vessels.140,141 Severe or complete renal vascular compromise
can result from subendothelial hemorrhage or dissection
within the wall of the renal artery, from direct laceration of
the vessel, or from extrinsic compression of the renal vascular
pedicle by adjacent hematoma in the perirenal space.
References
For complete list of references log onto www.expertconsult.com
Figure 5-43 Right renal fracture and lower-pole infarction with lac-
CHAPTER
endoscopes available today can be used for multiple functions. Cystoscopy, ureteroscopy, and nephroscopy can all be
accomplished with currently available multifunction pediatric
endoscopes.
Cystoscopes
Routine cystoscopic evaluation for diagnosis can be performed
with a 5F (1.65-mm) cystoscope (Fig. 6-2). This permits excellent visualization with minimal trauma to the urethra. Most
5F cystoscopes are one-piece units with a 2.5F (0.83-mm) or
3F (0.99-mm) working port. This limits their therapeutic utility to the insertion of guidewires or removal of stents or small
calculi. The 7F (2.31-mm) or larger cystoscopes provide a
5F working channel that allows many pediatric instruments
to be inserted. Cystoscopes with an offset lens allow a straight
path for the working channel (Fig. 6-3). Flexible cystoureteroscopes are also available for pediatric applications. Most
are 7.5F (2.48 mm) in diameter and provide a 3.6F (1.19-mm)
working channel for instrumentation (Fig. 6-4).
Resectoscopes
Rigid resectoscopes have similar setup to their adult coun
terparts. A variety of loops and cautery ends have been developed. In addition, hooked and straight blades for cold knife
incision are available. Most use the Hopkins rod-lens system,
but fiberoptic systems are also becoming available.
Fetal Endoscopes
Improvements in microendoscopy have allowed diagnosis
and, more recently, therapy in the fetus. The fetal eyes appear to
have natural protection against injury from the high-intensity
light used during in uteroendoscopy.4 The most frequently
used application of fetal endoscopy has been laser coagulation
of aberrant vessels in monochorionic twins with twin-twin
transfusion syndrome.5
This technology has increasingly been applied to the
antenatal management of urologic abnormalities. Fetal endoscopes used to date have a diameter of 1.3 mm. Diagnosis
of urethral obstruction can be made, and the technology has
been extended to management. Ablation of posterior urethral
valves has been performed with either a saline flush technique
or guidewire insertion.6 Antegrade valve ablation has also
been described.7
Working Instruments
Graspers, both flexible and rigid, are available in sizes from
3F to 5F for applications through rigid and flexible scopes.
Rigid graspers work well with the offset lens scopes. 3F
and 5F Bugbee electrodes are also available for fulguration.
Open-ended ureteral stents with a guidewire may also be
modified to permit cauterization. The tip may be bent to
form a coagulating hook. Recently, a 5F cutting electrode has
been developed that has a retractable, angled tip for pediatric
application (Fig. 6-5).
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85
infections, medications, diet, and renal medical disease. Cystoscopy usually is not indicated. Urinalysis and culture and
renal and bladder ultrasound studies should be performed.
Some boys may present with hematuria, typically at the end of
urination or as spots on the underwear. Endoscopic examination in these children is typically negative and is not indicated.
Pathologic examination demonstrates squamous metaplasia.9
Management is expectant with most children. Endoscopy is
reserved for those with significant and protracted bleeding. In
patients with a significant history of travel to endemic areas,
a high degree of suspicion should be maintained for potential parasitic infections10 that can manifest with hematuria
(Fig. 6-6).
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Figure 6-9 Ureteral duplication, with both ureters entering into the
bladder. (Upper-pole ureteral orifice, large arrow; lower-pole ureteral
orifice, small arrow.)
Patil, MD.)
Tumors
Tumors in children are noted rarely. Most often, cystoscopy is
used to identify a lesion that has been noted on radiographic
study. The most commonly noted lower urinary tract tumors
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B
in children are rhabdomyosarcomas of the bladder or prostate
(Fig. 6-13). Cystoscopy may be used to determine the preoperative extent of tumor and to obtain biopsies to confirm diagnosis. The increased utility of bladder preservation regimens24
may leave bladders with residual deformity.25 Cystoscopy
may be needed for follow-up in patients who have undergone
bladder-sparing procedures.
Ambiguous Genitalia
Endoscopy is routinely performed to plan reconstruction in
children with ambiguous genitalia. Endoscopy of the various perineal orifices may help to determine the relationships
among the components of the urogenital tract.26 The location
of the vaginal entry into the urogenital sinus in girls with virilization secondary to congenital adrenal hyperplasia is used
to determine the type of procedure required for reconstruction.27 The vaginal orifice in the urethra in these children may
be noted as a small orifice at the tip of the verumontanum
(Fig. 6-14). This opening can at times be entered with the
smaller cystoscopes and vaginoscopy performed (Fig. 6-15).28
Catheterization of the vagina with a Fogarty balloon catheter
is helpful for identification of the vagina during vaginoplasty
(Fig. 6-16).27
Figure 6-12 Ectopic ureter extending into the urethra cannulated
with guidewire.
Strictures
Strictures in children may be congenital,29 but more commonly
are secondary to instrumentation or trauma (Fig. 6-17).30 Urethral catheterization, fulguration of posterior urethral valves,
and hypospadias repair have all been implicated in the development of pediatric strictures (Fig. 6-18).31 Endoscopic incision
using a cold or hot knife or laser ablation can be performed.
Endoscopic approaches appear to be efficacious for short strictures, but recurrences are frequent, and open repair is necessary in a large percentage of children.32
Vesicoureteral Reflux
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89
Figure 6-16 A Fogarty catheter inserted into the vaginal orifice for
identification during vaginoplasty.
of trauma.
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assessment of bladder volumes prior to bladder neck reconstruction is essential. Additionally, assessment of the urethra
after initial closure to determine adequate patency is critical
to permit bladder emptying and prevent upper tract dilatation
and deterioration.
hyaluronidase (Dx/HA).
Bladder Calculi
Bladder calculi are infrequent in children in developed countries. Most instances of bladder calculi are related to congenital malformation or neurogenic bladder.40 The increased use of
continent pouches made of bowel in children with neurogenic
or other abnormalities with diminished bladder capacity have
made bladder calculi more frequent in this population.41 Transurethral stone fragmentation can be performed in children
with patent urethras. Endoscopy through the continent catheterizable stoma may be performed, but aggressive attempts
chapter
Urethral Polyps
Urethral polyps occur occasionally in infants and children
presenting with hematuria and voiding disorders. These
polyps are usually noted in the posterior urethra of boys45
but rare cases have been noted in girls.46 They may be identified as a filling defect on voiding cystourethrography. They
are universally benign, and transurethral resection is curative.45 They may also be ablated transurethrally with the use
of laser.47
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CONCLUSION
Improvements in instrumentation have permitted significant
advances in endoscopic evaluation of pediatric urologic problems. Increasingly, endoscopic means are being used for management of many pediatric lower urinary tract problems. As
experience increases, these techniques are changing the paradigms for management in pediatric urology. All but the smallest of infants can now be successfully instrumented. Caution
needs to be exercised when instrumenting the pediatric urethra, because aggressive efforts to visualize or treat problems
can lead to potential injury with lifelong consequences.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
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chapter
anatomy and access of the pediatric urinary tract deserve particular attention. For instance, endoscopic renal surgery in
children can be performed either from the anterior, through
a transperitoneal laparoscopic approach, or posteriorly,
through a retroperitoneoscopic approach. Either approach has
its advantages and disadvantages, and advocates as well as
opponents. We recommend a logical, selective use of the two
approaches to suit individual cases according to the position
of the diseased renal unit, the absence or presence of a dilated
refluxing ureter, and the need for ureterocelectomy and lower
urinary tract reconstruction. Likewise, endoscopic bladder and
ureteric surgeries in children can be performed by a transperitoneal or an extravesical technique, or with an pneumovesicoscopic, intravesical approach using carbon dioxide bladder
insufflation. Each surgical approach involves different equipment, operative room setup, and technical considerations.
Pediatric urologists should familiarize themselves with the
various techniques before embarking on more sophisticated
laparoscopic procedures.
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Kidney
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NEPHRECTOMY
Nephrectomy is perhaps the most popular urologic indication for the laparoendoscopic procedure.9 The first reported
case was managed with a transperitoneal approach, but a
large number of series now report successful retroperitoneoscopic nephrectomy.10-13 In children, the indications comprise
exclusively benign diseases such as multicystic or dysplastic
kidneys causing renal hypertension, nonfunctioning kidneys
associated with reflux nephropathy, obstructive uropathy,
xanthogranulomatous pyelonephritis, calculus disease, and
protein-losing nephropathy (pretransplantation nephrectomy).14 The contraindications for laparoscopic nephrectomy are relative and include previous intra-abdominal
or retroperitoneal surgery, renal trauma, severe cardiopulmonary disease, severe coagulopathy, and malignant renal
tumors. Recently, there have been reports on the feasibility of
laparoscopic nephrectomy for unilateral Wilms tumor after
chemotherapy.15
The surgical technique of laparoendoscopic nephrectomy
is similar regardless of the approach used. In transperitoneal
nephrectomy, the colon is first reflected from the kidney by
incision of the lateral line of Toldt. In most cases, the ureter
can be identified and used as a handle to lift the lower pole
of the kidney. This maneuver facilitates access to the hilar
vessels and their dissection. We use a 5-mm clip applicator
for the surgical clips (titanium and Hemolok) without any
problem. Some authors suggest using absorbable ties, bipolar
NEPHROURETERECTOMY
Das and associates16 reported the first laparoscopic nephroureterectomy in a child. Commonly, this procedure has been done
through a transperitoneal route regardless of the childs age,
underlying disease, or kidney size.17 This approach has also
been found useful in dealing with an atrophic ectopic pelvic
kidney with an ectopic ureteral insertion into the vagina.18 We
have used the transperitoneal approach, but in our experience
the lateral retroperitoneal approach has provided better access
for a complete ureterectomy.19 We find the retroperitoneal
approach very useful in children who have been undergoing
peritoneal dialysis and when extensive peritoneal adhesions
are anticipated from prior abdominal surgery. The entire specimen of kidney and the ureter is removed intact, although the
extent to which the ureter is removed usually depends on the
pathology. In the setting of reflux, the entire ureter must come
out. During complete removal of the ureter, care is taken to
pass the ureter under the gonadal vessels and to safeguard the
vas in boys. The ureter is traced to its insertion into the bladder, where it is closed with intracorporeal suturing, for a large
ureter, or by passing a snare ligature for the routine cases.
Kobashi and coworkers20 relied on cystoscopy and fulguration of the intramural ureter and ureteral stump when reflux
nephropathy was present and reported success in four of five
patients.
PARTIAL NEPHROURETERECTOMY
In children, partial nephroureterectomy is usually performed for a nonfunctioning renal segment of a duplex system associated with ectopic ureteroceles, VUR, or obstruction.
A potential advantage with a laparoscopic approach is that
wide mobilization of the whole kidney is not necessary in most
chapter
LAPAROSCOPIC ADRENALECTOMY
Laparoscopic adrenalectomy is not a very commonly performed operation in children. It has been performed in children
for the traditional indications, although it is contraindicated
in patients with malignant adrenal lesions.27,28 The approach
is either transperitoneal or retroperitoneal. Both approaches
have been used successfully and have demonstrated
comparable blood loss and hospital course.29,30 The transperitoneal approach has been used more commonly for the
resection of pheochromocytoma and bilateral adrenal tumors
(congenital adrenal hyperplasia) refractory to medical treatment. A retroperitoneal approach may be useful if the patient
has previously undergone an abdominal operation. In a
recent review of literature, a total 109 cases were reported; the
transperitoneal approach was undoubtly preferred for right
adrenalectomy (95.2% of cases), whereas left adrenalectomy
was performed by retroperitoneoscopy in 30% of reported
cases.31
LAPAROSCOPIC PYELOPLASTY
Open Anderson-Hynes pyeloplasty has been widely accepted as
the surgical treatment of choice for UPJ obstruction in children,
with a success rate of more than 90% in most reports.32-35 Laparoscopic pyeloplasty in children and infants is a technical challenge,
although it is feasible and has been reported with adequate early
results.36-38 Peters and colleagues39 described the first successful
case in a child in 1995. A three-port transperitoneal access technique is popular, and good results have been reported (Fig. 7-3).
On the left side, a transmesenteric approach is useful. A small
95
Figure 7-3 Three-port transperitoneal access for performing transmesenteric right pyeloplasty.
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Figure 7-4 Holding stitch on the pelvis passed through the anterior
abdominal wall.
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97
segment of a small feeding tube into the open end of the proximal ureter greatly facilitates the accurate placement of the first
corner suture. The availability of 3-mm laparoscopic instruments, particularly the needle holder, allows gentler handling
of fine 6-0 sutures, minimizing breakage. Laparoscopic pyeloplasty can be performed in small babies less than 3 months
old. Our mean operating time is approximately 120 minutes.
Postoperatively, most patients are observed for 24 to 48 hours.
Antibiotic prophylaxis is used until the stent is removed. A
renal ultrasound study is obtained 6 weeks after stent removal
to confirm decreasing hydronephrosis, and a diuretic scan is
done at 3 months.
Success of laparoscopic pyeloplasty in adults has been
greater than 95%, which is comparable to results with an open
approach.40 Reports in children have shown quicker return to
normal activities than after an open procedure, and comparable success.41 Pediatric laparoscopic pyeloplasty series are
still few and small. Further results will serve to document the
outcome of this approach.
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Figure 7-9 The 5-mm working ports are inserted along the interspinous skin crease on either side of the lower lateral wall of the distended bladder under vesicoscopic guidance.
Figure 7-10 A 3- to 4-cm long segment of a 4F (1.32-mm) or 6F (1.98mm) catheter is inserted into the ureter as a stent to facilitate subsequent ureteral mobilization and dissection and is secured with a 4-0
monofilament suture.
The ureter is mobilized by first circumscribing the ureteral
orifice, using hook electrocautery (Fig. 7-11). With traction
on the ureteric stent obtained by the use of a blunt grasper,
the fibrovascular tissue surrounding the lower ureter can be
seen and divided, using fine 3-mm endoscopic scissors and
a diathermy hook, while preserving the main ureteric blood
supply (Fig. 7-12). Mobilization of the ureter is continued for
2.5 to 3 cm into the extravesical space. Once adequate ureteral
length is obtained, the muscular defect in the ureteral hiatus
is repaired using 5-0 absorbable sutures, usually with an
extracorporeal knot-tying technique (Fig. 7-13). A submucosal
tunnel is then created, as in an open Cohen procedure. With
the use of a diathermy hook, a small incision is made over the
future site of the new ureteral orifice, usually chosen to be
just above the contralateral ureteral orifice. Dissection of the
submucosal tunnel is then started from the medial aspect of
the ipsilateral ureteral hiatus toward the new ureteral orifice,
using a combination of endoscopic scissor dissection and the
diathermy hook for hemostasis. Once the submucosal tunnel
dissection is completed, a fine grasper is passed, and the
mobilized ureter is gently drawn through the tunnel.
The anastomosis is performed under endoscopic guidance with intracorporeal suturing using interrupted 5-0 or
6-0 poliglecaprone or polydioxanone sutures (Figs. 7-14, 7-15).
A ureteral stent is not routinely used, except for selected
patients undergoing bilateral ureteral reimplantation and
those with megaureters requiring tapering ureteroplasty. The
working ports are removed under endoscopic vision with
evacuation of the pneumovesicum. The bladder-holding
stitches are then tied. Each port site entry wound is then closed
with a subcuticular monocryl suture. The bladder catheter is
kept in place for 1 day, and the patient is discharged home and
advised to refrain from play for a few days.
Our long-term results of this technique are encouraging, and
endoscopic intravesical ureteric mobilization and cross-trigonal
ureteral reimplantation can be safely and effectively performed
with routine pediatric laparoscopic surgical techniques and
instruments under carbon dioxide insufflation of the bladder.
This technique has been effective in achieving a high success
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CRYPTORCHIDISM
Figure 7-12 With traction on the ureteric stent obtained by the use of
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pable testes.
chapter
Results
A series from 10 different centers reported a 97% success rate
with a single-stage laparoscopic orchiopexy without division of the testicular vessels.71 Laparoscopic Fowler-Stephens
orchiopexy, with either a single- or a two-stage technique, has
also had high success rates. Microvascular orchiopexy showed
a high success rate of 80.3% in Docimos review.72 More recent
series of laparoscopically assisted microvascular anastomoses70 have demonstrated impressive success, but not higher
than that of contemporary series of standard abdominal or
staged laparoscopic Fowler-Stephens orchiopexy.
LAPAROSCOPIC VARICOCELECTOMY
Varicoceles are present in approximately 15% of adolescent
boys. Varicocelectomy is commonly performed for delayed testicular growth, cosmesis, or symptoms such as pain. Multiple
methods exist for the treatment of varicoceles, including
percutaneous sclerotherapy and open and laparoscopic surgical ligation of the spermatic vessels. With the recent trend
toward MIS, there have been many reports lauding the safety
and efficacy of laparoscopy for the surgical correction of
varicocele.73,74
Surgical Technique
Varicocelectomy can be performed via the transperitoneal route
with three trocars or via retroperitoneoscopy with only one trocar.75 The advantage of retroperitoneoscopy is that it makes the
lymphatic vessels clearly visible, allowing the surgeon to spare
them and thus reducing the rate of postoperative hydrocele.75,76
For a left-sided varicocele, we use a transperitoneal approach,
with the laparoscope placed through a 5-mm umbilical trocar.
Two more ports are placed, one at the level of umbilicus lateral
to the rectus and the other in the midline just above the bladder. Sometimes there are adhesions of the sigmoid colon to the
peritoneum, covering the varicocele, which must be separated
carefully. On visualization of the internal spermatic vessels, the
peritoneal reflection is incised in a T fashion, and the vessels are dissected out, ligated, and cut between clips or ligatures. Four clips are placed on the vessels, without separately
isolating the internal spermatic artery. After hemostasis of the
abdominal wall is ensured, the trocars are removed, and the
port sites are closed in standard fashion.
Regardless of surgical approach, one of the most frequent
complications of varicocelectomy is the formation of hydrocele.
The original Palomo repair involved a high ligation followed
101
INTERSEX
Laparoscopy has been regularly applied to intersex conditions84 and has also been integrated with operative interventions.85,86 The intersex states for which laparoscopy is more
frequently used are male pseudohermaphrodites, female
pseudohermaphrodites, true hermaphrodites, and those with
gonadal dysgenesis.87 Laparoscopy is helpful in gonadal evaluation, resection, or biopsy and for identifying internal ductal
derivatives.88,89 It is also useful for removing all normal structures that are contrary to the assigned phenotype, as well as
gonads that are dysgenetic, nonfunctional, malignant, or of
increased malignant potential.85,90
Laparoscopy gives an excellent view of the pelvic structures and the genital organs. In most cases, identification of
these structures is easy and their removal is straightforward.
However, the accuracy of identification of the gonads is not
total. In some intersex states, the risk for testicular germ-cell
tumors is increased more than 100 times, justifying prophylactic gonadectomy as soon as is feasible after the diagnosis is
established.91 The risk of gonadal neoplasia is not confined to
patients with a 46,XY karyotype but extends to patients with
gonadal dysgenesis and any mosaic karyotype containing a
Y chromosome or the SRY antigen.92
The male pseudohermaphrodite represents the most frequent indication for therapeutic laparoscopy.87 Historically,
the patient with an underdeveloped phallus has been generally orientated to the female gender, and the testes may
be resected. If the testes are palpable, orchidectomy can be
done through inguinal incisions, but because most of such
patients have impalpable testes, laparoscopic exploration and
gonadectomy is indicated.93,94 If the patient is assigned to or
assumes a male role, laparoscopic gonadectomy is still necessary if the gonads are dysgenetic or tumoral, but if the testes
are normal, orchidopexy is indicated. In cases of a male pseudohermaphrodite with male gender, resection of mllerian
duct derivatives may become necessary.95 In the rare case of a
female pseudohermaphrodite with a male phenotype, laparoscopic gonadectomy with resection of mllerian duct derivatives may be indicated. In the true hermaphrodite with female
phenotype, laparoscopic orchidectomy or resection of testicular tissue from the ovotestis is important. In patients who are
true hemaphrodites with male phenotype, laparoscopic resection of the mllerian duct derivatives, ovary, or ovarian tissue
from ovotestis is indicated, as well as orchidopexy in selected
cases. In patients with gonadal dysgenesis, particularly those
with a Y chromosome, gonadectomy is essential, whereas
resection of mllerian duct derivatives may be indicated in
patients with male phenotype.95
The laparoscopic evaluation is usually preceded by evaluation of the external genitalia with the patient under anesthesia, to plan the extent of evaluation and the eventual
reconstruction in the same procedure. The entire abdomen
and the genital area are cleansed and prepared. If combined
genitoplasty is planned, the patient is placed in the semilithotomy position. The video cart is positioned at the foot of
the patient. The surgical technique includes the classic steps
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LAPAROSCOPIC VAGINOPLASTY
Construction of an artificial vagina has undergone a long evolution. Zangl,96 in 1955, and Pratt,97 in 1961, proposed the use
of sigmoid colon in vaginal reconstruction. Today, most surgeons favor a technique in which a pediculated isolated sigmoid colon segment is used.98-100
The experience with a laparoscopic approach is limited
for vaginal reconstruction.101,102 The procedure is conducted
with the patient under general anesthesia and placed supine
on an operating table with stirrups, such as that designed for
perineal surgery. After insertion of a vesical catheter, laparoscopic ports are placed. A 10-mm trocar is placed below the
umbilicus, and the pneumoperitoneum is created. The second,
12-mm port is inserted on the right side, midway between the
iliac spine and umbilicus. At the corresponding contralateral
site, a 5-mm port is inserted. A 14- to 17-cm long, vascularized sigmoid segment is isolated using a harmonic scalpel
and a 12-mm endoscopic gastrointestinal stapler (Endo GIA)
stapler.
Next, with the patients legs placed in lithotomy position,
the perineal stage of the procedure is begun by the creation of
a U-shaped incision at the deepest depression at the vaginal
opening. Under laparoscopic guidance, a surgical plane is
developed between the urethra, bladder, and rectum, reaching
down to the pelvis to form a canal two fingers wide. Through
the created space, a clamp is introduced with a gauze pad
placed at the tip, and the site for incising the peritoneal fold
in the region of the hypoplastic uterus is selected under visual
control. The incision is performed using a hook cautery to
produce an opening sufficient to allow free passage of the
isolated sigmoid colon segment. Subsequently, the clamp
is used to bring the distal end of the sigmoid through the
canal, down to the level of the incised margins of the vestibule of the vagina. The open proximal end of sigmoid in the
abdominal cavity is closed with intracorporeal suturing or
with the Endo GIA stapler. Gastrointestinal continuity is reestablished with the use of a circular endoscopic stapler. The
external reconstruction is completed, resulting in a normal
appearance of the vulva.
PROSTATIC UTRICLE
The prostatic utricle, an enlarged diverticulum in the posterior urethra of males, was first described in 1874.103 Although
most prostatic utricles are asymptomatic, they may manifest
with symptoms as a result of their size or infection (Fig. 7-17).
Utricles have been associated with recurrent urinary tract
infections, stone formation, disturbed urination, recurrent
epididymitis, infertility, and neoplastic degeneration.104-107
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surgery is widely applicable for patients who require bladder reconstruction or antegrade continence enema stoma,
or both. Most of the patients reported in the literature have
had prior abdominal surgery, including ventriculoperitoneal
shunt placement and bladder exstrophy closure.114,115 The
benefit of laparoscopic mobilization is cosmetic; it results
in more rapid recovery and decreased intra-abdominal
adhesions.
Laparoscopic Enterocystoplasty
Figure 7-18 Laparoscopic view of the prostatic utricle under cystoscopic guidance.
polydioxanone suture inserted percutaneously under laparoscopic vision. The peritoneal reflection is incised using
electrocautery, starting immediately behind the bladder.
The prostatic utricle is easily identified with the guidance
of illumination from the cystoscope (Fig. 7-18). Dissection is
further facilitated by lifting and countertraction of the prostatic utricle by an assistant using the indwelling cystoscope.
Both ureters are clearly visualized laparoscopically and
protected throughout the course of dissection. A 5-mm ultrasonic scalpel is used to completely mobilize the prostatic
utricle and divide it at its confluence with the urethra. The
urethral defect is closed by intracorporeal suturing with the
use of fine absorbable sutures. The excised prostatic utricle
is removed through the supra-umbilical camera port. In
our series, laparoscopic excision of the prostatic utricle was
successful in all four patients, and none had any voiding
difficulties.
Laparoscopic Ureterocystoplasty
Laparoscopically assisted ureterocystoplasty is an appealing
MIS technique, because small kidneys are easily amenable to
laparoscopic mobilization followed by the ureterocystoplasty
through a cosmetically acceptable Pfannenstiel incision.117
The mobilization of the renal unit can be transperitoneal or
extraperitoneal, with 3- and 3.5-mm instrumentation. In our
approach, the upper ureter is completely mobilized in the
retroperitoneal cavity to the level of the iliac vessels. The
patient is then repositioned supine for a Pfannenstiel incision,
through which the mobilized kidney and ureter are accessed.
A standard ureterocystoplasty, using the entire ureter and
pelvis, is then performed.
Surgical Technique
Two parallel incisions are made about 1.5 cm apart, along the
posterior wall of the bladder extending from the anterior bladder neck to the level of the interureteric bridge, using monopolar diathermy (Figs. 7-19 and 7-20). The incision is deepened
to expose the detrusor muscle in the bladder neck area.
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Figure 7-20 Two parallel incisions are placed along the posterior
wall of the bladder extending from bladder neck to the interureteric
ridge.
Laparoscopic Autoaugmentation
Autoaugmentation, or detrusorraphy, is a technique that
involves dividing the bladder muscle and dissecting it free of
the mucosa.122 This allows the development of a large bladder diverticulum, which results in improved compliance
and low-pressure storage. Because this is a form of bladder
augmentation that does not involve the harvesting of gastrointestinal segments and requires very little suturing, it is
adaptable to minimally invasive techniques. Laparoscopic
autoaugmentation has been performed in animal models123
and in children,124-126 by both a transperitoneal and an extraperitoneal approach.127 Bladder autoaugmentation requires a
large incision of the detrusor with dissection of the underlying
mucosa over a large surface area, often followed by fixation of
the bladder muscle to the pelvic sidewall to prevent narrowing of the mouth of the newly formed bladder diverticulum.
Mitrofanoff Appendicovesicostomy
In recent years, several investigators have successfully incorporated laparoscopy into the pediatric urology reconstructive
procedure to minimize postoperative patient morbidity and
improve cosmesis.114,129-133 Pedraza and colleagues reported
on a robotically assisted laparoscopic Mitrofanoff procedure.134 Laparoscopic Mitrofanoff appendicovesicostomy is
performed using a transperitoneal, three-port approach. After
the initial access to the peritoneal cavity at the umbilicus using
the Hassan technique, in which a 10-mm trocar is placed, two
additional trocars are placed: a 12-mm trocar along the lateral
border of the left rectus muscle at the umbilical level and a
5-mm trocar along the lateral border of the right rectus muscle at the umbilical level. With laparoscopic visualization, the
appendix is identified. The right colon is mobilized medially.
The appendix is separated from the cecum, leaving a small
cuff of cecum with the appendix; this facilitates the stomal
anastomosis and decreases the risk of stenosis. The cecum
is closed in two layers. The appendix can be harvested with
the use of the Endo GIA stapler, including a 5-mm cuff of
cecum, with preservation of the mesentry and the vascular
supply. The cecal staple line is oversewn in two layers with
4-0 silk suture, using laparoscopic intracorporeal freehand
suturing and knot-tying techniques. The native bladder is
then identified with the aid of carbon dioxide insufflation at
12 to 14 mm Hg by way of an indwelling urethral catheter.
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Bladder neck
reconstruction
Figure 7-21 Tubularization of the incised strip over a catheter. The tube is closed in two layers using 5-0 absorbable sutures.
A 5-cm detrusor muscle trough is created along the right posterolateral aspect of the bladder, after which a small cystotomy
is created at the distal end of the trough. The distal 5 mm of
appendix is excised and spatulated, revealing a 1-cm lumen.
The appendiceal-vesical anastomosis is then performed circumferentially with eight interrupted stitches using 5-0 polyglycolic acid sutures. Next, the distal 5 cm of appendix is placed
in the newly prepared detrusor muscle trough, after which the
detrusor muscle edges are approximated over the appendix
with interrupted 4-0 polyglactin sutures, maintaining at least
a 5:1 ratio of trough length to tube diameter. Care is taken
to ensure absence of twisting or tension on the appendiceal
mesentery. All reconstructive maneuvers are performed using
laparoscopic intracorporeal freehand suturing and knot-tying
techniques. The base of the appendix is brought up to reach
the umbilicus without tension, and a catheterizable stoma is
created using a V-flap technique.
The bladder is filled with 200 mL of saline to check for any
leak from appendiceal-vesical anastomosis. Continence and
ease of catheterization are also checked and confirmed intraoperatively, after which a capped 10F Foley catheter is placed
through the appendiceal conduit into the bladder. Under laparoscopic guidance, a puncture suprapubic tube can also be
placed percutaneously. In our experience, the overall clinical
outcome of the present laparoscopic technique appears to be
satisfactory. Despite this preliminary success, additional clinical experience is necessary to define its role further.
Surgical Technique
The patient is placed supine. A three-port transperitoneal
approach is used, with the initial 10-mm port placed at the
inferior umbilical crease. Insufflation to an abdominal pressure of 12 mm Hg is established. A second port (10 mm) is
placed at McBurney point. A third port (5 mm) is placed in the
midline below the level of the umbilicus. The surgical table is
positioned so that the patient is in a 45-degree Trendelenburg
position with a 45-degree lateral rotation so that the ipsilateral side is exposed. The small bowel is manipulated medially,
and the cecum is identified. Once confirmation of an adequate
appendix has been obtained, the cecum is mobilized from
its attachments to the body wall with cautery. The colon is
mobilized approximately one third of the distance toward the
hepatic flexure, just enough to allow mobilization of the cecum
to the anterior abdominal wall during insufflation.
The appendiceal mesentery is freed with sharp dissection
and hook electrocautery at the base of the cecum, avoiding
injury to the appendiceal artery. The serosa at the appendicocecal junction is incised along the tinea, leaving the mucosal
lining intact. Then, 3-0 silk is used to imbricate the serosa onto
the appendix, reinforcing the valve mechanism. The appendix
is grasped with an endoscopic Babcock clamp and delivered
through the umbilical port. The abdomen is desufflated. The
tip of the appendix is transected and cannulated with an 8F
(2.64-mm) pediatric feeding tube to verify patency. The feeding
tube is left indwelling. A skin flap is fashioned in a V configuration at the umbilicus, incorporating the incision made for
the port. A stoma is created with this flap through the existing
fascial defect of the 10-mm port. The feeding tube is removed
and reinserted through the stoma to ensure patency and ease of
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in this technique. In the early part of the series, when the cannulas were not secured to the bladder wall, displacement of
the port outside the bladder wall occurred. This resulted in gas
leakage into the extravesical space, with compromise of the
intravesical space and endoscopic vision. It is usually possible
to reintroduce the ports, but securing the ports perfectly is
the key to the success of this technique.53,54 We have observed
mild to moderate scrotal and suprapubic emphysema immediately postoperatively, which subsided spontaneously within
24 hours. Persistent mild hematuria up to 72 hours has also
been observed and also settles spontaneously.
Intraoperative Complications
The cause of intraoperative complications in pediatric laparoscopy is most often the use of instruments that are inappropriately sized relative to the available limited working space,
which is the case in most small children. It is therefore crucial to use the correct small-size instruments. All of the 3- and
3.5-mm pediatric laparoscopy instruments are available in
20- and 30-cm lengths. Extra care is needed when operating
in confined space. With smaller telescopes, vision gets compromised easily by smoke, fluid, and light absorption due to
blood. All instruments must be exchanged with greater care,
because the safe range of movement is usually less. Smallerdiameter working instruments increase the risk for electrical
effects because the current density is higher, and with thinner
abdominal walls the current dissipates less efficiently.144,145
It is a good practice to always test the insulation and the optimum current needed during a particular surgery, to minimize
electrocautery-induced injury.
The effect of pneumoperitoneum on ventriculoperitoneal
shunt function has been an issue. However, clinical experience
has not confirmed these concerns, and numerous procedures
have been performed without ill effect. With a functioning valve in the shunt, there should be no risk of increasing
intracranial pressure.146
ROBOT-ASSISTED LAPAROSCOPY
chapter
to 60-degree elevation of the ipsilateral side after port placement, and the robot is brought in over the ipsilateral shoulder
for docking. The surgical steps principally remain the same as
previously discussed (see Laparoscopic Pyeloplasty). Various
surgeons have reported success rates similar to those obtained
with the gold standard open procedure, about 95%.151-153
We perform the Anderson-Hynes pyeloplasty repair using
the da Vinci robot mainly by a transperitoneal approach. The
robot allows us to deal with intrinsic problems, which are
easily excised and repaired. Extrinsic issues, such as crossing vessels, are readily addressed. We have seldom used this
technique in children younger than 1 year of age. Our initial
results in children older than 1 year have been comparable to
those of laparoscopic pyeloplasty, although the 8-mm robotic
instruments were discovered to be too big for a small child,
compared with the 3-mm instruments we use in laparoscopy.
The robot-assisted extravesical approach for treating VUR
can be performed unilaterally or bilaterally, following the
same steps as described earlier. Typically, the patient is in
the supine position and the legs are placed apart. An open
technique is used to place the first trocar, the 12-mm camera
port, in the umbilicus. The working ports (8 mm) are positioned in the midclavicular line bilaterally, about 1 cm below
the umbilical line. Ports are fixed and secured firmly to the
abdominal wall using a stitch that is also used to close the
fascia later. The robot is docked over the childs feet end to
perform the surgery.
For the robot-assisted Cohen procedure, the patient and
the robot docking position are same as described for the
extravesical approach. The major difference compared to the
conventional laparoscopic Cohen procedure is that a robotassisted procedure uses a 12-mm camera port and two 8-mm
working ports. Our initial experience with the da Vinci robot
has been far from satisfactory. Based on our working space
model and collision study model, we have recognized that
smaller working space is a major limitation on the performance of complex reconstructive tasks using the da Vinci
robot without collision.154,155
The major reconstruction applicability of the da Vinci system has been to do a pyeloplasty. A variety of other procedures
have been performed using robotic assistance for laparoscopic
surgeries in children, including ureteral reimplantation,156
Mitrofanoff technique,134 Mitrofanoff with MACE procedure
using divided appendix,121 as well as pyelolithotomy, adrenalectomy, bladder neck sling, pyeloureterostomy, and excision
of mllerian duct remnants. In all cases, the procedure could
be completed with surgical success. It is difficult to accurately
assess the impact on reduction of morbidity, but overall, the
enhanced visualization and dexterity are noticeable.149,156
Disadvantages of this robotic system include the lack of
tactile sensation; therefore, visualization of anatomic landmarks is the key to successfully completing the operation.
The unscrubbed surgeon is away from the operating table and
must depend on an experienced, scrubbed assistant. Active
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CONCLUSION
There has been a continued expansion in the application of
laparoscopy in the pediatric population. Improvements in
optics and instrumentation and the use of robotic assistance
have brought new dimensions to the use of MIS in the pediatric
population. Laparoscopy has provided a unique opportunity
for pediatric urologists to work in a small space around and
inside the urinary bladder. It has also allowed exploration of
the complete urinary system, from the kidneys to the urinary
bladder, with just a rotation of axis of trochars holding the laparoscope and the working instruments, thus aiding in dealing
with all the major pediatric urology surgeries in a minimally
invasive fashion. Smaller scars, less pain, and quicker recovery are all potential benefits of laparoscopy, but there is also
a potential for causing harm if the application of minimally
invasive technique is not done properly, particularly because
of the lack of adequate experience in this field. Technically,
most complex reconstructions in children have been achieved
with the use of laparoscopic technique, but their reproducibility has yet to be proved, as well as whether their long-term outcome is comparable to that of the established open technique.
It is therefore important to have proper clinical trials that can
objectively evaluate the use of these technically demanding
techniques in children.
REFERENCES
For complete list of references log onto www.expertconsult.com
S E C T I O N
FUNCTIONAL INVESTIGATIONS
CHAPTER
Acquisition Technique
Sedation of the child is only rarely necessary. A suitable environment, an adequate attitude toward the child and parents,
a well-trained radiographer/technologist for pediatric procedures, and well informed parents who are involved before
and during the procedure provide effective circumstances to
obtain adequate immobilization of the child during the acquisition. The most difficult age is between 1 and 3 years; in this
age group, sedation may be very occasionally required. The
safest drug is midazolam (intranasal or per rectum), which
helps reduce extreme anxiety.
It is envisaged that, because the clinical relevance of a small
scar seems negligible,1 DMSA single-photon emission computed
tomography (SPECT) will be performed only very seldom.
A DMSA scan gives a radiation burden of approximately
0.9 mSv, regardless of the childs age, provided that the injec
ted dose has been adjusted to body surface area. This exposure
is not insignificant, and care should be taken to make sure that
all possible information is extracted from the scan. The best
possible image quality should be sought. In a high-quality
DMSA study, it should be possible to clearly distinguish the
relatively hotter cortical columns of Bertin from the cooler
medulla and collecting system (Fig. 8-1).
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Indications
The main questions the clinician asks are, What is the relative
function of this kidney? and Is there any focal or global cortical abnormality? Within that broad context, there are specific accepted indications for a DMSA scan (Table 8-1).
Interpretation
The DMSA scan provides information on relative renal function and on functional status of the renal parenchyma. Normally, each kidney contributes between 45% and 55% of the
total renal function. A kidney that contributes between 40%
and 45% must be evaluated in the clinical context. For example, the contralateral kidney to a larger duplex kidney may
well contribute something in the range of 41% to 43% and be
perfectly normal (because the contralateral duplex is larger
and therefore has more renal cortex; see Fig. 8-1).
It is very important to recognize the normal variants of a
DMSA scan and to avoid interpreting them as an abnormality.
This would be a major disservice to the patient, because he or
she will be labeled as someone with a scar in his or her kidneys and therefore as a patient for life. The normal variants
are several (Table 8-2).
A focal abnormality with preserved outline may or may
not improve later on, and a follow-up scan may be advisable,
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Figure 8-2 Two-year-old boy with a urinary tract infection (UTI). A, The first DMSA scan was performed 6 weeks after the UTI: inflammatory
involvement at the right upper pole still persists. The left kidney contributes 65% to total renal function, and the right kidney 35%. B, The followup DMSA scan, performed 19 months after the UTI, shows improvement at the right upper pole. The left kidney carries 63% of total renal function,
and the right kidney 37%.
on DMSA Scan
Renal abscess
Systemic symptoms
Renal scar
Unusual microorganism
Calculi
Resistance to antibiotics
Renal cysts
Renal tumors
DMSA scan, static cortical scintigraphy using technetium 99mlabeled
dimercaptosuccinic acid.
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Posterior
Posterior
Figure 8-3 A, In a DMSA scan performed shortly after an acute pyelonephritis in a 6-week-old male infant, the right kidney shows global and
severe reduction of isotope uptake with focal defects. B, The follow-up DMSA performed 13 months after the pyelonephritis shows no change.
These findings are compatible with scarring involving the whole of the right kidney.
presence of renal scars to the presence of reflux on micturating cystography (MCUG), reflux is often found with normal
kidneys, whereas a significant number of scarred kidneys
show no reflux.16 This suggests that patients with reflux are
likely to be a heterogeneous group, some of them sustaining renal damage and others not. Reflux per se is therefore
unlikely to be a good predictor of renal damage, and the
use of a cystogram in every patient with UTI has been questioned. Low-grade reflux (grades I and II) is associated with
a low risk of renal scarring. High-grade reflux (grade IV and
occasionally grade V) has been shown to be a significant risk
factor for renal scarring, according to the International Reflux
Study.17 Another recent study showed that the higher the
grade of reflux, the higher the number and severity of renal
scars.18
Tracers
Tc99m-DTPA has been used for a long time in dynamic renography. It is a small molecule that diffuses within both the
intravascular and the extravascular spaces. It is filtered by
the glomeruli. The extraction fraction is approximately 20%.
Tc99m-DTPA gives a significant background activity due to the
small size of the molecule and the relatively low extraction
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Diuretic Renography
Frusemide stimulation, by inducing a high-flow diuresis, has
long been used during dynamic renography in the attempt
to separate urinary stasis within a capacious renal collecting
system from resistance to urine outflow.
Evaluation of Drainage
Drainage of a kidney depends on the hydration status, the
function of that kidney, the volume of the pelvis, the posture
of the patient (effect of gravity), and the status of the bladder.
Several parameters influence drainage. Methods of evaluating
drainage that are based only on the half-life (t12) of tracer washout from the pelvis are inaccurate, because they do not take
into account such factors as renal function, pelvic volume, and
bladder status (Table 8-5).
Hydration
A good hydration status is important. Ingestion of 7 mL/kg
fluids (water or fruit juice) 30 to 60 minutes before tracer injection is normally sufficient. The SNM guidelines, acknowledging that oral hydration may be sufficient in some cases,
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12
14
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Tc99m-MAG3
20
M
Renogram / Postmicturition
% Injected Dose
12%
Clearance
Image
0MN
30MN
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12
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Tc99m-MAG3
20
M
Renogram / Postmicturition
% Injected Dose
12%
Clearance
Image
Early
Computer
Generated
Functional
Image
0
0MN
30MN
60MN
Figure 8-5 A, A diuretic MAG3 scan in a 7-month-old girl shows stasis within a dilated left ureter (12 to 14 mm dilatation). The image obtained
after postural change (image M) does not show significant change: these findings are compatible with a dysfunctional left vesicoureteric junction
and a left hydroureteronephrosis. The child had a JJ stent placed. B, Clearance, or functional, image, showing a well functioning left kidney and
a slightly less functional right kidney. The time-activity curves show urinary stasis in the renal pelvis and upper ureter bilaterally, even following
change of posture and micturition.
Effect
of
Pelvic Volume
A large pelvis takes longer to drain than a small pelvis; this does
not mean that the pelvis is obstructed, but simply that there is
more urine in a large pelvis, and therefore a large pelvis will
take longer to clear. Also, when isotope-tagged tracer reaches
chapter
a large pelvis, it will dilute with a larger amount of nonradioactive urine that pools in that pelvis, and each drop of urine
leaving the pelvis will contain less isotope; therefore, isotope
will leave a large pelvis more slowly.
Effect
of
Renal Function
Effect
of
Gravity
Effect
of
Bladder Status
Quantification
of
Drainage
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10
12
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Tc99m-MAG3
February 2005
20
M
Renogram / Postmicturition
% Injected Dose
10%
Clearance
Image
Early
Computer
Generated
Functional
Image
February 2005
0
0MN
30MN
60MN
Figure 8-6 Obstruction is a condition of urinary outflow which, if left untreated, will lead to increase in dilatation of the renal pelvis and deterio-
ration of renal function. This case shows increasing hydronephrosis of the left kidney in a 3-year-old girl (A and B). At the time of the first isotope
scan (February 2005), the left renal pelvis measured 8 mm, and the left kidney contributed 45% to total renal function. The time-activity curves
show good drainage from the right kidney and progressive tracer accumulation in the left kidney, even after change of posture and micturition
(the postmicturition view was acquired approximately 47 minutes after the start of the dynamic renography).
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Tc99m-MAG3
July 2006
20
M
Renogram / Postmicturition
% Injected Dose
11%
Clearance
Image
Early
Computer
Generated
Functional
Image
0
0MN
July 2006
30MN
60MN
Figure 8-6, contd, C and D, On subsequent ultrasound scans, the size of the left renal pelvis progressively increased to 41 mm in July 2006,
when a repeat MAG3 scan showed a significant deterioration of the function of the left kidney, to 24%. The left kidney was obstructed, and this
caused deterioration of left renal function together with an increase in pelvic size. The clearance image shows a poorly functioning left kidney and
a well functioning right kidney. The time-activity curve of the left kidney (dotted line) clearly shows impaired drainage, even following change of
posture and micturition, while the right kidney drains well.
that perhaps not all of these patients needed surgery. The conservative approach of watchful waiting began to be adopted
by several groups. In some groups, the percentage of patients
with antenatal hydronephrosis who were referred to surgery
fell to about 20% or 25%.
Nowadays, most patients with antenatally detected hydronephrosis are treated conservatively. Some patients are treated
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CONGENITAL ABNORMALITIES
Duplex Kidney
An uncomplicated duplex kidney is a variation of normality.
The complicated duplex may be a complete or an incomplete
duplex. Both moieties may show equal function, and in such
cases the duplex kidney is typically longer than normal and
has divided renal function greater than 55% (Fig. 8-8). Reduced
1995
A
Figure 8-7 Slow drainage with urinary stasis at the pelviureteral junction does not necessarily mean obstruction. Obstruction is diagnosed if the
renal pelvis increases in size on repeat ultrasonography or the relative function of that kidney falls on follow-up MAG3 scanning, or both. This
case shows a 4-year-old girl with a left hydronephrosis who was monitored for 10 years: the dynamic renogram showed slow drainage from the
left renal pelvis at the first MAG3 renogram in 1995 (A) and on the follow-up renogram in 1999 (B). The relative function of the left kidney was
virtually unchanged and the size of the left renal pelvis was also stable.
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1999
B
Figure 8-7, contd
DrainageIncomplete Duplication
Drainage of the duplex kidney is by definition via two collecting systems. However, the two systems have many possible
formations. In the case of incomplete duplex, the two ureters
may join at any level above the bladder. Urine may reflux from
one moiety down the ureter and then up into the other moiety,
rather than going down into the bladder; this is known as
yo-yo reflux. It is only on dynamic radionuclide studies that
this diagnosis can be made with certainty.
DrainageComplete Duplication
In complete duplication, the ureters draining the two moieties
never join. If both ureters drain into the bladder, the ureter draining the lower moiety is prone to reflux. The ureter
Clinical Presentation
The child with duplex kidney may present with a number of
clinical conditions:
Asymptomatic (i.e., duplex system discovered as an
incidental finding)
Urinary tract infection
Pain, which can be secondary to an intermittent
obstruction at the PUJ level of the lower moiety or caused
by yo-yo reflux with incomplete duplication
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2005
10
12
14
16
18
20
Figure 8-7, contd, C, The final scan, at 14 years of age, shows stasis in the left renal pelvis when the girl lies supine on the camera couch and
good drainage after postural change and micturition. This girl never had any surgery, because the size of the left renal pelvis never increased
significantly, and the split function of the left kidney never fell significantly. This is an example of a dilated renal pelvis coping with the amount
of urine excreted without significant resistance to outflow.
Imaging
One of the cardinal signs of a duplex system is a change in
the axis of the lower moiety. This is best noted by the fact
that the calyces of the lower moiety are medial to the upper
group of calyces, giving the lower moiety of the kidney a
longitudinal axis pointing to the shoulder on the same side.
The appearance of a duplex kidney varies with the pathology of each moiety. 99mTc-MAG3 scanning can assess function, drainage, and reflux, especially with late images. If
a moiety is nonfunctional, it will not be visualized; this is
important when there is a small, severely dysplastic upper
moiety. A high index of suspicion when reporting on functional imaging allows the duplex kidney to be recognized
easily.
With incomplete duplication, the upper and lower moieties
may be normal, or there may be reduced function of either
element. With 99mTc-MAG3 scanning, the drainage from each
moiety can be evaluated and evidence of yo-yo reflux can be
sought.
Fusion Abnormalities
The most common fusion abnormality is that of the horseshoe
kidney with fusion of the lower poles; this is always associated
with malrotation so that the pelves and ureters pass anteriorly
over the fused lower poles. The two well-recognized complications are renal pelvis dilatation (with or without obstruction)
and renal calculi. The abnormal position also leaves the kidney
more susceptible to injury. A 99mTc-DMSA scan with an anterior view is useful to show all functioning renal tissue, especially over the spine (Fig. 8-12).
chapter
L 58%
121
R 42%
Figure 8-8 A left uncomplicated duplex kidney: there is normal uptake in both the upper and lower moieties, which function as a single unit.
The left kidney is larger than the right, and therefore the mass of functioning nephrons is bigger. This is why the relative function of the left kidney
is slightly higher (58%) than the accepted normal range of 55% to 45%. The right kidney is entirely normal, although it contributes only 42% to
total renal function.
Posterior
Figure 8-9 A 4-year-old girl who was constantly wet. The DMSA scan shows reduced uptake at the right upper pole, which in the clinical context is compatible with the upper moiety of a duplex kidney with reduced function. A previous ultrasound had missed this finding, which was
confirmed by a second ultrasound guided by the DMSA result. The girl underwent a right upper pole heminephrectomy with resolution of her
symptoms.
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10
12
14
16
18
Tc99m-MAG3
20
Figure 8-10 A 9-month-old boy with an antenatal diagnosis of a left duplex kidney and a ureterocele. The MAG3 study shows no uptake in the
left upper moiety and good uptake in the left lower moiety. At minute 8 of the acquisition, the child voided into the diaper, and there was concomitant reflux into the left upper moiety. The child underwent a left upper pole heminephrectomy.
Crossed fused renal ectopia occurs when one kidney is displaced across the midline and fused inferiorly to the other,
relatively normally positioned kidney. Both ureters enter the
bladder in a normal position. The importance of this condition
is that it may present as an abdominal mass or as an obstructive uropathy with a PUJ obstruction. A MAG3 renogram is
required, especially if surgery is being considered for PUJ
obstruction. There is an increased incidence of VUR into the
crossed fused kidney, and, if further anatomic information
concerning the ureter and pelves is required, an indirect radionuclide cystogram (IRC) may prove helpful (see later discussion). The 99mTc-DMSA scan may be normal or may show
patchy uptake of isotope owing to the anatomic abnormality
and dysplasia that may coexist to some degree.
Clinical Evaluation
Indications
and nontoilet-trained boys who require follow-up cystography (having previously had an MCUG). There are no contraindications.
Method
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Tc99m-MAG3
20
Figure 8-11 Bilateral duplex kidneys with symmetrically reduced function in the lower moiety bilaterally. The dynamic renogram also shows
bilateral reflux coincident with an episode of micturition (images 10 and 12).
Indications
The IRC is indicated under the following circumstances:
Whenever renal reflux must be excluded in the older,
toilet-trained child
Ureteric dilatation in the toilet-trained child
In children with bladder dysfunction, including posterior
urethral valves, where the entire nephrourologic system
can be evaluated
Method
After a routine 99mTc-MAG3 scan, the child returns to the
gamma camera, which has been turned to the vertical position,
when she or he wishes to void. The child sits with the camera
at his or her back; often, boys prefer to stand. Acquisition starts
30 seconds before micturition and continues for 30 seconds
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Post
Ant
Left
Right
LPO
RPO
Left
Left
Figure 8-12 Horseshoe kidney. The DMSA scan presented in this illustration shows good uptake in each portion of the horseshoe kidney and
in the isthmus as well. With ultrasound, it may be difficult to visualize the isthmus, as in this case where it was missed. (From Bajpai M. Imaging
of the urinary tract in congenital anomalies. In: Bajpai M, Gearhart JP, Hjalmas K, et al., eds. Progress in Paediatric Urology. Vol 8. London: Penwel
Publishers; 2006:138, Fig. 2b, with permission.)
Clinical Evaluation
The IRC is the only completely physiologic examination
that can show in vivo the pathophysiology of bladder filling
(during dynamic renography) and emptying (during cystography). Although it does not grade reflux with the anatomic
definition of the MCUG (grades I through V), it is possible to
distinguish a mild from a moderate or a severe reflux and to
roughly quantify the volume of urine refluxed.
Debate exists concerning the real usefulness of the IRC.
Critics maintain that its sensitivity is significantly lower than
that of the direct techniques, which involve the use of a catheter,31 and that high-grade reflux with severe cortical damage
can be observed on DIC even when the IRC is negative. Those
in favor of the IRC point out that reflux can be missed by both
REFERENCES
For complete list of references log onto www.expertconsult.com
chapter
125
A
Bladder/Renal
Renal
100%
7.3%
1200
Lt Kidney
80
Rt Kidney
(Counts)
(Counts)
Bladder
800
400
Duration
3mn47sc
40
80 120 160
(Seconds)
60
40
20
200
40
80 120 160
(Seconds)
200
Figure 8-13 A, Example of a direct isotope cystogram, showing bilateral vesicoureteric reflux. B and C, Time-activity curves describing the
variation in counts within each kidney when the counts from the kidneys have been scaled to the bladder (B) or are considered in isolation
(C). The curves (especially in C) show clear increase in counts over the two kidneys, in keeping with reflux.
I: Basics
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Bladder/Renal
Renal
100%
7.3%
Lt Kidney
1600
200
Rt Kidney
Bladder
160
(Counts)
(Counts)
1200
800
40
80
80
Duration
5mn33sc
400
120
120
(Seconds)
240
320
80
120
240
(Seconds)
320
Figure 8-14 A, Example of an indirect isotope cystogram in a 9-year-old girl with a history of urinary tract infection and scarred kidneys. There
is bilateral reflux and complete bladder emptying. Note that there are two episodes of reflux into the right kidney during the cystogram. B and C,
Time-activity curves showing the variation in counts within each kidney when the counts from the kidneys have been scaled to the bladder (B) or
are considered in isolation (C). The curves (especially in C) show clear increase in counts over the two kidneys, in keeping with bilateral reflux.
CHAPTER
Rien J. M. Nijman
STANDARDIZATION OF TERMINOLOGY
Standardization of terminology and methodology should
facilitate comparison of results by investigators using urodynamic methods in children. The definitions of the International
UROFLOWMETRY
The uroflow should be analyzed in detail in all children with
urinary incontinence, recurrent urinary tract infections, or other
voiding disorders. The graphic registration, with a simple flow
meter, of the urinary flow curve and rate is a standard office procedure. Several recordings may be needed to obtain consistency.
Because the flow rate depends on the voided volume, the
force of detrusor contraction, and the outflow resistance, it
cannot simply diagnose the cause of impaired voiding.
Although a modern flow meter is a simple device, it is not
so simple to obtain a reliable flow curve. The child should be
stimulated to come with a full bladder, which can be checked
with ultrasonography. If the bladder is almost empty, the child
should be asked to drink some water until the bladder is full
enough for a reliable flow.
Definitions
The voided volume is the total volume expelled via the urethra.
The maximal flow rate is the maximum measured value of the
flow rate.
The average flow rate is the voided volume divided by flow
time (this is meaningful only if the flow is continuous and
without terminal dribbling).
The flow time is the time over which a measurable flow actually occurs.
The time to maximal flow is the elapsed time from onset of flow
to maximum flow.
The average flow rate, flow time, and time to maximal flow
are of lesser importance than the voided volume and the flow
pattern.
Test Setup
The test should be explained beforehand, and the best results
are obtained when the child voids in a sitting position,
although older boys may prefer a standing position. While the
child is seated, care must be taken that proper support of the
legs is providedwithout pants and preferably with a toilet
seat adapted to age, so that the child can completely relax
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Figure 9-2 Improper position on the toilet. Note that the legs are not
supported. In this position, the pelvic floor muscles are not relaxed.
In children, a poor correlation exists between the maximal
flow rate (Qmax) and the outflow resistance: an increase in outflow resistance is usually compensated by a strong detrusor
contraction, resulting in an adequate Qmax but with the typical
flow pattern of obstruction. However, a real anatomic obstruction is infrequently found in children; most of the obstructions
have a functional nature, and, therefore, the pattern of the
curve is most informative.
Urinary flow may be described in terms of rate and pattern
and may be continuous, intermittent (in fractions), or staccato.
In children with a so-called urge syndrome, the flow shows
a normal pattern, but usually a less-than-normal volume is
voided, whereas the Qmax may be very high. This is caused by
a very strong detrusor contraction in combination with minimal or no outflow resistance.
An intermittent flow pattern shows an interrupted flow.
In staccato voiding, the flow does not stop completely but
fluctuates due to incomplete relaxation of the sphincter, as
in dysfunctional voiding with poor relaxation of the pelvic
floor muscles (Fig. 9-4). Sometimes, this finding is artifactual
because the child stops voiding when urine is not directed
into the collecting funnel. The pattern may also occur when
abdominal straining is used to void (as in children with a
hypocontractile bladder). To further evaluate discoordinated
voiding, urinary flowmetry may be combined with a perineal
EMG to demonstrate intermittent relaxation of the pelvic floor
in combination with an intermittent flow pattern.
chapter
50
Qb
Qmax
44
89
129
Qe
40
30
20
10
0
250
Vura (mL)
200
150
218
100
50
0
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Time (sec)
Figure 9-3 Normal flow curve. The maximal flow rate (Qmax) is 44 mL/sec; the voided volume is 218 mL. Qb, start of flow; Qe, end of flow;
20
15
10
0
00:00
01:00
02:00
Time (min:sec)
03:00
130
part
I: Basics
Interpretation
Measurement of urinary flow is performed either as an isolated procedure, with bladder filling by diuresis (spontaneous
or forced), or as part of a pressure-flow study, with bladder
filling by catheter. Patterns and rates should be consistent to
allow for evaluation, and several recordings are needed to
obtain consistency. The same parameters used to characterize
continuous flow may be applicable, if care is exercised, in children with intermittent or staccato flow patterns. In measuring
flow time, the time intervals between flow episodes are disregarded. Voiding time is total duration of micturition, including interruptions (see Fig. 9-4).
The study should be combined with an ultrasonographic
study of the kidneys and bladder before and immediately
after voiding, to detect residual urine. In addition, ultrasonography provides information on the influence of a full
bladder on the degree of dilatation of the upper urinary tract.
Both uroflowmetry and ultrasonography are noninvasive and
can therefore be repeated at regular intervals to monitor the
therapeutic results.
The results of flow studies should always be interpreted
with care: all studies are complementary to the clinical findings. Normal findings do not rule out pathology, and abnormal studies do not necessarily reflect bladder dysfunction.
Ultrasound-Flow-Ultrasound
This combination of imaging and noninvasive urodynamics is
a standardized procedure used to obtain representative data
on both flow rate and flow pattern, as well as postvoid residual volume. Bladder filling is assessed with ultrasound; when
the bladder capacity is equal to the functional or expected
c apacity for age, the child is asked to void into the flow meter.
After the flow is recorded, the postvoid residual is assessed
again by ultrasound. This procedure avoids the registration of
flow rates at unrealistic bladder volumes.
Alternatively, children can be asked to use a flow meter at
home. A special flow meter has been designed for this purpose. This option can overcome any difficulty the child has
voiding in a strange environment.
The use of a flow meter in combination with real-time
monitoring offers the advantage that the child can actually see
how she or he is voiding (Fig. 9-5). Biofeedback as a treatment
modality for children with dysfunctional voiding is based on
this concept and has proved to be highly effective.19
BLADDER CAPACITY
In order to interpret the findings with various urodynamic
modalities, it is necessary to be able to estimate normal bladder
capacity for the childs age and gender. Numerous attempts
have been made to develop linear formulas to calculate bladder capacity. The difficulty is that many anatomic variables
change in a nonlinear way with respect to age, height, and
weight in the growing infant and child. In general, bladder
capacity increases during the first 8 years of life at a rate of
about 30 mL/year. Therefore, with an average capacity of 30 mL
in the neonatal period, a childs bladder volume can be roughly
calculated as Y = 30(Age) + 30 mL, where Y is the bladder
capacity in milliliters and Age is the childs age in years.
Attempts at estimating bladder capacity accurately in children have been published by Koff,20 Berger and coworkers,21
Hjlmas,22 Fairhurst and colleagues,23 and others, but they
all have flaws. The Berger21 and Koff20 formulas estimated
bladder capacity in ounces (Yoz = Age + 2 oz), using data
obtained from children under general anesthesia. Koff used
urodynamic measurements, whereas Berger and coworkers
infused saline solution by hand at pressures of approximately
60 cm H2O. Fairhurst23 determined the bladder capacity in
milliliters to be equal 7 times the childs weight in kilograms;
this formula was derived by injecting contrast medium with
a syringe during a voiding cystography until there was a leak
around the catheter. In none of these studies were intravesical
pressures recorded.
The formula for bladder capacity (in milliliters) used
by Hjlmas22 in infant boys (up to 2 years of age) was Y =
24.8(Age) + 31.6 mL; in infant girls, it was Y = 22.6(Age) +
37.4 mL. For older children, the formula Y = 30(Age) + 30 mL
was used.
Kaefer and associates24 calculated capacity in ounces and
used the formulas Yoz = 2(Age) + 2 oz for children younger
than 2 years old and Yoz = Age/2 + 6 oz for older children.
Their studies used radionuclide cystography in which the
capacity was determined when the child became uncomfortable or voiding occurred.
In 1999, a group in Japan25 found that, because Japanese
children appear to have somewhat smaller bladders, the best
formula for bladder capacity (in milliliters) in that population
was Y = 25(Age + 2).
Another approach was described by Houle and coworkers.26 They determined what volume of urine a child could
normally store in the bladder at a safe pressure. The minimal
acceptable total bladder capacity was determined to be 16
times the childs age in years + 70 mL.
Landau and colleagues27 determined bladder capacity in
children with neurogenic bladders at safe pressures; the minimal accepted capacity was found to be 18 times age in years
+ 45 mL.
chapter
25
Qb
Qmax
Qe
11
131
Qura
(mL /sec)
20
15
10
50
16
EMG
(V)
25
0
50
25
250
Vura
(mL)
0
155
100
0
10
20
30
40
50
60
70
80
90
243
130 140
Time (sec)
Figure 9-5 Example of a flow curve combined with pelvic floor muscle electromyography (EMG). The flow curve is of the staccato type (there is
intermittent relaxation of the pelvic floor muscles, but the flow does not stop completely). This pattern can be seen in children with dysfunctional
voiding and discoordination between detrusor contraction and sphincter relaxation. Qura, flow rate; Vura, flow volume.
be insufficient during the filling phase, adding extra information with regard to possible causes of incontinence. Radiologic
visualization of the urethra during voiding usually is more
accurate than the EMG or measurement of urethral pressure
in cases of urethral overactivity.
Urodynamic investigation is an invasive procedure, and
one must be aware of some artifacts that may influence the
interpretation of the results of the examination.28 It is not a
natural situation, and most children are anxious to varying
degrees. A transurethral catheter may influence voiding, and
in some children the catheter irritates the bladder, inducing
overactivity (a suprapubic catheter may eliminate the first
problem, but not the second). The filling rate and temperature
of the saline solution or contrast medium may also influence
detrusor activity during both filling and voiding. Certain precautions must be observed: the filling rate should not exceed
10% bladder volume per minute, with a recommended maximal filling rate of 10 mL/min (physiologic filling). In cases
of severe overactivity or diminished compliance, the filling
rate is best reduced to 5% of bladder capacity per minute. The
fluid used to fill the bladder (contrast medium or saline solution 0.9%) should be at 25 to 36 C. The bladder capacity is
based on the maximum capacity noted on the bladder diary;
therefore, before a urodynamic study is performed, the child
132
part
I: Basics
Figure 9-6 The setup for video-urodynamics. Note that the table is
in the vertical position with a seat attachment (adjustable according to
age). Underneath the seat is the flow meter; the feet are supported.
inserted into the bladder and fixed to the penis. An 8F (2.64-mm) feeding tube is used for rectal pressure recording. The catheters are connected to external pressure transducers, the filling channel to a pump.
The skin electrodes are later covered with Tegaderm to prevent their
becoming wet.
Capacity
In cases of sphincter incompetence or lack of bladder sensation, the maximum bladder capacity is difficult to determine.
A Foley catheter may be used to occlude the bladder neck to
determine the capacity; if there is lack of filling sensation, the
clinician stops filling when the resting pressure in the bladder
has reached 30 cm H2O.
The functional bladder capacity is a more relevant parameter for the clinician. It is defined as voided volume and
is estimated from the frequency/volume diary. Consistent
values can be obtained if the child voids only when there is
a genuine desire to void, but this can be achieved only when
voiding is supervised.
Sensation
In general, bladder sensation is very difficult to evaluate in children,
and it can be a relevant parameter only in toilet-trained children.
Previously used terms such as first desire to void or strong
chapter
Pves
(cm H2O)
100
Ce
133
Leak
C1 Cb
43
11 15
44 47
C4
50
0
Pabd
(cm H2O)
100
11
16 14
50
Pdet
(cm H2O)
0
100
32
5 0.
50
11
12
33
36
0
Qura
(mL /sec)
25
0
0
4 4
4
151 152
10
0
EMG
(V)
100
0
Vinf
(mL)
100
250
152
100
0
0:00
0:30
1:00
1:30
2:00
2:30
3:00
3:30
4:00
4:30
5:00
5:30
6:00
6:30
7:00
7:30
8:00
Time (min:sec)
Figure 9-8 A urodynamic study in a 10-year-old girl with spina bifida. There is a gradual rise in detrusor pressure (Pdet), indicating reduced
elasticity of the bladder wall. The compliance is calculated between the points marked Cb and Ce (here, leakage occurred at leak-point pressure).
The compliance is V/Pdet = 152/36, or 4.2 mL/cm H2O. If the bladder were filled more slowly, the compliance might become normal. Diminished compliance is a typical finding in neurogenic bladders and in some infectious diseases (tuberculosis, bilharziasis). EMG, electromyographic
activity; Pabd, abdominal pressure; Pves, intravesical pressure; Qura, flow rate; Vinf, infused volume.
Compliance
Bladder compliance indicates the relationship between change
in bladder volume and change in detrusor pressure. It is calculated by dividing the volume change (V) by the change in
detrusor pressure (Pdet) during that change in bladder volume (V/Pdet) and is expressed as milliliters per centimeter
of water (mL/cm H2O) (Fig. 9-8).
134
part
I: Basics
Pves
(cm H2O)
Qmx
100 C
1
1S
24
32
Qb
C4
50
Qe
78
50
0
85
20
Pabd
(cm H2O)
100
50
24
25
27
24
23
24
Pdet
(cm H2O)
100
0
23
50
0
54
62
Qura
(mL /sec)
25
0
10
0
20
EMG
(V)
100
0
14
13
100
Vura Vinf
(mL) (mL)
300
200
100
10 4 5
302
162
54
109
0
0:00
0:30
1:00
1:30
2:00
2:30
3:00
3:30
4:00
4:30
5:00
5:30
6:00
6:30
301
302
7:00
7:30
302
301
8:00
Time (min:sec)
Figure 9-9 A urodynamic study showing severe detrusor overactivity during filling. Note that each detrusor contraction is accompanied by
increased pelvic floor muscle electromyographic (EMG) activity. Voiding is complete with a detrusor pressure (Pdet) of 62 cm H2O and good relaxation (no visible EMG activity) and without abdominal straining (no increase in Pabd). Pves, intravesical pressure; Qura, flow rate; Vinf, infused
volume; Vura, volume voided.
Detrusor Activity
Detrusor activity is interpreted from measurement of the
detrusor pressure (Pdet). It may be normal, overactive, or
underactive.
chapter
C1
100
Pves
(cm H2O)
135
C4
27
50
85 81
0
Pabd
(cm H2O)
100
43
22
50
88
Pdet
(cm H2O)
0
100
4
50
43
0
Qura
(mL /sec)
25
0
0 0
88
34 10
28 28
10
0
EMG
(V)
100
0
Vinf
(mL)
100
50
25
0
0:00
0:30
1:00
1:30
2:00
2:30
3:00
3:30
4:00
4:30
5:00
5:30
6:00
Time (min:sec)
Figure 9-10 A 2-year-old girl with a tethered cord. Severe overactivity of the detrusor occurs because of the neurologic lesion. In combination
with an overactive pelvic floor, these high pressures without normal voiding (some dribbling of urine is usually seen) are typical for detrusor
sphincter dyssynergia. EMG, electromyographic activity; Pabd, abdominal pressure; Pdet, detrusor pressure; Pves, intravesical pressure; Vinf, infused
volume.
Leakage
The normal urethral closing mechanism maintains a positive urethral closure pressure (guarding reflex).33 Shortly
before micturition, the normal closure pressure decreases to
allow flow. An incompetent closure mechanism is defined as
one that allows leakage of urine in the absence of a detrusor
contraction. In genuine stress incontinence, leakage occurs
136
part
I: Basics
Pves
(cm H2O)
100
Qmx
75
Vmx
50
25
0
69
82
49
58
20
24
16
17
EMG
(V)
25
0
25
Pabd
(cm H2O)
100
75
50
25
Pdet'
(cm H2O)
0
100
50
10
Qura
(mL /sec)
25
10
0
500
Vinf
(mL)
423 423
250
0
18:30
18:50
19:10
19:30
19:50
20:10
20:30
20:50
21:10
21:30
21:50
22:10
22:30
Time (min:sec)
Figure 9-11 A urodynamic study in a 12-year-old boy with voiding difficulties, urinary tract infections, and incontinence. During the filling
phase, no detrusor action is recorded; voiding takes place only with abdominal straining (increased Pabd) and no visible detrusor contraction
(Pdet). Note that pelvic floor muscle activity (EMG) is increased with each straining effort. There was significant residual urine volume, and the
flow pattern was intermittent and prolonged. This is an example of a so-called underactive bladder. Pves, intravesical pressure; Qura, flow rate;
Vinf, infused volume.
chapter
Pves
(cm H2O)
100
C1
Qb
C4
1S
51
24
34
50
0
75
Pabd
(cm H2O)
100
50
137
16
17
Qmx
98
Qe
27
18
22
41
18
0
34
Pdet
(cm H2O)
100
0
16
35
50
80
Qura
(mL /sec)
25
0
1 5
10
0
13
EMG
(V)
100
8
13
15
12
0
100
Vura Vinf
(mL) (mL)
250
100
118
0
0:00
117
92
0:30
1:00
1:30
2:00
2:30
3:00
3:30
4:00
4:30
118
118
27
102
0
5:00
5:30
6:00
6:30
7:00
tmin:s
Figure 9-12 A, Urodynamic study 2 years after treatment for posterior urethral valves. There is significant detrusor overactivity as well as an
obstructed flow. Pabd, abdominal pressure; Pdet, detrusor pressure; Pves, intravesical pressure; Qura, flow rate; Vinf, infused volume; Vura, voided
olume.
v
138
part
I: Basics
PRESSURE-FLOW EVALUATION
140
PRESSURE
Pdet [cm H2O]
P(uo)
P(Qmax)
Pmax
P(ef)
Pmuo
120
100
=
=
=
=
=
33.1
79.9
81.5
4.3
0.9
FLOW
Qmax = 4.1 mL / sec
Qave = 2.7 mL / sec
Volume = 102 mL
38 sec
t(Q 0) =
t =
38 sec
t(Qmax) = 10.5 sec
Accel. = 0.4 mL / sec2
t(uo) = 14.7 sec
80
AG-NOMO
AG-Number = 71.7 cm H2O
URA = 58.1 cm H2O
Wmax = 11.6 W/m2
W(Qmax) = 11.4 W/m2
60
40
Result = Obstructed
20
GENERAL VALUES
Calc. residual vol. = 16 mL
0
10
15
20
25
Figure 9-12, contd B, The pressure-flow evaluation shows high pressures (Pdet) with low flow rates (Qura), consistent with an obstructive
Infravesical obstruction
Obstructive uropathy
The evaluation of bladder dysfunction after posterior urethral
valve ablation or resection is another example of the significant role urodynamics may play in the management of such
conditions.
CLINICAL IMPLICATIONS
Urodynamic investigations should be conducted only if a treatment strategy has been defined beforehand. Without implications, such a study should not be performed. Table 9-1 lists
some of the clinical urodynamic implications.37,38
Urodynamic studies in children are best performed
by the urologist. To obtain a complete picture, one has to
be present during the investigation to see how the child
behaves during the study and also to monitor the parents.
This observation provides an ideal opportunity that may
completely alter the treatment protocol. Another advantage
is that, after a while, history taking and initial workup will
be more accurate and specific, and a lot of extra investigations may be avoided. This is also an important factor,
because urodynamic investigations are invasive, the surroundings are frightening, and, although the parents may be
present, the whole procedure remains quite unnatural to the
child. Not all children can void with a transurethral catheter
inserted, and sometimes they void only when everybody,
including the parents, have left the room temporarily. The
availability of a television, videocassette recorder, or digital
videodisc (DVD) player is a major advantage, because the
children may watch their favorite tape to distract them. For
very small children, the parents are advised to bring a bottle
and some toys.
chapter
C1
100
Pves
(cm H2O)
139
Qmx
Qb
Qe
23
93 82
133
40
18 14
22
14
75 69
111
26
50
0
Pabd
(cm H2O)
100
50
0
100
Pdet
(cm H2O)
14
50
0
Qura
(mL /sec)
25
0
0 1
14
24 49
17
330 331
331
331
0 0
109
296
10
0
EMG
(V)
100
0
Vinf
(mL)
100
500
Vura
(mL)
250
0
0:00
1:00
2:00
3:00
4:00
5:00
6:00
7:00
8:00
9:00
10:00
11:00
12:00
13:00
14:00
tmin:s
PRESSURE-FLOW EVALUATION
140
PRESSURE
Pdet (cm H2O)
P(uo) = 69.9
P(Qmax) = 110.8
Pmax = 121.3
P(ef) = 37.0
Pmuo = 23.1
120
100
FLOW
Qmax = 3.3 mL / sec
Qave = 2.0 mL / sec
Volume = 296 mL
t(Q 0) = 148 sec
t = 149 sec
t(Qmax) = 63.3 sec
Accel. = 0.1 mL / sec2
t(uo) = 36.6 sec
80
AG-NOMO
AG-Number =104.2 cm H2O
URA = 82.5 cm H2O
Wmax = 13.7 W/m2
W(Qmax) = 12.8 W/m2
60
40
Result = Obstructed
20
GENERAL VALUES
Calc. residual vol. = 36 mL
0
10
15
20
25
urinary tract infections and incontinence after reconstruction for an ectopic ureterocele in childhood. Note the
diminished compliance and extremely
high voiding pressures with a very low
flow rate. This is typical of an anatomic
obstruction at the level of the bladder
neck. EMG, electromyographic activity;
Pabd, abdominal pressure; Pdet, detrusor pressure; Pves, intravesical pressure;
Qura, flow rate; Vinf, infused volume;
Vura, voided volume. B, pressure-flow
evaluation in the same child. Low flow
rate in combination with very high
voiding pressures indicate an anatomical obstruction (at the level of the bladder neck). P(Qmax), pressure at maximal
flow rate.
140
part
I: Basics
Findings
Diagnosis
Treatment
Reflux + instability
Anticholinergics
Anticholinergics,
a ugmentation
Residual urine
Infravesical obstruction
Cystoscopy + incision or
resection
Urethral overactivity
Medical or behavioral
odification
m
Poor relaxation/dyssynergia
Medical or behavioral
odification
m
CONCLUSION
Urodynamic investigation has become a major tool in the
evaluation of bladder dysfunction in many children. However, urodynamic investigation is invasive and, by definition,
far from natural, and artifacts may influence to a great extent
the correct interpretation of these studies. Furthermore, the
studies do not always show reproducible results. Urodynamic
studies are part of the whole diagnostic workup and must not
be taken out of the right context.
In many cases, it is very tempting to treat the results of
a urodynamic study rather than the actual condition in the
individual child. Many such therapies will fail, and parents,
doctors, and, most importantly, the children themselves will
end up disappointed.
REFERENCES
For complete list of references log onto www.expertconsult.
com
CHAPTER
10
Hydronephrosis is defined as the dilatation of the urinary collecting system (hydro, from Greek hydor, meaning water;
nephros, meaning kidney; and osis, meaning condition).
It can be associated with either an impediment in antegrade
urinary flow or the retrograde reflux of urine. Among those
kidneys that develop hydronephrosis as a result of some form
of antegrade obstruction of the collecting system, there is a tremendous variability in the natural history observed. Whereas
some kidneys undergo progressive irreversible renal injury,
others remain stable for long periods or even undergo spontaneous improvement. For those hydronephrotic kidneys that
have been identified as needing medical intervention, wellestablished surgical treatment is available. This treatment is
effective in stabilizing or even improving renal function after
successful surgical correction. Given that some hydronephrotic
kidneys are at risk for renal injury and others are not, the current controversy in the clinical management of hydronephrosis lies not so much in how to treat the condition but rather in
the identification of which kidneys require surgical treatment.
There is currently no general consensus on how best to identify those hydronephrotic kidneys that are in need of surgical
repair.
In this chapter, the role of upper urinary tract urodynamics is discussed in the context of the continuing pursuit of
diagnostic tools to better identify hydronephrotic kidneys in
need of surgical treatment. Because upper tract urodynamics pertains primarily to the evaluation of antegrade urinary
flow, the discussion in this chapter is limited to hydronephrosis that results from the impediment of antegrade urinary
flow. Dilatation of the collecting system that results from the
retrograde reflux of urine, or vesicoureteral reflux (VUR), is
addressed in other chapters in this textbook.
Hydronephrosis that results from an impediment in
antegrade urinary flow is a highly complex process at the
physiologic as well as the molecular level. However, it is
fundamentally still a physical problem in which the collecting system has excessively high resistance to urine flow. The
source of the problem is physical in nature, and the solution is
also a physical one, in which the obstructive site is surgically
corrected or mechanically bypassed. Recognizing that hydronephrosis is fundamentally a mechanical drainage issue, the
diagnostic tools used in the evaluation of hydronephrosis can
rely on one of two general principles: direct assessment of
resistance to flow in the collecting system through measurement of physical parameters, including pressure and flow, and
assessment of effects that occur secondary to the increased
resistance to urine flow in the collecting system, including
morphologic, physiologic, and functional alterations. Most of
the currently available diagnostic tools belong to the second
category, demonstrating effects secondary to the increased
resistance to urine flow. For example, imaging modalities
evaluate for dilatation of the collecting system proximal to
*In memory of Leo Fung, a great friend and a dedicated surgeon-scientist,
whose investigative work as a fellow at the Hospital for Sick Children in
Toronto provided the data upon which this chapter is based.
the suspected site of obstruction. Contrast-enhanced studies may reveal delays in excretion of contrast material, and
nuclear medicine renography differential renal function testing assesses for alterations in renal function. Although these
diagnostic tests are noninvasive in nature and play important roles in the assessment of hydronephrosis, they do not
address the fundamental issue of resistance to urine flow in
the collecting system. In contrast, obstruction in the upper
urinary tract can also be diagnosed by a direct demonstration
of increased resistance to urine flow in the collecting system.
Such direct mechanical evaluation of the efficiency of urine
flow in the collecting system constitutes the primary objective
of upper tract urodynamic studies.
Upper tract urodynamics encompasses the study of urinary transport efficiency and pressure-flow characteristics of
the collecting system, originating anatomically at the renal
calyces and ending at the ureterovesical junction (UVJ). In
order to study urodynamic parameters of the upper urinary
tract, access to the collecting system is customarily obtained
via percutaneous nephrostomy needles or tubes; pressure and
flow characteristics of the collecting system can then be evaluated. The diagnostic procedures that evaluate upper tract
urodynamics can in general be referred to as percutaneous pressure-flow studies (Fig. 10-1). The evaluation of upper urinary
tract urodynamics using percutaneous pressure-flow studies
provides unique and valuable physiologic and diagnostic
information. To provide a comprehensive view of the role of
upper tract urodynamics in the evaluation of hydronephrosis, this chapter discusses relevant biomechanical principles,
pathophysiology of renal obstruction, the evolving understanding of a variety of urodynamic parameters, and the relative advantages and limitations of upper tract urodynamics,
comparing percutaneous pressure-flow studies with other
commonly used diagnostic tools.
BIOMECHANICAL PRINCIPLES
In any biologic fluid conduit system, the resistance of the
conduit is directly proportional to pressure divided by flow
(resistance pressure/flow), a modification of the PoiseuilleHagen law, which was originally applied to the flow of newtonian fluids through rigid tubes.1 Based on this principle,
both pressure and flow must be taken into account simultaneously to derive a measurement of resistance within the
conduit. Unlike other diagnostic modalities, pressure-flow
studies are unique in having both the pressure within the collecting system and the rate of fluid flow taken into account
simultaneously. Pressure-flow studies therefore provide the
basis for deriving a true measure of the resistance of the collecting system, which is ultimately the fundamental source of
pathology in hydronephrosis. However, one must be aware
of an important caveat: because the urinary tract is not composed of rigid tubes, the compliance of the tissue must be
taken into account, especially when the degree of dilatation
is extensive.
141
142
part
I: Basics
B
E
C
Figure 10-1 Intravenous pyelogram (A) and ultrasonogram (B) of a 9-month-old boy show right hydronephrosis. There is no ureteral dilatation
(C), and the left kidney is normal (D) by ultrasonography. The patient was further evaluated using a percutaneous pressure-flow study, in which
a percutaneous nephrostomy needle was inserted with the patient in the prone position, and antegrade contrast agent infusion (E) demonstrated
excellent anatomic detail of the right collecting system compatible with ureteropelvic junction obstruction.
chapter
PATHOPHYSIOLOGY
A clear understanding of the compensatory changes that
occur in response to congenital renal obstruction is critical
for the correct interpretation of diagnostic information and
to establish a sound management plan. Whereas the majority
of experimental work on obstruction of the urinary tract has
focused on acute obstruction in mature adult animal models, it
is now increasingly apparent that congenital pediatric hydronephrosis behaves much differently than obstruction in the
adult kidneys. First of all, the physiologic profile of congenital hydronephrosis lacks the dramatic swings in renal blood
flow, glomerular filtration rate (GFR), and RPP seen in acute
obstruction and can even be practically indistinguishable
from that of a normal kidney. These differences are important
in the interpretation of the significance of a positive diuresis
pressure-flow study. Second, congenital hydronephrosis has a
profound influence on the development of the fetal and infant
kidney that is dramatically different from what is seen in the
adult kidney.
143
part
I: Basics
Mean left ureteral pressure (mm Hg)
144
60
Standard error
N=5
55
50
45
40
35
30
25
20
II
III
5.0
4.0
3.0
2.0
1.0
L Ureter obstructed
Control
6.0
evidence supporting this cascade of events is derived primarily from experimental models of acute renal obstruction, it
appears that these events are also at work, at least in part, in
congenital hydronephrosis.
In contrast to acute renal obstruction, congenital hydronephrosis is consistently found to have normal RPP at baseline
hydration levels (Fig. 10-3).5 Because of the complex interactions among stimuli for renal growth and effects on renal injury, kidneys with congenital hydronephrosis can have normal,
decreased, or even increased renal blood flow compared with
normal kidneys.6,7 Therefore, a congenitally hydronephrotic
kidney with physiologically significant obstruction can maintain physiologic parameters difficult to distinguish from those
of a normal kidney at baseline conditions. In order to develop
strategies that will be effective in accurately detecting those
hydronephrotic kidneys that have physiologically significant
obstruction, it is important to identify pathophysiologic features that distinguish the congenital hydronephrotic kidney
with significant obstruction from the normal kidney.
The mode of renal injury in obstructed kidneys may provide an important clue for formulating effective diagnostic
strategies. Although there is much evidence showing that persistently elevated RPP is linked to irreversible renal injury,8,9
there is as yet no conclusive evidence that the direct pressure
effect is harmful to renal cellular elements. On the other hand,
the obstructed kidney with decreased renal blood flow as part
of the compensatory response has been shown to be associated
with an upregulation in vascular endothelial growth factor,
a molecular marker for physiologically significant ischemia
at the cellular level.9 Therefore, the mode of injury for the
8 9 10 11 12 13 14 15 16 17 18
Time in hours
obstructed kidney appears not to result directly from the pressure effects but is instead ischemic in nature, resulting from
the compensatory response in renal blood flow reduction.
From a teleologic point of view, it is unclear what protective
advantage is provided to someone with an obstructed kidney
by these compensatory events. Nevertheless, these compensatory responses remain activated until the RPP is brought back
to normal, even at the expense of decreased renal blood flow,
decreased GFR, and, ultimately, renal cellular ischemia.
Although there is little information on exactly how the congenitally hydronephrotic kidney consistently maintains normal RPP at the baseline hydration state, it seems reasonable to
presume that the response of a congenitally hydronephrotic
kidney to obstruction shares features with that of the acutely
obstructed kidney. In this view, RPP would be maintained at
the expense of compensatory changes in renal blood flow and
GFR, similar to what is seen in the acute obstruction models.
This postulate is supported by the changes in RPP observed in
congenitally hydronephrotic kidneys in response to diuresis,
when compared with normal kidneys.
Whereas it is our experience in a pig model that it is practically impossible to induce an elevation in RPP in normal
collecting systems by instituting a forced diuresis, in children
with congenital hydronephrosis RPP rises from the normal
level of less than 10 cm H2O to as high as 63 cm H2O after
a furosemide-induced diuresis (see Fig. 10-3).5 This pattern
was also observed when rats with congenital hydronephrosis
were compared with normal controls.10 Therefore, it appears
that RPP is normal in a nonhydronephrotic kidney because
the normal collecting system has a huge reserve capacity
chapter
50
40
30
20
10
10
20
30
Time (min)
Figure 10-3 Composite graph of data from a representative group of
patients with hydronephrosis undergoing diuresis pressure-flow studies, in which renal pelvic pressure (RPP) is plotted against time. RPP at
time 0 represents baseline pressure. Intravenous furosemide, 1 mg/kg
up to a maximum of 10 mg, was given at time 0, and RPP was monitored for 30 minutes. The furosemide-induced diuresis constituted the
sole form of fluid challenge, and no infusion of fluid took place during
these studies. In our experience studying more than 55 hydronephrotic
kidneys to date (data not all plotted on this graph in order to maintain
clarity), it has been consistently observed that the prediuresis baseline
RPPs remain relatively low and do not exceed 10 cm H2O. The highest RPP that we have recorded after furosemide-induced diuresis was
63 cm H2O, which was observed in a patient with ureteropelvic junction (UPJ) obstruction, and no contrast material was seen draining
across the UPJ throughout the entire pressure-flow study.
145
potential of the hydronephrotic kidney ranging from complete nonfunction, as in the case of total dysplasia, to entirely
normal renal function indistinguishable from that in normal
kidneys. More interestingly, the possibility has been raised
that congenital hydronephrosis may result in a kidney that
functions at a level in excess of the normally expected range.6
This phenomenon, termed supranormal differential renal function, describes a unilaterally hydronephrotic kidney that has a
significantly higher differential renal function than the normal
contralateral mate. The significance of these findings remains
unclear.
Several clinical series have evaluated the phenomenon of
supranormal differential renal function. Fung and coworkers7
studied 16 patients who had a differential renal function of 53%
or higher in the unilateral hydronephrotic kidney. Whereas
the supranormal differential renal function phenomenon
appeared convincing based on the findings of diethylenetriamine penta-acetic acid (DTPA) nuclear renography (mean,
58.3%; range, 53% to 66%), the differential renal function
observed was less dramatic when these same patients were
evaluated using dimercaptosuccinic acid (DMSA) nuclear
renography (mean, 51.1%; range, 42% to 57%). The results
from the DMSA renal scans were not significantly different
from the intuitively expected normal differential function of
50%. Therefore, the phenomenon of supranormal differential
function appeared to be an artifact specific to DTPA nuclear
renal scans, presumably secondary to the accumulation of
background activity in the region of the dilated renal pelvis
and calyces which prevents an accurate assessment of the true
differential renal function. This confounding variable would
not apply to DMSA renal scans, in which background activity
is less of an issue.
Contrary to these findings, Capolicchio and associates14
reported a similar study on 15 patients, defining supranormal
differential renal function as greater than 55%. The mean
differential renal function in these 15 patients was 55% 4%
based on DTPA renal scan (range, 46% to 61%) and 55% 3%
based on DMSA renal scan (range, 51% to 62%). The authors
concluded that there was no significant difference between the
differential renal function assessments performed by DTPA
and by DMSA renal scans and that supranormal differential
renal function was a real phenomenon. A report by Kim and
colleagues15 concluded, similarly, that supranormal differential renal function was a real phenomenon. Fourteen patients
had differential renal function assessments by DTPA renal
scan and were further assessed by split urinary collection and
split creatinine clearance measurements. Supranormal differential renal function was confirmed by split creatinine clearance in 2 patients and was shown to be a spurious finding in 1.
DTPA renal scans had a tendency to overestimate differential
renal function when compared with split creatinine clearance,
especially for those kidneys that had a significantly reduced
renal function.
From these clinical series, it appears that supranormal
differential renal function is a real phenomenon in unilateral
hydronephrosis. It also seems that DTPA renal scans have a
tendency to overestimate differential renal function, compared
with DMSA renal scans or split urinary creatinine clearance
measurements. Experimental work in fetal sheep by Peters
and Fung and their associates16,17 provided further evidence
to support the validity of supranormal differential renal function in unilateral hydronephrosis. Partial unilateral ureteral
obstruction was observed to produce hydronephrotic kidneys
that had a larger renal weight than their contralateral normal
mate or age-matched controls. DNA, RNA, and protein contents were analyzed to distinguish hyperplasia from hypertrophy. An increase in DNA content signified a hyperplastic
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I: Basics
Nephrostomy Access
The invasive nature of pressure-flow studies stems from the
need to obtain direct access to the lumen of the collecting system in order to provide a means to measure the fluid pressure
within the system. In spite of the astounding technological
advances occurring in the field of biomedical sciences, there
is as yet no truly noninvasive way to measure fluid pressure.
Fluid pressure can be measured by one of two methods: (1)
by direct access to a fluid column that comes into continuous contact with the site of interest, as in the typical pressure
transducer used in urodynamics, arterial line pressure, central
venous pressure, cerebrospinal fluid, and other similar fluid
pressure monitoring systems, or (2) by applying circumferential
compression of variable pressure to the structure of interest
the pressure at which flow resumes within the structure of
interest is equivalent to the fluid pressure within (the same
principle that is behind blood pressure measurements using
a blood pressure cuff). This second method is not applicable
to pressure-flow studies, because circumferential compression
of the collecting system cannot be easily achieved. Therefore,
pressure-flow studies of the upper urinary tract remain invasive in nature, requiring direct access to the lumen proximal to
the suspected site of obstruction. For pragmatic reasons, this
access is generally established via percutaneous hollow needles or angiocatheters or by an indwelling nephrostomy tube.
For technical reasons that are further addressed in the discussions of individualized infusion pressure-flow studies, it
is advantageous to have two separate nephrostomy accesses
to the renal pelvis, one for pressure monitoring and one for
fluid infusion. For elective pressure-flow studies, insertion of
two 22-gauge 2-inch angiocatheters under ultrasonographic
guidance and fluoroscopic monitoring by our pediatric interventional radiologist has been found to be effective and safe.
For older children, the 2-inch angiocatheters may be too short.
In such cases, 22-gauge spinal needles have been found to be
effective. Whereas percutaneous nephrostomy accesses can be
safely established under local anesthesia in adults, we routinely employ general anesthesia for such procedures in children. Bilateral percutaneous pressure-flow studies can also
be performed safely simultaneously, with two nephrostomy
accesses established for each side (Fig. 10-4).
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147
Table 10-1 Current Pressure-Flow Study Protocol at the University of Massachusetts Memorial Medical Center,
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Figure 10-4 A, With the patient in the prone position and under general anesthesia, two angiocatheters or needles are inserted into the renal
pelvis with ultrasonographic guidance. B, With the nephrostomy accesses in place, antegrade infusion of contrast medium verifies satisfactory
nephrostomy placement. C, Bilateral percutaneous pressure-flow studies can also be performed safely simultaneously, with two nephrostomy
accesses inserted in each side. In this 112-year-old boy, the pressure-flow study indicated significant ureteropelvic junction obstruction bilaterally.
He is currently well after successful staged pyeloplasties.
collecting system pressure. There are a number of studies, both
experimental and clinical, that help answer this question.
In the rat model, it was found that the proximal tubular,
intratubular, and peritubular capillary pressures remain constant until the collecting system pressure exceeds the normal
tubular pressure. In this context, the normal proximal tubular
pressure was established to be 14.1 0.5 cm H2O in the rat.19
Human data have been shown to be in keeping with these
results. In the human, intrarenal arterial resistance increases
acutely once the RPP rises to greater than 14 cm H2O.20
Furthermore, Fichtner and coworkers10 showed, in the congenital hydronephrosis rat model, that the hydronephrotic
kidneys with an empty bladder had a mean RPP of 14.1
1.6 cm H2O under very high urine output, and the mean RPP
increased further if the bladder was filled. Conversely, the
normal control kidneys with the bladder empty resulted in a
mean RPP well below 14 cm H2O, even with very high urine
output; additionally, with the bladders filled to capacity, the
highest mean RPP recorded was only 13.2 1.6 cm H2O. These
lines of evidence all indicate that 14 cm H2O is the upper limit
of normal RPP, above which undesirable physiologic changes
begin to occur.
Whereas these results indicate that RPPs greater than 14 cm
H2O produce undesirable physiologic changes, additional evidence indicates that elevation in RPP leads to acute and irreversible renal injury within a relatively short time span (<24
hours). In a porcine model in which RPP was kept constantly
elevated at between 20 and 40 cm H2O, the urinary level
of N-acetyl--d-glucosaminidase was found to be elevated,
indicative of acute renal tubular cell membrane disruption.21
Similar experiments also demonstrated that elevation in RPP
led to acute onset of apoptotic cell death, suggestive of a component of irreversible injury.8 Such acute tubular disruption
and apoptotic cell death were further found to be associated
with decreased renal blood flow and alterations in vascular
endothelial growth factor messenger RNA levels, providing
chapter
160
CCr (mL/min/1.73 m2 surface area)
149
+2 SD
120
80
2 SD
40
3
Age (yr)
Normal adult
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Table 10-2 Height, Weight, and Glomerular Filtration Rate (GFR) Values Obtained from Population Nomograms*
Height (cm)
Age
(Yr)
10th
Percentile
90th
Percentile
4 wk
50.5
56.5
8 wk
53.0
60.0
12
wk
55.5
16
wk
Weight (kg)
10th
Percentile
90th
Percentile
10th
Percentile
90th
Percentile
3.3
4.8
0.210
0.260
3.9
5.6
0.225
0.290
63.0
4.6
6.6
0.250
58.0
66.0
5.3
7.5
20
wk
60.0
68.0
5.9
0.5
62.5
71.0
0.6
64.5
0.7
66.5
90th
Percentile
GFR (mL/
min/1.73 m2)
Maximum Physiologic
Urine Output per
Kidney (mL/min)
10th
Percentile
90th
Percentile
70
0.85
1.05
80
1.04
1.34
0.320
90
1.30
1.66
0.275
0.350
98
1.56
1.98
8.3
0.295
0.375
105
1.79
2.28
6.6
9.4
0.320
0.405
108
2.00
2.53
73.0
7.1
10.0
0.340
0.430
111
2.18
2.76
75.0
7.5
10.5
0.355
0.445
114
2.34
2.93
0.8
68.0
76.5
7.8
10.9
0.360
0.460
116
2.41
3.08
0.9
69.5
78.5
8.1
11.3
0.380
0.480
118
2.59
3.27
74.0
80.0
8.4
11.7
0.400
0.490
120
2.77
3.40
80.0
90.0
10.5
14.5
0.470
0.630
138
3.75
5.03
88.0
99.0
12.5
17.0
0.540
0.660
144
4.49
5.49
94.5
107.0
13.0
19.0
0.560
0.730
144
4.66
6.08
101.0
114.5
14.5
21.5
0.630
0.810
144
5.24
6.74
107.0
121.0
17.0
24.5
0.700
0.890
144
5.83
7.41
112.0
128.0
19.0
28.0
0.760
0.980
144
6.33
8.16
117.5
133.5
21.0
31.0
0.820
1.050
144
6.83
8.74
123.0
139.0
23.0
35.0
0.870
1.150
144
7.24
9.57
10
128.0
144.5
25.0
40.0
0.930
1.260
144
7.74
10.49
11
133.5
150.0
27.5
44.5
1.000
1.360
144
8.32
11.32
12
138.5
157.0
30.0
51.0
1.070
1.480
144
8.91
12.32
13
143.5
164.0
32.5
59.5
1.140
1.640
144
9.49
13.65
14
152.0
169.0
39.5
64.5
1.300
1.740
144
10.82
14.48
15
154.0
177.0
47.0
68.0
1.420
1.830
144
11.82
15.23
16
154.5
181.0
48.5
71.5
1.450
1.900
144
12.07
15.82
17
154.5
182.5
48.5
73.5
1.450
1.940
144
12.07
16.15
18
154.5
183.0
49.0
74.5
1.460
1.960
144
12.15
16.31
19
154.5
183.0
49.0
75.0
1.460
1.970
144
12.15
16.40
*The calculated maximum physiologic urine outputs are provided as rough guidelines for determining the individualized pressure-flow study infusion rate.
Note: The maximum urine output estimates tabulated here are expressed as the infusion rate per kidney, representing half of the total calculated urine output estimate. For patients with a solitary kidney, the infusion rate may need to be increased in proportion to its compensatory increase in GFR.
chapter
For proponents of the constant-pressure perfusion alternative, the lack of information regarding normal pressure-flow
relationships has also been problematic.26-28 Pending further
validation, it would appear logical that the upper limit of
normal RPP of 14 cm H2O should be applicable regardless of
the form of pressure-flow study used. Similarly, the optimal
flow challenge to the collecting system as calculated in the
individualized infusion pressure-flow study (the estimated
maximum physiologic urine output) should provide physiologically relevant guidelines as to what amount of urine flow
should be anticipated across the suspected site of obstruction.5
In other words, when the RPP is brought to the physiologically tolerable upper limit (14 cm H2O), a resultant flow rate that
is greater than or equal to the calculated estimate of the maximum physiologic urine output (see Table 10-2) is indicative
of efficient urine transport. Conversely, a resultant flow rate
less than the calculated estimate of the maximum physiologic
urine output indicates that the collecting system is incapable
of handling maximal physiologic diuresis without raising the
RPP above the upper limit of normal.
When performed using the pressure-flow guidelines as
established for the individualized infusion pressure-flow
study,5 the constant-pressure perfusion variation should theoretically generate comparable results. However, we do not
employ the constant-pressure perfusion method in the evaluation of our patients, primarily for two reasons. First, the exact
measurement of the rate of flow across the suspected site of
obstruction is difficult. Measurement of flow by timed (1- to
2-minute) volumes28 entering the bladder does not provide
continuous monitoring that would reflect real-time changes
(as one would obtain from conventional RPP monitoring),
and it also fails to exclude the urine flow contribution from
the contralateral ureter. Second, we have now identified a
substitute for external fluid infusion, namely a pharmacologically induced diuresis. As discussed in the next section, this
modification both appears to be more physiologic and reveals
additional diagnostically important information. Because the
constant-pressure perfusion study is conceptually not adaptable to accommodate an induced diuresis, the concept is currently not applicable to our pressure-flow study protocol.
151
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153
D
Figure 10-6 A male patient was identified as having right hydronephrosis compatible with ureteropelvic junction (UPJ) obstruction, as shown
by an intravenous pyelogram (A). Ultrasonography demonstrates marked right hydronephrosis with significant thinning of the renal cortex (B)
and a normal left kidney (C). A percutaneous pressure-flow study was performed when the patient was 7 weeks of age. D, A right antegrade
nephrostogram with the patient in the prone position is shown. The pressure-flow study was negative for significant obstruction; the peak renal
pelvic pressure was only 5 cm H2O, well below the upper limit of normal (14 cm H2O), under both furosemide-induced diuresis and a supraphysiologic infusion rate of 200%. Despite significant cortical thinning and pelvicaliectasis, the patient was managed with an observational approach
in view of the negative pressure-flow study. His initial right differential renal function of 30% spontaneously improved to 52% after 1 year and
further increased to 58% at his 2-year follow-up. It is unclear why the differential renal function increased to beyond 50%, but nevertheless the
initial negative pressure-flow study was ineffective in excluding ongoing significant UPJ obstruction in this case.
part
I: Basics
154
30
20
10
10
Bladder pressure (cm H2O)
20
Figure 10-7 Diuresis pressure-flow studies were performed in 19 hydronephrotic kidneys, with the bladders initially kept empty by an indwelling catheter. Once optimal diuresis was induced and peak renal
pelvic pressure (RPP) was reached, the intravesical pressure was then
systematically varied by filling the bladder. As the intravesical pressure increased from 0 to 10 cm H2O and then to 20 cm H2O, it was observed that the RPP did not always increase linearly. Whereas some of
the kidneys exhibited RPPs that remained constant despite alterations
in intravesical pressure, others exhibited RPPs that increased rapidly
and disproportionately to the increase in intravesical pressure.
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155
Figure 10-8 Voiding cystourethrogram in a 3-year-old girl shows vesicoureteral reflux (VUR) into a nondilated left ureter compatible with
grade II reflux (A), and yet the renal pelvis and calyces are disproportionately severely dilated (B). This discrepancy in pelvicaliectasis that exceeds
the degree of dilatation usually associated with low-grade reflux suggests the concomitant presence of ureteropelvic junction (UPJ) obstruction.
A percutaneous diuresis pressure-flow study confirmed high-grade left UPJ obstruction. After the administration of intravenous furosemide, the
left renal pelvic pressure rose to 63 cm H2O, the highest value we have recorded to date. There was no efflux of contrast material across the left
UPJ, compatible with a Dietl crisis-type intermittent high-grade UPJ obstruction induced by diuresis. A left antegrade nephrostogram with the
patient in the prone position is shown C.
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I: Basics
50
n = 43
40
30
20
10
2
3
4
5
Time (min)
Figure 10-9 Pressure decay curves show the decline in renal pelvic pressure over time after cessation of nephrostomy infusion in 43
patients.
50
n = 25
Renal pelvic pressure (cm H2O)
n = 18
40
30
20
10
40
30
20
10
0
0
1
2
3
4
5
2
3
4
5
Time (min)
Time (min)
B
A
Figure 10-10 Pressure decay curves (renal pelvic pressure [RPP] versus time) are separated into two groups based on the individualized pressure-flow study results. The group with efficient urine transport according to the individualized pressure-flow study (peak RPP 14 cm H2O)
had a mean pressure decay T of 0.36 0.22 minutes (A), whereas the group with inefficient urine transport (peak RPP >14 cm H2O) had a mean
pressure decay T of 3.47 2.77 minutes (B).
0
chapter
more compliant system. Similarly, the volume of the proximal collecting system also plays an important role in the
pressure decay dynamics. Consider the situation in which
two collecting systems have the same outflow resistance but
one has a larger renal pelvis than the other: even though their
pressure decay curves would begin with drainage at identical rates, the larger collecting system would drain a smaller
percentage of its total volume during any given period and
would have a slower pressure decay as a result.
These theoretical considerations demonstrate that the
pressure decay T is not a specific measurement of outflow
resistance but is in part determined by the compliance and
volume of the collecting system. It is therefore not surprising that some efficient collecting systems had relatively high
pressure decay T values whereas some inefficient systems
had relatively short pressure decay T values. Consequently,
in spite of the overall strong correlation between urine transport efficiency and the pressure decay T, the pressure decay
T should not be used in isolation as the sole diagnostic criterion for physiologically significant hydronephrosis. If used
in conjunction with other diagnostic modalities, however, the
pressure decay T provides an objective, quantitative measure of the relative tendency for elevated RPPs to persist.35
In addition to the differences in renal pelvic compliance,
the anatomic configuration of the UPJ also plays a role in
pressure decay. In three of the pressure decay curves, the
pattern of RPP decline showed two distinctly different
phases. The decline in RPP was initially very slow, with the
RPP remaining relatively high for several minutes after the
infusion was stopped. Once the RPP was less than approximately 25 cm H2O, however, the remainder of the pressure decay curve declined to normal exceedingly rapidly.
157
Figure 10-11 This 6-year-old girl was initially misdiagnosed as having a chronic gastrointestinal disorder when she presented with recurrent
abdominal pain, nausea, and vomiting. A, When she underwent a percutaneous pressure-flow study to evaluate her left hydronephrosis, contrast
material was seen to drain across the ureteropelvic junction (UPJ) into the proximal ureter early in the study. B, As the renal pelvis became progressively more distended, the drainage of contrast material across the UPJ ceased entirely. Renal pelvic pressure continued to rise sharply, and
the pressure-flow study was terminated at 40 cm H2O. No drainage of contrast material was seen across the UPJ until fluid was aspirated out of
the renal pelvis to decompress the grossly distended collecting system. C, When the renal pelvis dimension returned toward its initial baseline,
drainage across the UPJ resumed with a gush of contrast material into the proximal ureter. This pattern of intermittent high-grade obstruction was
presumed to be secondary to a kink at the UPJ that was accentuated by overdistention of the renal pelvis. Her recurrent abdominal pain, nausea,
and vomiting episodes (Dietl crises) were successfully corrected by a dismembered pyeloplasty.
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Figure 10-12 A and B, Antegrade nephrostograms can provide excellent anatomic detail, such as in this 5-year-old boy in whom there are multiple anomalies at the ureteropelvic junction, midureter, and ureterovesical junction levels. C, In a 4-year-old girl, partial ureteral duplication is
identified.
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159
UVJ obstruction (see Fig. 10-12); and sequential hypoperistaltic segments involving the UPJ and the proximal ureter like a
string of beads (Fig. 10-14).
Based on the principle that elevation in RPP constitutes the
initial physical stimulus triggering the obstruction-induced
compensatory cascade (see Pathophysiology), it would be
logical to conclude that only the pressure effects directly
perceived by the renal parenchyma have an impact on subsequent alterations in renal physiology. Thus, the collecting
system pressure immediately adjacent to the renal parenchyma would ultimately determine the effects of obstruction
on the kidney, regardless of whether one level or multiple
levels of ureteral obstruction are present. In other words, RPP
as recorded in a typical percutaneous pressure-flow study
should be equally applicable to situations in which there are
multiple sites of obstruction in the collecting system, provided
there is no significant obstruction proximal to where the RPP
is recorded, such as infundibular or calyceal stenosis.
Whereas a percutaneous pressure-flow study should be
equally applicable to single-level and multiple-level ureteral
obstructions, the result of the study is primarily helpful only
in determining whether there is physiologically significant
obstruction present as a result of the combined effect of all levels of ureteral obstruction. The alterations observed in RPP do
not allow us to selectively discern the contribution from each
individual level of obstruction to the overall obstructive effect.
Nevertheless, observations of the antegrade transit of contrast
material and ureteral peristalsis by real-time fluoroscopy can
provide important clues to guide the clinician in formulating
an appropriate treatment plan. For example, if contrast material can be seen passing through a proximal site of obstruction at low RPP but it is held up at a more distal obstructive
site with subsequent progressive elevation in RPP, the more
distal site constitutes the more significant site of obstruction.
Figure 10-14 Retrograde pyelogram in a 3-month-old patient demonstrates right hydronephrosis and a right ureter with apparent
anomalies at multiple levels of the ureter.
Conversely, if a proximal level of obstruction is seen to produce a holdup of contrast material along with an elevation in
RPP, and any contrast material that transits across is promptly
cleared by the more distal sites of obstruction, then the most
proximal site constitutes the most significant level of obstruction. In this situation, however, repair of the proximal site may
increase the rate of urine flow to the more distal obstructive
sites. A previous seemingly innocuous ureteral narrowing
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161
References
For complete list of references log onto www.expertconsult.com
CHAPTER
11
Magnetic resonance imaging (MRI) is emerging as a powerful diagnostic tool for imaging of the pediatric genitourinary
tract and will probably become the primary tool for comprehensive evaluation of urinary tract anomalies. Despite their
widespread use, ultrasonography, renal scintigraphy, computed tomography (CT), and intravenous urography (IVU)
have inherent shortcomings. Ultrasonography is an accurate
and cost-effective method of diagnosing urinary tract dilatation, but it is operator dependent, does not allow visualization of the middle and lower ureter, and does not provide
functional information about the kidneys. Renal scintigraphy
provides functional assessment of the kidneys but supplies
little anatomic information. Although CT and IVU provide
both anatomic and qualitative function evaluation, they rely
on both ionizing radiation and nephrotoxic contrast agents.
Voiding cystourethrography (VCUG) provides information
regarding vesicoureteral reflux (VUR) and the anatomy of
the lower urinary tract. MRI has intrinsically greater spatial and contrast resolution compared with other modalities,
and, with the advent of new imaging strategies, it can combine this high spatial and contrast resolution with excellent
temporal resolution. The use of intravenous contrast agents
such as gadolinium-diethylenetriamine penta-acetic acid (GdDTPA) enables one to assess renal perfusion, concentration,
and excretion.
Since 2001, we have developed and refined our protocols
for evaluating the urinary tract in children using magnetic
resonance urography (MRU).1-5 In addition to high-resolution
anatomic images of the entire urinary tract, functional information about the concentration and excretion abilities of the
individual kidneys can be obtained. By scanning dynamically
after injection of a contrast agent, the signal changes related to
perfusion, concentration, and excretion of the contrast agent
can be sequentially evaluated in both the renal cortex and the
medulla. Pelvicalyceal and ureteric anatomy is assessed using
both T2-weighted and contrast-enhanced images. The functional information obtained routinely includes renal transit
time (RTT) calculation, signal intensity versus time curves,
differential renal function (DRF) calculation, and estimation
of individual kidney glomerular filtration rate (GFR). The
improved anatomic and functional information obtained with
MRU provides insights into the pathophysiology of urinary
tract disorders. As a result, it is likely that MRU will replace
renal scintigraphy in the evaluation of renal tract disorders in
children in the near future.
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Figure 11-1 Three-dimensional gradient echo sequences. Magnetic resonance urogram in a 3-month-old boy with antenatal hydronephrosis
and nonobstructive megaureter. Images A through C are maximum intensity projections derived from three separate time points; D through F
show the same slice from each of the three volume acquisitions. A and D show the cortical phase; B and E were acquired 60 seconds later and
demonstrate enhancement of both cortex and medulla, with the signal intensity of the medulla exceeding that of the cortex. C and F were acquired
120 seconds after the vascular phase and show excretion into the calyces, renal pelves, and ureters.
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Figure 11-2 Magnetic resonance urograms of renal dysplasia. A, T1-weighted contrast-enhanced images demonstrate nonfunction of the right
multicystic dysplastic kidney. Differential function is 100% on the left. B, Coronal T2-weighted image again demonstrates right multicystic dysplastic kidneys and apparently normal left kidney. C, Axial high resolution T2-weighted images show multiple cysts of varying sizes in the right
kidney with no normal parenchyma. The left kidney is also dysplastic with multiple, small peripheral cysts and loss of the normal corticomedullary differentiation. D, T2-weighted maximum intensity projection (MIP) shows multicystic dyplastic kidney as well as small caliber proximal
ureter. Multiple cysts are more apparent in the left kidney on MIP image.
separate the boundaries between the upper- and lower-pole
moieties by delineating the column of cortex separating the
upper and lower poles, so that the relative contributions of the
upper and lower poles can be estimated.
Our initial approach to analyzing the dynamic data was
to segment the cortex and medulla and obtain time-intensity
curves for each of these regions.1,2,4 The resulting signalversus-time curves were then converted to relative signalversus-time curves by calculating (St S0)/S0, where St is the
signal at a given time point and S0 is the mean precontrast
signal, for each time point. The relative signal has a linear
relationship with contrast agent concentration over a limited
range of concentrations and compensates for spatial variations in the background signal, facilitating comparison of the
two kidneys.2 Several characteristic features are seen in the
curves. The cortex shows an initial peak caused by concentrated contrast material in the vasculature, and a subsequent
peak is seen at a later time point due to the arrival of contrast
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Figure 11-3 A 6-month-old boy with ureteropelvic junction (UPJ) obstruction. A, T2-weighted maximum intensity projection (MIP) shows mor-
phologic UPJ on the left with transition to a normal-sized ureter. The T2-weighted images highlight static fluid collections and are particularly
useful in poorly functioning or markedly hydronephrotic systems. B, Postcontrast MIP again demonstrates typical morphologic features of UPJ
obstruction. The postcontrast images are T1 weighted, and the signal intensity is determined by the excreted contrast agent. The postcontrast MIPs
tend to have greater spatial resolution.
Figure 11-4 Calculation of differential renal function (DRF) using renal volumes. A, Medullary phase source image at the time point used for
calculation of DRF. The time point chosen occurs when there is symmetric enhancement of the renal cortex and medulla immediately before excretion of contrast into the collecting systems. B, In the maximum intensity projection image, the enhancement of the kidney allows easy separation
from background tissues, so that the volume calculation can be generated semiautomatically. The DRF was calculated to be 51% on the left and
49% on the right.
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6.00
2.50
5.00
2.00
DS(t)/b(t)
Relative signal
4.00
3.00
1.50
DS(t)/b(t) L
DS(t)/b(t) L
DS(t)/b(t) R
DS(t)/b(t) R
1.00
2.00
1.00
0.00
1.00
2
0.50
Aorta
L Cx
R Cx
L kidney
R kidney
0.1
0.2
0.3
0.4
0.5
Integral[b(t)]/b(t)*V
ESTIMATED GFR DATA FROM CLINICAL PATIENTS
10
120.00
Time (minutes)
100.00
Estimated SK GFR (mL /min)
80.00
60.00
40.00
20.00
0.00
10
15
20
Age (years)
B
Figure 11-6 A, The Patlak plot is used as an index of the individual
kidney glomerular filtration rate (GFR). The slope of each plot reflects
the GFR of each kidney (9.5 mL/min on the left and 10.4 mL/min
on the right). The Y intercept represents the fractional blood volume
of each kidney. When corrected for body surface area, these values
become 42 and 46 mL/min, respectively, so that the total GFR index is
88 mL/min. B, Plot of GFR based on the Patlak plot versus age in our
clinical population. SK, single kidney.
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with Society of Fetal Urology (SFU) grade III and most of those
with grade IV hydronephrosis on confirmatory sonography.
We have used MRU to evaluate more than 1500 children with
hydronephrosis. MRU has been found to be particularly useful
for the diagnosis and evaluation of a wide range of obstructive
urinary tract anomalies, including ureteropelvic junction (UPJ)
(Fig. 11-8) and ureterovesical junction obstruction, megaureters, and ectopic ureters. Furthermore, we have used the technique to evaluate the surgical results of pyeloplasty.17 After
correction of UPJ obstruction, DRF, RTT, and Patlak scores
(GFR index) improved significantly, further validating the use
of MRU parameters for predicting obstruction.
Although MRI has been dismissed as a poor procedure for
the diagnosis of urolithiasis, primarily because of the radiolucency of calculi, excretory MRU has demonstrated sensitivity
between 90% and 100% in patients with stones.21-23 In addition to excellent anatomic characterization of the parenchyma
and collecting system, the unique ability of MRU to provide
quantitative functional information such as DRF, RTT, and
GFR (Patlak score) makes it the most comprehensive of the
currently available diagnostic procedures in the assessment of
upper urinary tract dilatation.
Figure 11-8 Ureteropelvic junction obstruction with delayed and dense nephrogram. A, T2-weighted maximum intensity projection (MIP)
showing marked hydronephrosis with transition at ureteropelvic junction. B, T1-weighted MIP image 5 minutes after contrast administration
showing delayed dense nephrogram on the right. C, T1-weighted MIP image 15 minutes after contrast administration showing contrast into the
calyceal system but not yet filling the renal pelvis.
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Figure 11-9 Duplex left kidney with ectopic upper-pole ureter to urethra. A, Coronal T2-weighted image showing duplex left kidney with
hydroureteronephrosis of the upper pole. B, T1-weighted maximum intensity projection (MIP) image 1 minute after contrast administration
showing normal parenchymal enhancement of the right kidney and left lower pole. There is little enhancement of the upper pole on the left.
C, T1-weighted MIP image 10 minutes after contrast administration showing minimal excretion into the upper pole moiety. Note spiral appearance of lower pole ureter as it intertwines with dilated upper pole ureter. D, Oblique T2-weighted image showing the insertion of the upper pole
ureter ectopically into the urethra.
the ureter in poorly functioning moieties.28 Additionally, Riccabona and colleagues29,30 demonstrated MRU to be superior
to conventional imaging procedures in the assessment of children with a suspected single functional kidney, through better characterization of the contralateral dysplastic or ectopic
moiety.
Evaluation of Hydronephrosis
The most common indication for MRU has been the evaluation of pediatric hydronephrosis. In children, hydronephrosis is usually a result of chronic partial obstruction, typically
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Figure 11-10 T2-weighted (A) and postcontrast (B) magnetic resonance urograms in a child with autosomal dominant polycystic kidney disease.
C, Multiple cysts associated with tuberous sclerosis complex.
Figure 11-11 Duplex left kidney with large intravesical ureterocele. A, Coronal T2-weighted image showing fluid-filled ureterocele (arrow)
in the bladder. B, T1-weighted maximum intensity projection image 10 minutes after contrast administration showing duplex left kidney with
contrast in both ureters as well as filling defect in bladder representing the urine-filled ureterocele (arrow).
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The early vascular phase of the MRU provides a detailed evaluation of the vascular system. Anomalies of the renal vessels (e.g.,
multiple renal arteries, crossing vessels) are easily identified
(Fig. 11-13). The presence of such anomalies does not necessarily implicate the vessels as the cause of obstruction, however. In
addition, high-insertion ureter may lead to intermittent obstruction and may not be seen on MRU when obstruction is absent.
Vesicoureteral Reflux
VCUG has long been the established gold standard for the
detection of VUR. Despite its ability to provide excellent visualization of the entire urethra and to assess the presence and
grade of VUR, conventional VCUG involves direct radiation
Figure 11-12 Bilateral primary obstructing megaureters seen on T1-weighted (A) and T2-weighted (B) magnetic resonance images.
Figure 11-13 Images of left ureteropelvic junction obstruction on T2-weighted magnetic resonance urogram (A), showing poor excretion on
T1-weighted images (B) and associated with a crossing vessel (C).
chapter
exposure to the gonads. Magnetic resonance voiding cystourethrography (MRVCU) was first described in 1992 but did
not become a potential alternative until the advent of near
real-time magnetic resonance fluoroscopy.36 MRVCU is composed of T1-weighted images of the entire genitourinary tract
obtained before the transurethral administration of Gd-DTPA,
as well as images obtained during and after micturition. Rodriguez and coworkers37 performed MRVCU before excretory
MRU and demonstrated reflux in four of five children with
known VUR. In another study38 using conventional VCUG as
the standard reference, MRVCU was found to have a sensitivity of 76% and a specificity of 90% in the detection of VUR.
In addition, renal scarring was detected in 13 of 17 kidneys
confirmed by nuclear scintigraphy. Therefore, MRVCU allows
for an accurate determination of VUR and reflux nephropathy.
Limitations may include difficulty voiding in the supine position for some patients and incomplete voiding in some infants
and young children due to sedation. Although the procedure
is technically feasible, it seems unlikely that MRVCU will gain
widespread acceptance.
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MRI has the advantage over DMSA in its ability to differentiate between pyelonephritis and renal scarring. On MRI, renal
scarring is visualized as an area of focal parenchymal loss.
Using DMSA as the reference standard, gadolinium-enhanced
T1-weighted MRI was found to have 100% sensitivity and
78% specificity for the detection of renal scarring in a group
of 24 children with spina bifida.43 More recently, however,
Kavanagh and associates40 suggested that a T1-weighted MRI
sequence without gadolinium enhancement was sufficient for
detection of scarred kidney, demonstrating 77% sensitivity and
87% specificity, compared with 82% and 91%, respectively, for
the gadolinium-enhanced scan. We have used the technique
of inversion recovery sequencing to differentiate between
acute pyelonephritis and renal scarring and believe this to be
a highly sensitive modality. In this way, renal scarring may be
accurately detected by a rapid (<5 minutes) examination without the use of intravenous contrast or ionizing radiation.
CONCLUSION
MRU has the potential to revolutionize the imaging of the
urinary tract in children, providing an unprecedented level
of anatomic information combined with quantitative functional evaluation of each kidney. MRU can now provide useful
assessment of obstructive uropathy and may provide predictive information about which children will benefit from surgery. Further technical developments in the field will produce
greater insights into the pathophysiology of not only urologic
disorders but also disorders of the kidney itself.
The ability of MRI to provide detailed information regarding anatomy, function, and drainage in a single study without
the use of ionizing radiation sets it apart from conventional
imaging techniques. As an additional advantage, it can be
used in patients with contrast allergy or impaired renal function. MRI is likely to emerge as the modality of choice for
children with complex genitourinary pathology, high-grade
hydronephrosis, suspected single functional kidney, or diagnostic dilemmas regarding pyelonephritis. Finally, MRI should
be thought of as a problem-solving tool to define anatomy and
function when conventional methods fall short.
REFERENCES
For complete list of references log onto www.expertconsult.com
S E C T I O N
SPECIAL CONSIDERATIONS
Chapter
12
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Table 12-1 Urinary Tract Malformations in Mice with Mutations of Defined Genes*
Gene Symbol
Gene Name
Associated Malformations
Renal hypoplasia
Brn1
Brain 1
Emx2
Empty spiracles 2
Renal agenesis
Foxc1
Forkhead box c1
Duplex kidney
Foxc2
Forkhead box c2
Renal hypoplasia
Foxd1
Forkhead box c2
Fused kidneys
Hnf1b
Hoxa11/Hoxd11 ()
Lim1
Lim homeobox 1
Absent kidneys
Lmx1b
N-Myc
Myelocytomatosis-related oncogene
Hypoplastic mesonephros
Pax2
Paired box 2
Pod1
Podocyte 1
Rara/Rarb2 ()
Sall1
Renal agenesis
Tshz3
Six1
Renal agenesis
Wt1
Wilms tumor 1
Angiotensinogen
Agtr1a/Agtr1b ()
Hypoplastic papilla
Agtr2
Angptl2
Angiopoietin 2
Bmp4
Bmp7
Renal dysplasia
Efnb2
Ephrin b2
Persistent cloaca
Fgf7
Renal hypoplasia
Gdnf
Renal agenesis
Gremlin
A Bmp antagonist
Renal agenesis
Notch2
Pdgfrb
Ret
Robo2
Duplex kidneys
Shh
Sonic hedgehog
Slit2
Duplex kidneys
Spry1
Duplex kidneys
Wnt4
Renal hypoplasia
Wnt11
Renal hypoplasia
Vegf
(Continued)
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Table 12-1 Urinary Tract Malformations in Mice with Mutations of Defined Genescontd
Gene Symbol
Gene Name
Associated Malformations
Fraser syndrome 1
Renal agenesis
Frem2
Itga8
Integrin 8
Dysplastic kidneys
Lamab2
s-Laminin/laminin 2
Nephrotic syndrome
Nephrin
Cox2
Cyclooxygenase 2; enzyme
Renal hypoplasia
Eya1
Eyes absent 1
Renal agenesis
Hs2st
Renal agenesis
Mpv17
Glomerulosclerosis
nNOS
Pkd1
Polycystin 1
Pkd2
Polycystin 2
UpII
Uroplakin II
UpIII
Uroplakin III
*Unless otherwise stated, the malformations occur in null mutants with no gene activity; in other cases, the disease occurs in mice with one copy of the gene
ablated (i.e., heterozygous mice). A dagger () indicates that the phenotype is present when two similar (homologous) genes are mutated.
case, the expression of the Wt1 transcription factor is dramatically reduced in the nascent renal mesenchyme. In humans
and animals, high doses of vitamin A are associated with renal
agenesis, and sometimes with so-called caudal regression,
the reduction of distal structures including the sacrum and
hindlimbs.47-49
In view of the possible teratogenic effects of ACEIs (and
angiotensin receptorblocking drugs), the use of such agents
should be avoided in hypertensive women who are pregnant.50-52 Diverse renal disorders have been reported in offspring of mothers treated with ACEIs, including renal tubular
dysgenesis, neonatal acute renal failure, and hypotension;
skull malformations also occur. On the other hand, such complications are by no means inevitable after fetal exposure to
such agents. For example, in a study of 19 such pregnancies,
only 1 infant had anuria needing dialysis. Although some
have attributed all the detrimental effects to hypotension and
hemodynamic alterations, it is clear from animal experiments
that angiotensin also directly mediates renal tract differentiation, especially by modulating apoptosis in early metanephrogenesis, and then morphogenesis of the renal papilla and
ureteral smooth muscle at later stages.53
Data from animals show that maternal diet (e.g., the
amount of protein ingested by the mother) programs the
trajectory of growth of the embryonic kidney, altering cell
turnover and gene expression at a time when nephrons and
glomeruli have yet to form.54,55 The human implication is that
the amount of protein ingested from the time of conception
through the first 5 or 6 weeks of gestation may affect kidney
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Table 12-3 Selected Human Multiorgan Syndromes Associated with Urinary Tract Malformations
Syndrome
Genetic Basis
Associated Malformations
Aperts syndrome
Bardet-Biedl syndrome
Beckwith-Wiedemann syndrome
Branchio-oto-renal syndrome
Camptomelic dysplasia
Renal dysplasia
CHARGE association
Denys-Drash syndrome
DiGeorge syndrome
Fanconi anemia
Fraser syndrome
HDR syndrome
Kallmanns syndrome
Klinefelters syndrome
47,XXY
Renal agenesis, small firm testes, gynecomastia, azoospermia, and hypergonadotropic hypogonadism
Meckels syndrome
MURCS association
Polands syndrome
Renal-coloboma syndrome
Rokitansky-Kuster-Hauser syndrome
Simpson-Golabi-Behmel syndrome
(Continued)
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Table 12-3 Selected Human Multiorgan Syndromes Associated with Urinary Tract Malformationscontd
Syndrome
Genetic Basis
Associated Malformations
Smith-Lemli-Opitz syndrome
Townes-Brocks syndrome
VACTERL association
WAGR syndrome
Williams-Beuren syndrome
Microdeletion of 7q11.23
CHARGE association = coloboma, heart malformation, choanal atresia, retardation, genital and ear anomalies; HDR syndrome = hypoparathyroidism, sensorineural deafness, and renal anomalies; MURCS = mllerian duct aplasia-hypoplasia, renal malformations, and cervicothoracic somite dysplasia; VACTERL association = vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia, plus cardiac abnormalities and nonradial limb defects; WAGR
syndrome = Wilms tumor, aniridia, genital and renal malformations, mental retardation.
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Kallmanns Syndrome
X-linked Kallmanns syndrome is caused by mutations of
KAL, a gene on the short arm of the X chromosome.74,75 Anosmia and hypogonadotropic hypogonadism occur in affected
males because of defective prenatal migration of olfactory and
gonadotrophin-releasing hormone neurons from the nasal
placode into the forebrain; moreover, the olfactory bulb fails to
grow and is hypoplastic.76 The syndrome affects 2% of hypogonadal males.77 This syndrome is a human genetic model of
renal agenesis; the absent kidney is usually unilateral, resulting in a solitary functioning kidney.78,79 Patients with urinary
tract agenesis also lack the vas deferens, itself derived from
the mesonephric duct, which also gives rise to ureteric bud
derivates. The KAL gene is expressed in the developing central
nervous and urinary tract80 and the encoded protein, called
anosmin 1, immunolocalizes to basement membranes of the
mesonephric duct and its collecting duct branch derivatives.81
Antibodies to anosmin 1 block the formation of the collateral
branches of rat olfactory bulb output neurons,82 and there is
evidence that anosmin 1 modulates growth factor signaling
in neuroblasts.83 Collectively, the data are consistent with a
role for KAL1/anosmin 1 in mediating cell adhesion during
ureteric bud growth, although the exact mechanisms remain
unknown.
and the second with unilateral agenesis and contralateral dysplasia. Others reported that first-degree relatives of patients
with bilateral urinary tract agenesis had a 10-fold higher incidence of solitary kidney compared with controls.89 In fact, there
is considerable anecdotal evidence establishing the possibility
of a genetic basis of diverse other nonsyndromic urinary tract
malformations. These include kindreds with renal agenesis,90-93
renal dysplasia,93-95 multicystic dysplastic kidney,96,97 renal
hypoplasia,95,98,99 pelviureteral junction obstruction,100 vesicoureteric reflux,101,102 and posterior urethral valves.103,104
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CONCLUSION
Malformations of the urinary tract are common causes of
chronic renal failure in young children, and it is evident that
mutations alter gene expression during development to cause
some of these disorders. The most convincing studies come
from the multiorgan malformation syndromes for which specific mutations have been defined. However, these syndromes
are relatively rare, and most urinary tract malformations
appear to occur in isolation. In some of these conditions, however, a genetic pathogenesis is strongly suggested by a positive family history and genetic linkage studies. One common
example is primary VUR. Furthermore, sporadic malformations have been shown to be associated with polymorphisms
of genes expressed during construction of the urinary tract.
In the long term, an understanding of the genetic aspects of
human urinary tract malformations will help to unravel the
pathogenesis of these disorders and may facilitate the design
of genetic screening tests with a view to early diagnosis and
appropriate genetic counseling.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
13
CLASSIFICATION
Previously, UTIs were classified in numerous descriptive ways,
such as complicated versus uncomplicated, or upper versus
lower tract. For practical purposes, pediatric UTIs may simply
be categorized into two types: first infections and recurrent
infections. The recurrent infections may then be categorized as
(1) unresolved bacteriuria during therapy, (2) bacterial persistence at an anatomic site, and (3) re-infections. This simplified
approach underscores the importance of the first occurrence
of a UTI and the management and treatment implications surrounding these infections.
In infants and children, urinary infections are often associated with underlying anatomic abnormalities that predispose
and complicate bacteriuria. First infections should therefore
be considered complicated and should undergo an imaging
evaluation. Typically, correctable causes of bacterial persistence are discovered early, on this initial radiologic evaluation
(Table 13-1).
Most recurrent UTIs are re-infections with the same or a
different pathogen; the infecting organisms ascend from the
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PATHOGENESIS
Bacterial genetic clonal studies confirm that entry into the urinary tract occurs through the suspected fecal-perineal-urethral
route, with subsequent retrograde ascent of periurethral bacteria.8 Once bacteria have gained entry into the urinary system,
they must overcome host defenses including urethral washout, epithelial shedding, periurethral glandular secretion, and
Tamm-Horsfall glycoprotein before they can adhere to the
bladder mucosa. These factors vary by gender, age, and individual host characteristics, resulting in variable likelihood for
bacterial ascent.9
Other routes of infection include hematogenous, lymphatic, and direct extension from adjacent organs. Infection
of the urinary tract via hematogenous spread is uncommon
and usually occurs in children who are immunocompromised.
Organisms that may spread hematogenously to the urinary
tract include Staphylococcus aureus, Candida species, and tuberculosis. Infection of the urinary tract by means of lymphatic
channels is rare. It is hypothesized that bacteria may travel
through rectal, colonic, or periuterine lymphatics to infect the
urinary tract. Genitourinary tract fistulas, such as vesicovaginal fistulas and vesicointestinal fistulas, can result in urinary
infections by direct extension.
Bacteria
The enteric gram-negative Enterobacteriaceae, most frequently
Escherichia coli, are the bacteria most commonly infecting the
urinary tract.10-12 Specific E. coli serotypes (e.g., O1, O2, O4,
O6, O7, and O75), identified by their cell wall O-antigens, are
associated with pediatric UTIs.11,12 With increased treatment
of gram-negative infections with broad-spectrum antibiotics,
the gram-positive Enterococcus faecalis is a more commonly
found uropathogen.13
Bacterial cell surface structures called pili or fimbriae may
increase virulence potential by mediating bacterial adherence
to uroepithelial cells. These pili are classified on the basis of
their ability to agglutinate red blood cells (hemagglutination)
of different animal species as well as the ability of various
sugars to block this hemagglutination reaction.14,15 Using
chapter
Persistence in Children
Infection stones
Infected nonfunctioning or poorly functioning kidneys or renal
segments
Infected ureteral stumps after nephrectomy
Vesicointestinal or urethrorectal fistula
Vesicovaginal fistula
Infected necrotic papillae in papillary necrosis
Unilateral medullary sponge kidney
Infected urachal cyst
Infected urethral diverticulum or periurethral gland
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Age
these characteristics, Kallenius and associates discovered that
pyelonephritogenic E. coli cause mannose-resistant hemagglutination (MRHA) of human red blood cells.16 Characterization
of this reaction demonstrated that the terminal glycolipid
of the human red cell P blood group antigen is a receptor
that binds P-fimbriae on these E. coli cells.17-19 Receptors for
P-fimbriae are also present on uroepithelial cells, as well as
renal tubular cells in the kidney, and in a similar fashion mediate the binding of bacteria to these cells. MRHA characteristics
and P blood groupspecific adhesins (P-fimbriae or P-pili) are
two important markers for E. coli virulence.17,19
The importance of these two virulence characteristics
has been supported by studies examining their association with clinically diagnosed pyelonephritis and cystitis.
Vaisanen and colleagues demonstrated that both MRHA
and P-fimbriae are present on most E. coli strains causing
clinically diagnosed pyelonephritis in children: 29 (91%) of
32 strains were positive for MRHA, and 81% of those were
also positive for P-fimbriae.19 Similarly, in a study of 35
children with pyelonephritis, Kallenius and associates found
P-fimbriae on 94% of E. coli causing acute pyelonephritis. In
contrast, only 19% (5/26) of children with clinically diagnosed cystitis, 14% (5/36) of E. coli causing asymptomatic
bacteriuria, and 7% (6/ 82) of E. coli from the feces of healthy
children had P-fimbriae expression.16
More recently, however, when dimercaptosuccinic acid
(DMSA) renal scanning has been used to differentiate pyelonephritis from cystitis, the relationship between P-fimbriated
strains of E. coli and susceptibility to pyelonephritis has been
less clear. There is evidence to suggest that P-fimbriated E. coli
are simply more likely to induce a febrile reaction in the host,
irrespective of kidney involvement.20,21 A possible mechanism
or mediating factor is the demonstration of higher urinary
interleukin-6 response in children infected with P-fimbriated
E. coli than in those infected by other strains.22 It has been suggested, moreover, those UTIs caused by P-fimbriated strains23
and those generating bacterial biofilms may need longer antimicrobial courses than those caused by other strains.
Animal models have revealed a potential new paradigm for
acute and recurrent UTI. Attachment between the uroepithelial cell and the bacterial cell via factors such as type 1, P-pili,
and fimbriae is known to be the initiating event. This attachment has now been discovered to trigger a series of molecular
interactions in which the adhesion-receptor complexes cause
uptake of the bacteria into the bladder surface umbrella cell.24
In a defensive response, the uroepithelial cells are rapidly
shed.25 The bacteria are able to enter the epithelial cells, interacting with lipid rafts and uroplakins to form intracellular
Gender
As discussed earlier, males younger than 1 year of age are
more inclined to develop UTI than similarly aged females, and
girls are more susceptible thereafter. Although many factors,
including urethral length, prostate, and foreskin, have been
hypothesized to account for this difference, the reasons are not
entirely known.
Periurethral Colonization
Times and conditions of increased periurethral colonization
are associated with increased risk of UTI. During the first few
months after birth, the periurethral area of healthy girls and
boys is heavily colonized with aerobic bacteria (especially
E. coli, enterococci, and staphylococci).28 Epidemiologic data
have shown that the incidence of UTI is much higher during
this time than at any subsequent time in the next few years.
This colonization decreases after 6 months, and it is unusual
in children who are without recurrent infections after age
5years. Thereafter, only those women and children who
suffer repeated UTIs remain colonized by periurethral gramnegative bacteria.28-30
Preputial Skin
The association of the foreskin and neonatal UTI has caused
controversy regarding the advantages and disadvantages of
circumcision.31 This controversy has resulted in numerous
editorials and recommendations by the American Academy of
Pediatrics.32-40
During the first few months of life, there appears to be
an association between the presence of foreskin, periurethral
and preputial colonization, and UTI. Wiswell and associates
found that, during the first 6 months of life, periurethral
uropathogenic bacteria were cultured more frequently (using
intraurethral and glanular cultures) from uncircumcised boys
than from circumcised boys.41 Uncircumcised male infants,
moreover, have an increased relative risk of UTI (3.12) when
compared to circumcised boys, but this risk decreases to
3.7 at 1 year and 3.0 at 3 years.42 Several factors, including
early immune status, unusual nosocomial colonization, breast
182
part
I: Basics
Native Immunity
The influence of the hosts native cellular and humoral
immunity on risk of UTI is unclear. UTIs are more commonly
seen in infants during a time when their immune system is
incompletely developed. Serum immunoglobulin G (IgG) as
well as IgA are lowest during the first few months after birth,
at a time when periurethral colonization is high in normal
children.55 Moreover, secretory IgA, an important human
immunoglobulin at the secretory and mucosal surfaces of the
body, is either absent or almost absent in the nasopharynx,
gut, and urothelium during this time.56-58
The role played by urinary IgA in infants and children
with UTI has not been examined extensively. Studies have
demonstrated that children with recurrent UTI have lower
urinary secretory IgA concentrations than children without
infections.56 Urinary IgA levels in infants and children during
acute pyelonephritis were elevated compared with children
without UTIs. These levels, however, are far below those
found in adults.
The benefits of breast milk in preventing infection in
infancy have been expounded for some time, but whether
these benefits are related to colostral IgA or other factors is
not known.59 Case-control studies suggest that breast feeding
may confer a protective effect against UTI during the first
7months of life. These studies revealed that ongoing exclusive
breast feeding produced a significantly lower risk of infection,
and a longer duration of breast feeding resulted in a lower
risk of infection after weaning, indicating a long-term mechanism. The protective role of breast feeding was strongest
at birth and decreased after 7 months of age.60 Further studies showed duration of breast feeding to be shorter in children who had UTI (9 versus 16 weeks in children who had
exclusive breast feeding)61 but concluded that full or partial
breast feeding may confer a protective effect against UTI for
the first 6 months of life.62,63 Although the protective mechanism is unknown, the oligosaccharide content of the mothers
breast milk and urine are the same as that of the breast-fed
infants urine, and these oligosaccharides may inhibit adherence of pathologic E. coli to the uroepithelium.64 In addition,
urinary secretory IgA levels were found to be higher in
breast-fed compared with formula-fed infants.65
As expected, children with specific immune deficiency
syndromes have altered immunity and often have increased
risk of bacteriuria and progression of infection. About 20%
of children infected with the human immunodeficiency virus
get bacterial UTIs with both common and opportunistic
organisms.66
Fecal Colonization
The composition of human fecal bacterial flora depends on the
surrounding microbial ecology, native immunity, and microbealtering drugs and foods. The importance of abnormal fecal
colonization in neonates is emphasized by studies showing
that fecal colonization with specific pyelonephritic bacteria
chapter
Vesicoureteral Reflux
VUR is common in children with UTI. Epidemiologic surveys
have shown that between 21% and 57% of children who have
had bacteriuria are subsequently found to have VUR.11,70-72
However, no correlation between reflux and UTI predisposition has been found. The importance of reflux lies in the fact
that it allows bladder bacteria renal access with subsequent
potential for renal damage.
in
Peripubertal Girls
183
Neurogenic Bladder
Children with neurogenic bladders and abnormally elevated
bladder pressures risk increased renal damage from UTI for
two reasons: elevated urinary tract pressures and increased
frequency of instrumentation with subsequent infection. The
combination of increased pressure from within the neurogenic
urinary tract and the physiologic effects of UTI substantially
increases the likelihood of renal parenchymal damage.77 Specifically, a neurogenic bladder with chronically elevated bladder pressures may realize secondary VUR via decompensation
of the ureterovesical junction.78 Alternatively, elevated bladder pressures associated with a neurogenic bladder may cause
obstruction with risk of renal damage.79
With a higher incidence of bacteriuria, a child with a neurogenic bladder may be at higher risk for febrile infections
and possible renal damage. Clean intermittent catheterization
(CIC) programs are useful for emptying the neurogenic bladder, but these catheterizations introduce bacteria. Although
conclusions from previous studies involving CIC in children
are limited, they all emphasize that bacteriuria and even pyuria
occur commonly80-83 but are usually asymptomatic.81,82,84
Although complications of urinary calculi and epididymitis
have been noted,85 the long-term complications of children
on CIC programs must be better defined. One investigation
showed that the costly use of sterile catheters in CIC programs
does not reduce the incidence of bacteriuria and therefore
appears to have no proven benefit.86
Whereas prophylactic antibiotics may decrease, but not
eliminate, bacteriuria in the short term,81 their actual benefit
is unproven. A study of 15 children receiving nitrofurantoin
prophylaxis demonstrated a small decrease in bacteriuria
(74% placebo versus 65% treated); however, the organism
responsible for bacteriuria shifted to resistant organisms such
as Klebsiella and Pseudomonas.87
NATURAL HISTORY
The natural history of the pediatric UTI is unpredictable and
incompletely understood. Although it has been recognized that
the pathogenesis of UTI in children differs from that in adults,
UTI in children has often been studied without regard for
age and other pediatric-specific factors. Research has shown,
however, that about 3% of girls and 1% of boys develop a prepubertal UTI12 and, of these children, 17% or more develop
infection-related renal scarring. Among those with scarring,
10% to 20% become hypertensive, and a rare child develops
progressive renal dysfunction culminating in end-stage renal
disease (ESRD) (Fig. 13-1).
184
part
I: Basics
Periurethral colonization
Genetic determinants
Age
Gender
Prepuce
Native immunity
Fecal colonization
GU abnormalities
Virulence
Host
Bacteria
Pili
Bacteriuria
GU abnormality/VUR
Pyelonephritis
Renal Scarring
Previously, the coarse renal scarring defined radiologically by
calyceal deformity and parenchymal thinning over localized
or multiple calyces was called reflux nephropathy. Now that
it is clear that such scarring is as likely to occur with or without
reflux, this kind of scarring would probably be better termed
pyelonephritogenic or simply pyelonephritic scarring.
With older imaging techniques (before the advent of
DMSA), renal scarring was identified in about 17% of school
children with screening bacteriuria.7,70,72 This finding supports Winbergs observation that 4.5% and 17% of children
have renal scars on imaging studies after their first and second
symptomatic UTI, respectively.12 Current studies employing
DMSA scintigraphy yield almost double the incidence of scarring, so these rates are probably underestimates. Nevertheless,
these older data emphasize that children with both covert and
symptomatic UTI risk significant renal scarring. Although,
by definition, the natural history and pathogenesis of scarring in covert or asymptomatic bacteriuria cannot be known,
scars may actually reflect injury from previously undiagnosed
Renal scarring
Hypertension
ESRD
chapter
185
experienced a recurrent UTI developed new diurnal enuresis, persisting for as long as 12 months, even though the urine
remained clear.117
Urodynamic testing of otherwise radiologically normal children with recurrent UTI and incontinence showed
abnormal cystometry and voiding patterns.118-125 In 35 such
children, Bauer and associates120 found that 12 (34%) had
normal filling cystometry, 9 (26%) had large hypotonic bladders, 9 (26%) had small-capacity hypertonic bladders with
increased intravesical filling pressure and sustained uncontrolled detrusor contraction at a low volume, and 5 (14%)
had hyperreflexic bladders showing uninhibited detrusor
contractions during filling. Voiding dysfunction has also been
described, with staccato urinary flows, increased pelvic floor
activity during voiding, and resulting incomplete bladder
emptying.116,120,124-126
Voiding dysfunction in neurologically normal children
also appears to influence the natural history and treatment
of VUR. Koff and coworkers127 examined 143 children with
primary VUR and noted that 66 (43%) had voiding dysfunction defined by evidence of bladder instability, infrequent
voiding, the Hinman syndrome, and constipation. Of these
66 children, 54 (82%) underwent reimplantation secondary
to breakthrough infections, compared with only 18% of those
who were without voiding dysfunction. Of 70 children who
had breakthrough UTI, voiding dysfunction was present in 54
(77%) and absent in 16 (23%). The authors also noted that lowgrade VUR required, on average, 1.6 years longer to resolve in
children with voiding dysfunction.
Bowel dysfunction with constipation is commonly seen in
children with bladder filling and voiding dysfunction.128,129
When 47 girls with normal urinary tracts but recurrent
UTIs (with or without incontinence) and cystometry-proven
bladder instability were studied by digital rectal examination
and rectal manometry, all had signs of functional constipation.
Importantly, these findings were present even when constipation or encopresis was specifically denied. Others have not
found constipation or daytime incontinence to be predictive
of recurrent UTI.130
Although these findings do not establish causality
between UTI and voiding dysfunction, UTI may initiate
symptoms of bladder dysfunction with variable persistence.
In some situations, treatment of constipation or voiding
abnormalities, or both, has resulted in decreased frequency
of urinary infections118-121,125,126,128,131-133 and this possible
relationship should be considered in the management of
VUR127,134 even though the association is unclear.135 The data
suggest that bacteriuria may provoke abnormal detrusor
activity.
186
part
I: Basics
3. Generalized scarring
Third, neonatal UTI symptoms are often vague and nonspecific, leading to delayed or inadequate treatment.161 This
delay may result in a kidney that responds to bacterial invasion with an inflammatory response characterized by vascular
granulocytic aggregation and hypoperfusion with subsequent
scarring and loss of renal parenchyma.12
Recently, research has focused on the effects of the reninangiotension system on renal scarring. It is hypothesized
that increased angiotensin II may increase scarring through
its hemodynamic as well as its growth-related and prosclerotic effects. Studies provide evidence that the homozygous
deletion polymorphism (DD genotype) that is associated
with increased activity of the renin-angiotensin system and
angiotensin II may be a genetic susceptibility factor contributing to renal scarring.162,163 Ozen and associates163 found
that 28 (80%) of 35 patients with a DD genotype developed
scarred kidneys on DMSA. Of 53 patients with scarring,
28 children possessed the DD genotype. Nevertheless, no
association between DD genotype and hypertension or
decreased renal function was observed. Recent studies have
chapter
PYELONEPHRITOGENIC HYPERTENSION
The incidence of hypertension in childhood ranges from 1% to
11% depending on age and sex. Pyelonephritic scarring associated with UTI remains the most common cause of hypertension in childhood.165 In particular, approximately 10% to 20%
of children with pyelonephritogenic nephropathy will develop
hypertension in the future.166-171
Wallace and associates found that 12.8% of 141 patients
with urinary infections and surgically corrected VUR developed hypertension during the first 10 years of follow-up.167
Of those with renal scarring, 17% became hypertensive during
follow-up. In another series with 4 to 20 years of follow-up,
30% of children who were found to have renal scars developed infection-related hypertension; 13% (11/83) had initial
hypertension.168 Others have reported that 23% of children
with nonobstructive focal renal scarring developed hypertension after 27 years, and, of these, 10% developed ESRD.169
In these series, hypertension was independent of the degree
of scarring. More recent examination of 24-hour ambulatory
blood pressure measurements suggested that hypertension
measured in this fashion correlates directly with the degree
of reflux nephropathy. Nocturnal hypertension was the most
sensitive indicator, but whether it is predictive of daytime
hypertension has not been validated.172
The etiology of pyelonephritogenic hypertension is poorly
understood. It is likely that the renin-angiotensin system is
involved. Although some evidence of elevated plasma renin
activity exists, no direct correlation of blood pressure with
degree of scarring, plasma renin activity, or creatinine has
been found.173 Further indirect evidence of the role of renin
in pyelonephritogenic nephropathy has been the successful
treatment of hypertension with agents specifically aimed at
blocking the renin-angiotensin system.
DIAGNOSIS
Clinical Symptoms
UTI is a common cause of pediatric bacterial infection174-176
and accounts for 4.1% to 7.5% of febrile illnesses.177,178 Early
diagnosis of UTI and rapid treatment with antimicrobial
agents are essential in preventing renal damage. However,
the clinical symptoms of UTI are variable and differ by age. In
infants, the symptoms of UTI may be difficult to discern, with
the only signs being those of generalized illnessfever, irritability, poor feeding, vomiting and diarrhea. Moreover, febrile
infants who are not suspected of having a UTI are as likely
to have a urinary source of infection as those who are (5.1%
versus 5.9%).176 It has been recommended that testing for UTI
be performed for all infants younger than 8 weeks of age who
present with asymptomatic jaundice.179 In febrile infants, neither clinical symptoms nor laboratory tests can be used to presume or eliminate the likelihood of a UTI, even if other sites of
infection are suggested clinically.174
The manifestations of UTI symptoms in young children
(<2 years) may be similar to those in infants. To avoid unnecessary urine cultures, clinical guidelines have been proposed.
When evaluating febrile young girls, urine cultures should be
obtained if two of the following five parameters are present:
(1) age younger than 12 months, (2) white race, (3) absence of
other fever source, (4) fever greater than 39 C, and (5) fever
lasting 2 days or longer. If followed, these parameters would
187
Signs
There are no signs specific to UTI in the infant or child; nevertheless, physical examination should focus on findings
that, when present or absent, will be diagnostically helpful.
Pertinent areas include the flank for renal masses or pain; the
abdomen for masses or pain; the perineum for ectopic ureteral
openings, prolapsed ureterocele or urethra, or urethral discharge; the sacral area for back scars, dimple, pits, or fat pad
that could be associated with tethered cord or dysraphism;
and the testes for masses, epididymitis, and tenderness.
Diagnostic Tests
Urinalysis and Culture
Collection
of the
Urinary Specimen
188
part
I: Basics
Urinalysis
The gold standard for the diagnosis of UTI is quantitative
urinary culture. Yet, controversy exists regarding the interpretation of urinalysis and culture results. Four determinations
from the urinalysis may be useful in supporting a diagnosis of
UTI: (1) microscopic urinary examination for white blood cells
(WBCs), called pyuria; (2) microscopic urinary examination
for bacteria; (3) urinary leukocyte esterase; and (4) urinary
nitrite (Table 13-2).
The microscopic identification of bacteria in the urine is
more sensitive and more specific for diagnosing UTI than is
identification of pyuria.188,189 The finding of urinary sediment
red cells and WBC casts is even less reliable. Hoberman and
associates proposed the use of an enhanced urinalysis, in
which an uncentrifuged specimen is examined for WBCs and
a Gram stain is performed for bacteria, with pyuria defined as
the presence of greater than 10 WBCs/mm3.190 For identifying
positive urine cultures, those with greater than 50,000 colonyforming units (CFU) per milliliter, this method produced a sensitivity of 84%, compared with 66% for standard urinalysis.
Urinary leukocyte esterase detects urinary esterases produced by the breakdown of WBCs in the urine, yet WBCs
may not be present with the infection. The test may be less
reliable in infants.191 The urinary nitrite test measures dietary
nitrates that are reduced to nitrite by many gram-negative urinary bacteria and has a high specificity. (Most gram-positive
bacteria do not perform this reduction.) A serious drawback
of this test is that the bacterial reduction to nitrite may take
several hours; therefore, this test is most useful on first morning voided specimens. Although both tests may be performed
by dipstick in the urine, the tests are more unreliable when the
bacterial count is lower than 100,000 CFU/mL.
No combination of urinary tests meets the gold standard
of culture, but several tests may help predict patients in
whom culture will be positive. In febrile children younger
than 2years of age, Hoberman and coworkers found that
catheter-obtained specimens had a positive predictive value
for UTI diagnosis of 88.3% if microscopic examination
showed bacteria and greater than 10 WBC/mm3, but they
emphasized that UTI in these children is best defined by a
urinary leukocyte count of greater than 10 WBCs/mm3 and
greater than 50,000 CFU/mL on culture.191 In a more general child population, others have shown that, when urinary
specimens are properly collected and promptly processed,
positive leukocyte esterase and nitrite tests, in combination with microscopic confirmation of bacteria, have 100%
sensitivity for detection of UTI. When all tests (or leukocyte
esterase and nitrite tests) are negative, the negative predictive value approaches 100%.192,193 In febrile children 3 to
24 months old, a risk-benefit analysis based on the current
literature, which had the goal of preventing the majority
of cases of UTI-related ESRD and hypertension, concluded
that both urinalysis and culture are needed to optimize
prevention.161,194 The arguments for and against relying on
urinalysis characteristics for the presumptive diagnosis of a
UTI were well summarized by Lohr.189
Urine Culture
Defining urine culture parameters that result in a significant UTI is challenging. As already discussed, the technique
by which the urinary specimen is collected correlates with
its reliability for UTI diagnosis (Table 13-3).195 Classically, a
clinically significant UTI has greater than 100,000 CFU/mL
Test
Sensitivity,
%(Range)
Specificity,
% (Range)
Leukocyte esterase
83 (67-94)
78 (64-92)
Nitrite
53 (15-82)
98 (90-100)
Leukocyte esterase or
nitrite positive
93 (90-100)
72 (58-91)
Microscopy: white
blood cells
73 (32-100)
81 (45-98)
Microscopy: bacteria
81 (16-99)
83 (11-100)
Leukocyte esterase or
nitrite or microscopy
positive
99.8 (99-100)
70 (60-92)
Imaging Studies
Imaging evaluation is important to the diagnosis and management of UTI with the goal of altering or preventing further
morbidity. Radiologic imaging can be used to (1) evaluate and
localize the acute urinary infection, (2) detect renal damage
from the acute infection, (3) identify genitourinary anatomy
that increases the risk of future renal damage from infection,
and (4) evaluate changes in the urinary tract over time. An
algorithm for deciding which studies are necessary in a child
with a presumptive or diagnosed UTI is provided in Figure
13-3. It should be kept in mind that imaging studies are recommended only if their findings may change clinical management. A detailed review of the relevant imaging studies can be
found in Chapter 3.
Radiologic Studies
in the
Acute Setting
chapter
189
Suprapubic aspiration
>99
Catheterization
>105
95
104
to
105
Infection likely
103 to 104
Suspicious; repeat
<103
Infection unlikely
>104
Clean-voided (male)
Clean-voided (female)
Infection likely
Three specimens:
>105
95
90
>105
80
5 104 to 105
Suspicious; repeat
104
to 5
104
104 to 5 104
<104
Infection unlikely
Reprinted with permission from Hellerstein S. Recurrent urinary tract infections in children. Pediatr Infect Dis. 1982;1:271.
Initial UTI
Other studies,
surgery
VCUG
VUR
present
Renal/bladder
ultrasound
(RBUS)
VUR present
RBUS normal
Normal RBUS
no/low-grade
VUR
Initial
Abnormal
RBUS
Other studies,
e.g., diuretic
renogram
Re-evaluate
as needed
evaluate infants and children with urinary tract infection (UTI). PUV,
posterior urethral valves; VCUG, voiding cystourethrogram; VUR,
vesicoureteral reflux.
and
Voiding Cystourethrography
The VCUG is the most important examination in assessing
VUR in children. The VCUG may be performed either with
fluoroscopy and iodinated contrast or with nuclear imaging
190
part
I: Basics
Renal
and
Bladder Ultrasonography
Nuclear Renography
Nuclear scintigraphy can detect areas of acute renal inflammation and chronic scarring, and this capability has changed
imaging of pediatric UTIs. DMSA is clearly more sensitive
than renal sonography or even IVU at detecting renal scarring.
Approximately 60% of injected Tc99m-DMSA is bound to
proximal tubular cells and is subsequently secreted slowly
in the urine, thus delineating the cortical anatomy. After the
acute episode is healed, the scans may show (1) a normal
pattern, (2) generally diminished uptake and small kidney
volume, (3) diminished uptake in the medial kidney, or (4)
polar defects with diminished uptake in the renal poles.199
Because recurrent pyelonephritis appears to occur in the
same areas, it may be difficult to differentiate new from old
or progressive renal scarring unless serial studies have been
performed.96,218 Finally, for children in whom severe renal
scarring has occurred, the radionuclide renogram has been
found to give an accurate estimate of relative function, even
in young children.224-226
MANAGEMENT
Treatment of Acute Urinary Tract Infection
The therapeutic goal of management in pediatric UTI is to
minimize acute morbidities, prevent urosepsis, and minimize
the risk of future renal damage from subsequent infections.
Rapid recognition of a UTI and rapid, appropriate antimicrobial treatment are keys to preventing renal damage. Treatment
varies depending on the childs age and severity of illness.
When treatment of UTI is considered, infants younger than
90 days are usually considered separately from older children.
Children younger than 90 days of age are more likely to have
their course of disease change rapidly because of their physiology and incompletely developed immune system.232 The child
younger than 2 to 3 months who has a presumptive UTI and
looks systemically ill, has a fever or flank or abdominal pain,
is unable to take fluids, or is immunocompromised should be
treated with parenteral broad-spectrum antimicrobial agents
(e.g., aminoglycoside and ampicillin, third-generation cephalosporin, aminoglycoside, and cephalosporin; Table 13-4) and
chapter
Parenteral Agents
Oral Agents
Aminoglycosides
Cephalosporins
Gentamicin
First-Generation
Tobramycin
Cephalexin
Cephalosporins
Cefadroxil
Cefazolin
Second-Generation
Cefotaxime
Cefaclor
Ceftriaxone
Cefuroxime axetil
Ceftazidime
Cefprozil
Penicillins
Loracarbef
Ampicillin
Third-Generation
Ticarcillin
Cefixime
Piperacillin
Penicillins
Ampicillin
Amoxicillin
Clavulanate/clavulanate
Sulfonamides
Sulfisoxazole
Trimethoprim-sulfamethoxazole
Other Agents
Nitrofurantoin
Ciprofloxacin*, Levofloxacin*
considered for hospitalization. For this patient population, particularly those who are 30 days of age or younger, consideration
must be given to antimicrobial coverage of Listeria monocytogenes (perinatally acquired) and E. faecalis (usually postnatally
acquired), for which ampicillin provides coverage, thus making ampicillin and gentamicin recommended at this age.233
Whereas those younger than 1month are most often hospitalized for treatment, UTI in those between 30 and 90 days old has
been managed on an outpatient basis, depending on the childs
clinical status and the presence of a reliable follow-up plan.
In appropriate infants and young children with presumptive UTI who are maintaining oral hydration and have
cooperative, reliable parents with whom daily contact is possible, outpatient therapy may be offered. Third-generation
cephalosporins, such as ceftriaxone, allow once-daily outpatient parenteral therapy.234,235 Most of these third-generation
cephalosporins have a broad spectrum with high serum
levels, treat even Enterobacter species and some Pseudomonas
aeruginosa, and conveniently require only once- or twice-daily
dosing. Several studies have shown that once-daily parenteral
administration of gentamicin or ceftriaxone in a day treatment
center is safe, effective, and cost-effective in children with
UTI.234,236,237 However, Enterococcus species are still resistant
to most third-generation cephalosporins.
Usually, parenteral treatment is continued for 48 to
72hours, until the child is afebrile, clinically improving, and
taking fluids. Antibiotic therapy can then be tailored based
on bacterial sensitivities, and the patient can be switched to
191
192
part
I: Basics
Drug
Age Limitations
Nitrofurantoin
>1 mo
Trimethoprim-sulfamethoxazole
>2 mo
Urethral instrumentation
Cephalexin
None
Immunosuppression or immunocompromise
Possibly Useful
Amoxicillin
None
Sulfisoxazole
>2 mo
Trimethoprim
>2 mo*
Antimicrobial Prophylaxis
Because renal scarring and damage have been shown to occur
only in the presence of infection, the goal of antimicrobial
prophylaxis is to sterilize the urine and prevent infection.260
Urinary prophylactic antimicrobial agents are effective to
varying degrees in preventing bacteriuria under certain circumstances. In children, these agents are most commonly used
to prevent UTI in the situations listed in Table 13-5. Whereas
urinary tract prophylaxis has been widely accepted, randomized clinical trials comparing prophylaxis to surveillance regimens have not been performed.261-263 In a recent multicenter,
randomized controlled trial, antimicrobial prophylaxis did not
decrease the risk of recurrent UTI or the development of renal
scarring in children with low-grade reflux (grades I toIII) compared with controls.264 However, for children with high-grade
reflux (grades IV and V), retrospective data have shown that
reflux nephropathy is less likely in children with high-grade
VUR who present without UTI.265 Currently, there are inadequate data to definitively support the use of antimicrobial
prophylaxis, and further investigation is warranted.266
Although a number of agents may be used for treatment of
a UTI, fewer agents have been studied for low-dose prophylaxis in children. The ideal prophylactic agent should have
low serum levels, high urinary levels, and minimal effect
on the normal fecal flora; should be well tolerated orally;
and should be inexpensive. The potency of these antimicrobial agents is based on the general susceptibility of most fecal
Enterobacteriaceae to these agents at urinary levels. Because
these agents are generally concentrated in the urine, the urinary drug levels should be much higher than the drug levels
found simultaneously in serum, gut, or tissue. If gut levels
are sufficiently low, antimicrobial resistance patterns in the
gut should not develop. This characteristic of the prophylactic
antimicrobial agents is most likely dose-related, so that
inappropriately high dosing for prophylaxis may be ineffective because bacterial resistance will be created.267
*Data
Because urinary prophylaxis is usually initiated after treatment of an infection for which long-term (7 to 10 days)
therapeutic dosing was given, the fecal flora may already be
resistant to the treating drug and many of the prophylactic
agents, creating a risk for re-infection. This accounts for frustrating breakthrough infections that occur soon after the
child begins taking prophylactic antimicrobial agents or after
treatment of other common infections such as otitis media. The
period of greatest risk for recurrent infection is usually the first
few weeks after any full-dose treatment. For this reason, the prophylactic agent should not necessarily be the treating agent.
Once urinary tract antimicrobial prophylaxis is initiated,
the drug is usually administered until the urinary tract abnormality for which prophylaxis is being given has resolved (e.g.,
spontaneous or surgical resolution of VUR or obstruction). If
resolution does not occur within a few months to years, the
time for stopping prophylaxis is unclear. Some evidence exists
that renal scarring in girls with pyelonephritis may be less
likely after 5 to 6 years of age and may occur less frequently
until age 15 to 16 years.268 Consequently, it may be reasonable
to perform a trial of discontinuing prophylaxis when a patient
reaches age 5 to 8 years or older if there is no history of UTI
and no renal scarring. Although select groups of children have
been monitored for years after discontinuing prophylaxis
and usually have done well without evidence of UTIs or new
scars, these studies have been limited by lack of randomization, radiologic screening technique, and the small number of
subjects studied.263,269,270
The long-term effects of prophylactic agents on the child
and his or her microbial ecology have not fully been examined.
A literature review of nitrofurantoin and trimethoprimsulfamethoxazole prophylaxis in children supported the longterm safety of these agents.271 More recently, some data have
suggested an association between long-term use of antibiotics
and increased risk for breast cancer in the adult population.
The results from multiple studies in the adult population have
been inconclusive and controversial; therefore, further investigation is warranted.272,273
In children with normal urinary function, useful agents
for urinary prophylaxis that have been studied are nitrofurantoin, cephalexin, and trimethoprim-sulfamethoxazole.274
Amoxicillin, sulfisoxazole, and trimethoprim alone may also
be useful as urinary tract prophylactic antimicrobial agents,
but they have not been as well studied in children. In the
continent child, urinary tract prophylactic antimicrobial drugs
should be given once nightly, so they will be excreted into and
remain in the urine overnight (Table 13-6).
chapter
193
194
part
I: Basics
chapter
195
References
For complete list of references log onto www.expertconsult.com
CHAPTER
14
The role of the nurse caring for infants, children, and young
people in urology includes the following:
Education and preparation: possibly antenatal, preadmission, at admission, during the hospital experience, and
after discharge
Communication: with children and their families and
among professionals
Support and counseling
Clinical skill in the coordination, delivery, and management of care
Pediatric urologic surgery is often planned, allowing parents
and nurses the opportunity to have an active role in preparing
children for surgery. Hospital and surgical interventions can
create real or imagined fears for children, so it is important
to prepare children for surgery.1,2 Hospital attendance and
surgical intervention and investigations can also cause parents anxiety.3 Parents need to be reassured that they will be
able to accompany their child throughout their stay, including during investigations and into the anesthetic and recovery
room. Anticipatory anxiety about a hospital admission can be
influenced by factors such as previous hospital experience and
the childs developmental level.4 Children with chronic and
complex urologic issues, such as bladder exstrophy, may have
different worries from those experiencing their first or perhaps
their only admission for surgery.
Infants
Primarily, the information provided in the case of a infant
should be focused toward the parents or caregivers. Parents
may have concerns about the practicalities of the elective admission, such as sleeping at the hospital, staying with their child,
and visiting. Parents are often involved in the care of their children during admission, and this may need to be acknowledged
or negotiated.11 Developmentally, infants have a secure relationship with a parent or caregiver, and separation can have an
emotional impact on the child.12 Whenever possible, urologic
procedures (e.g., orchidopexy) should be managed in the outpatient or day care surgery setting, to minimize both the length
of stay in the hospital and the changes to routine.
Preschool Children
Children in the preschool-age group (1 to 4 years) are becoming
more aware of their surroundings and beginning to explore.
Some children may view admission to the hospital as a punishment and may experience regressive behavior or anxiety
as a result of separation from their parent. Familiarizing the
environment with toys and smells (e.g., blankets from home)
may help to settle a child. Hypospadias surgery is often carried out at this age, to limit any possible future psychological
or psychosexual effects of genital surgery.13 Educating parents about possible changes in their childs behavior after an
admission maybe helpful.14 Parents may notice that their child
is more clingy after a hospital admission, and there may be
disruptions to normal routines, such as sleeping. This behavior
is often self-limited, and parents may benefit from accessing
their local community services, such as a health visitor in the
United Kingdom, for ongoing support.
School-Age Children
Children in the school-age group (5 to 11 years) are becoming more autonomous and questioning about their health and
reasons for surgery. The goal of the nurse is to gain the trust
of the child and family, giving them the opportunity to question in a nonjudgmental and empathic atmosphere. Education
and checking out the childs understanding are important.
chapter
Adolescents
Young people should be involved in making decisions about
their health and surgical procedures.8 Preoperative preparation for adolescents can be especially difficult if they wish to
discuss sensitive issues. The adolescent should be offered the
opportunity to explore concerns without their parents being
present (if they wish). A variety of media can be used to manage this situation, including a journal or e-mail (if the local
organization considers this appropriate or policies are in place
to safeguard both the child and the professional). Confidentiality and privacy should be maintained and support given to
the parents, because they may be reluctant to relinquish control about decisions and often feel very protective toward their
child.8 For example, discussions about sexual activity, risky
behaviors, genital sensation, fertility, and body image are topics that are highly sensitive yet need to be considered with the
young person. Ongoing psychological support may be of benefit, and the nurse should be able to refer the adolescent to the
most appropriate health care professional.
Adolescence is a time of change and growth for both the
child and the childs relationship with the parents.16 Changes
can include physical and psychological growth, experimentation, sexual exploration, changes in behavior, school life, and
mental health needs (including easting disorders, self-harming
behavior, body image issues).
Additional pressure, such as a chronic urologic condition
or difficulty with continence, can further impact the adolescent. Often adolescents challenge their health needs, resulting
in a lack of adherence to bladder management routines. The
nurse needs to be able to continue to support the adolescent,
listen, and help manage parent/adolescent disagreements
relating to health issues.
197
Postoperative Care
Most hypospadias surgery procedures in the United States
are performed on an outpatient basis; in the United Kingdom,
some hypospadias surgeries may necessitate an overnight
stay. Because of the short length of stay and parents anxiety, it
is very important that parents receive appropriate and precise
written information about caring for their son at home after
surgery. Written information should consider the aspects covered in the following paragraphs.
Surgical Site
and
Dressing
Absorbable sutures are used for the repair; only a stay suture
securing any stent (if used) will need to be removed. Over the
last 20 years, various dressings have been used17; however,
the surgeons discretion determines the dressing type, duration, and removal approach. Many centers opt for clear dressings such as Op-site or Tegaderm, whereas others may use
foam dressings such as Cavicare (Fig. 14-1). Some centers do
not advocate the use of a dressing postoperatively.18,19
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B
Figure 14-1 Two examples of hypospadias dressings. A, Translucent
dressing. B, Foam dressing. This dressing was soaked in the bath just
before removal, after being in place for 1 week. (Photograph in A courtesy of W. Snodgrass.)
Drainage
Some surgeons use a urethral stent postoperatively to minimize the chance of urine coming into contact with the neourethra and to support the surgical site during the healing
process.13 Other surgeons use a stent but drain the bladder via
a suprapubic catheter. Any type of stent or drainage tube can
cause parental anxiety, especially if the parents must care for
it at home.
Analgesia
Parents are often surprised when their son experiences
very little postoperative pain initially after hypospadias
surgery. This is due to the use of caudal analgesia during
the surgery, which is often effective for 6 hours postoperatively. Oral analgesia can be given to the child as prescribed, and parents should be cautioned to give only the
medication prescribed, and only in the correct dose and
frequency.13
Bladder Spasms
Bladder spasms occur in children with a urethral stent, and
the frequency varies among individual patients. A sudden
intense pain that usually passes very quickly, which differentiates it from incisional pain, characterizes bladder
spasms. Older children may complain of pain in their penis
or rectum. As long as the stent is in place, no medication can
completely eliminate the spasms; however, administering
a prescribed anticholinergic and carefully monitoring the
stent for kinks and for small clots of mucus or blood will
make the child more comfortable. Ensure that any drainage device fitted to a stent or catheter is appropriate for the
childs size. Empty the drainage before it is too full. Sometimes it is helpful to place the drainage bag on a level with
chapter
Antibiotic
Some surgeons advocate the use of antibiotics until the dressing is removed; these can be given in either a prophylaxis dose
or a treatment dose. Limited empiric evidence exists to guide
clinical use or effectiveness of antibiotics after repair, either
while the dressing is in place or after removal.20
Diet
Clear fluids, very dilute juice, or popsicles are encouraged
immediately after recovery from anesthesia, building back to
a normal diet and fluid intake. Many children have decreased
appetite for 2 to 3 days after surgery. This is not a cause for
concern, but parents should encourage adequate fluid intake
to maintain urine flow. To prevent constipation, offer the child
high-fiber foods such as fruits and cereals.
Activity
Quiet, gentle activity is allowed after surgery, although some
centers suggest very little activity after surgery until the dressing is removed. The child should not use any straddle toys or
engage in any activity that requires straddling. Clothing can
hide the dressing and stent and may discourage the child from
handling the repaired penis.
Parental Support
and
Management
of
Problems
Dressing Removal
Typically, the dressing stays in place for 3 to 5 days for distal
repair, 5 to 7 days for proximal repair, or 7 to 10 days for twostage repairs or grafts. This is at the surgeons discretion, and
little rigorous evidence exists in the literature to substantiate
the most effective duration of dressing.17
199
If the dressing falls off before scheduled removal, some centers suggest that parents apply topical antibiotic ointment to the
penile area. Sometimes, when the dressing comes off, the penis
swells slightly; parents should be made aware of this possibility
and given advice to contact the nurse if the child has any difficulties in voiding. It has also been suggested that application of
the ointment may stop the penis from adhering to the diaper.
Removal of the dressing ultimately depends on the type of
dressing used. The urology nurse should be knowledgeable
about those techniques used in his or her own clinical area. Once
the dressing has been removed, some centers advocate the use
of antibiotic ointment to the repaired area or urethrally. Once the
stent has been removed, parents are asked to stop administer
ing the anticholinergic medication. Swimming is allowed after
2 weeks. Older children may resume contact sports after
6 weeks.
Complications
The incidence of complications after hypospadias surgery varies and is reported in the literature.21 Complication rates vary
depending on the severity of the hypospadias, the surgical
approach used, and the experience of the surgeon.
Postoperative
and
Short-Term Complications
Long-Term Complications
Meatal Stenosis. This is a narrowing of the urethra at the
glans penis. The urethral opening looks very small and may
be described by parents as having a pinhole opening. Often,
parents report that their son has a fine urinary stream, but
some may report that their son takes a long time to void. A
uroflow study can be helpful to identify an obstructive flow
rate. For some boys, treatment can be daily urethral dilatation
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Vesicoureteral Reflux
Vesicoureteral reflux (VUR) is the retrograde flow of urine
from the bladder into the upper tracts of the urinary system.
Its causes and treatments are covered in detail in other chapters. The nurse has several roles in caring for children with
VUR, which can include
Diagnostic investigations
Education (of parents and child)
Monitoring of treatments, including early urine testing
and management of breakthrough infection
Bladder training or biofeedback in those children with
low-grade VUR and dysfunctional voiding or overactive
bladder
Care of the child who needs surgical intervention to
correct VUR (STING operation or reimplantation of
ureter)
Investigations
Although diagnostic investigations are often undertaken in
the ultrasound, x-ray, or nuclear medicine departments, some
nurses have a role in catheterizing the child for the investigation. The nurse has a role in educating the child and family
using the methods previously discussed. In some circumstances, sedation may be necessary, and this should be prescribed and administered according to local policy.
Monitoring of Treatment
Because the goal of medical management for VUR is to prevent any urinary tract infections and subsequent renal damage, parents need to know how to collect a urine sample. The
collection of an uncontaminated urine specimen from infants
is challenging.23 Varying techniques are reported in the literature, including clean-catch technique, cotton-wool pads, and
urine bags, with clean-catch remaining the gold standard. If a
sample has been collected, parents should inform the nurse, so
that early effective treatment can be initiated as necessary.
The use of prophylaxis and outcome is well documented
in children with VUR.24 Parents need to be able to administer
the medication regularly and should report any side effects or
Bladder Dysfunction
Some children with VUR experience voiding dysfunction or
overactive bladder.25 Interventions that aim to improve the
childs voiding dysfunction can possibly improve outcomes
for the child with VUR. A good history from the child and parents can help identify voiding dysfunction; questions should
focus on voiding patterns, postures, urge, stream, pain, flow,
and continence. A history of bowel habit should also be taken,
because constipation can lead to poor bladder emptying. Various approaches may be used to encourage the child to establish a good, relaxed voiding routine, including biofeedback26
and possibly anticholinergic medications.27
chapter
pain relief is well managed. This often means that they will
go home with one or more stents in place. The parents should
be advised on how to care for any catheters or stents in place
along with general wound care advice. It is advisable to warn
parents that the urine will be blood stained and the child may
experience a small degree of urinary incontinence, which will
resolve once the bladder has healed. Parents should contact
the nurse if they have any worries or concerns, but especially
if the child experiences any of the following:
Unmanageable bladder spasms
No drainage or passing of urine for more than 8 hours
Pyrexia
Difficulties taking or tolerating the medication prescribed
Unmanageable pain
Wound redness or swelling
The child is reviewed in the clinic 1 week after surgery to
check the surgical wound and remove the stents. Analgesia
and distraction are used as tools to facilitate the childs comfort while the stents are removed. The child can continue
on prophylaxis until the postoperative ultrasound is clear
(1 month after surgery) or until the surgical team evaluates
the child 4 to 6 months after surgery.
201
Surgery
Staged bladder surgery involves initial closure of the bladder
(early after birth) and later repair to the epispadias (at 12 to
18 months of age). Some surgeons have advocated combined
repair of the exstrophy and epispadias defect as the initial
management, closing the bladder and repairing the epispadias
in one procedure. Nursing care for either the staged approach
or complete primary closure is similar.
Preparation is imperative, as discussed previously. To facilitate bladder closure, the pubic bones must be brought closer
together; this is usually done by cracking the pelvic bones
(osteotomy) to allow the pubic bones to be moved closer to the
anterior midline. If closure is done within the first 24 hours of
life, osteotomy may be unnecessary, because the effects of the
maternal hormone relaxin allows the newborns pubic bones
to be brought together more easily. Bony healing of the pelvic
ring takes 4 to 6 weeks. Immobilization of the pelvis is necessary to promote bone healing and to avoid dehiscence of the
newly closed bladder. In the newborn or infant younger than
1 year, usually a spica cast or modified Bryants (gallows) traction is used to immobilize the pelvis. In older infants and children, the external fixator is often used. If a spica cast is used, a
window is cut in the cast for observation of the operative area
and to allow diaper changes. When the cast has completely
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I: Basics
Epispadias Repair
Surgery
For boys undergoing staged reconstruction, closure of the epispadias defect is usually started between 12 and 18 months of
age. The goal is to create a straight penis, achieving the best
length possible from the available tissue, with the meatus at
the tip of the penis. In some cases, closure of the epispadias
defect increases resistance to bladder emptying, resulting in
increased bladder capacity or difficulties with voiding. In the
United States, epispadias repair is often done on an outpatient
basis or with an overnight stay.
Discharge
from
Hospital
and
Management
at
Home
Bladder Augmentation
If the child has a small-capacity neuropathic bladder or a
high-pressure risky bladder, an augmentation is necessary
to minimize long-term risk to the upper tracts and to help
attain continence. This type of surgery is rarely an emergency;
therefore, the admission can be planned and organized for a
time that will minimize family disruption. A vesicostomy31
may be necessary to manage the at-risk bladder quickly, but
this approach does not offer continence: the urine drains into a
diaper or a urostomy bag applied to the stoma.
Essentially, a segment of gut (usually ileum) is augmented
into the bladder, or a neobladder is created from gut in the
child who has previously had a cystectomy (e.g., after pelvic
clearance for tumor). The augmented bladder has a low contractility and therefore can generate high postvoid residuals.
Children who undergo a bladder augmentation and will be
catheterized urethrally after surgery are taught preoperatively
how to perform intermittent self-catheterization. If a child is
unable to catheterize via the urethra (due to sensation, urethral anomaly, poor dexterity, or other reasons), a continent
stoma can be created at the time of bladder surgery. A continent stoma (Mitrofanoff stoma) is a piece of bowel (appendix
or tabularized gut or ureter) that joins the bladder to the
abdominal surface, thereby allowing a catheter to be passed
into the bladder (see Figure 56-8 in Chapter 56).
As with other surgeries, parents and children will need
education and preparation. They will also have to learn new
skills before surgery, and changes to their routines need to be
considered. These changes include
Handling of catheters, because hydrophilic catheters can
be slippery
Learning to perform intermittent self-catheterization,
which may take the child and parent several weeks to
master; the nurse needs to support them during this time
Knowing how to order equipment they will need postoperatively from community sources
Storage and disposal of products
chapter
Postoperative Care
The child who has undergone bladder repair will have several
tubes in place postoperatively, including the following:
Nasogastric tubeto allow the bowel to rest after surgery,
minimizing risk of ileus
Cannulato administer intravenous fluids, because the
child will be taking nothing by mouth until bowel sounds
return
Patient-controlled analgesiato minimize discomfort
Possibly a wound drain
Suprapubic catheterthis will stay in place for at least
3-4 weeks
Possibly a urethral catheterto ensure adequate bladder
drainage
Possibly ureteric stents if the ureter was moved during
surgery
Catheter to the continent stoma (Mitrofanoff) if one was
created at the same time as the augmentation
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I: Basics
impact on their ability to have erections. Discussions concerning sexuality and activity need to be answered honestly. For
some young people, additional psychological support may be
necessary.
Preoperative Care
Education and preparation should be provided, as previously
outlined. Additional considerations include the following:
The child must be physically big enough for the device to
fit.
The child must be mature and motivated to care for the
device.
The child must have sufficient manual dexterity to be able
to use the device.
Many will still have to catheterize, and they should be able
to undertake this preoperatively.
The child (or parents) must be able to make an informed
choice, because the AUS can be problematic. Difficulties
include infection, erosion, and failure of the device.
Concordance with treatment is very important. If the child
or young person is reluctant to engage, then use of this
device is potentially problematic.
Some surgeons request a pubic shave for adolescent
children and skin preparation with an antibacterial wash
to minimize infection of the device at insertion.
Antibiotics will be given as treatment and then
prophylactically to minimize the risk of infection until
healing is complete.
Young men may have questions in relation to their fertility when they have a device in place, as well as any possible
References
For complete list of references log onto www.expertconsult.com
CHAPTER
15
BIOMATERIALS
Living organisms, particularly humans, represent the pinnacle
of chemical self-assembly with cells forming from an array of
biomolecules and complex cellular arrangements arising from
a single cell. The extracellular matrix (ECM) has long been
appreciated for its role in serving as the scaffolding that permits three-dimensional positioning of cells into tissues and,
subsequently, organs. More recently, a greater awareness has
developed for the importance of the ECM in cellular differentiation, migration, and proliferation.17 A cell must know
where to go, what type of cell it should become, and what function it should perform when it reaches its proper position. The
ECM participates in all three of these processes, and should
be viewed as an extension of the cytoskeleton, rather than acting as a simple scaffold.18 Entrapped growth factors and oligopeptide moieties interact with transmembrane receptors on
the cell surface to initiate intracellular biochemical cascades
that affect a cells behavior. These pathways include effectors
on the cells nucleus, which influence movement, growth,
and production of specialized products. Basic research into
embryologic development19 and wound healing20 elucidated
the interdependence between construction and degradation of
ECMs and the cellular components of biologic tissues.
Construction of man-made biologic tissues requires a strategy that provides a functional substitute for the ECM. With
particular attention to polymer-based systems that provide
support for the growth and development of specific cells,
several aspects of chemical and engineering design must be
considered. Primarily, a candidate material must be biocompatible and elicit a negligible immunogenic response from
the host. Because permanently implanted materials pose
long-term risks for infection, rejection, and untoward migration, most currently studied materials are designed to be biodegradable. The rate of degradation must be appropriate to
allow the cellular components to develop sufficient structural
integrity. Until this process is complete, the biomaterial must
retain biomechanical properties specific to the tissue that it
is replacing.21 A polymer scaffolding for a bladder substitute
would have to maintain an adequate amount of distensibility
over its useful lifetime.
Because most methods for tissue engineering involve a cellular component, more complex issues have arisen regarding
the interaction between the cells and the supporting materials. Implantable substances widely used today were simply
designed to minimize the disturbance to surrounding tissues.
Ureteral stents have to resist stone formation, and penile
prosthetics must minimize local inflammatory responses. A
greater sophistication is required, however, if the goal is to
integrate cells within the matrix of the biomaterial. In contrast
to currently available materials, which interact nonspecifically with biomolecules and cells, newer innovations require
205
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I: Basics
chapter
207
208
part
I: Basics
chapter
CELLULAR COMPONENTS
Choices for cells that can be used in tissue engineering and
regenerative medicine include mature, differentiated native
cells and stem cells. Stem cells include adult and embryonic
stem cells, and other progenitor cells with probably a more
limited, but not yet completely defined potential. This is exemplified by animal studies (described later) that have used cell
therapies based on progenitor cells. Cells used in urologic tissue engineering need to achieve the stringent characteristics of
the highly specialized urothelium and the skeletal and smooth
muscle tissue that compose the various organs of the urinary
system.
Native Cells
Urothelium
The urothelium is stratified and displays a regular, polarized
architecture of increasing morphologic complexity and differ
entiation from base to surface.66 It is composed of basal,
intermediate, and superficial cells. Basal cells are small
(approximately 10 m in diameter), form a single layer, and
serve as precursors for the other cell layers. Intermediate cells
are piriform in shape, are 10 to 25 m in diameter, and form a
layer of variable thickness. The highly specialized superficial
or umbrella layer comprises very large, hexagonally shaped
cells with diameters of 25 to 250 m. The umbrella cells have a
long half-life; however, they are rapidly regenerated when the
urothelium is damaged. This regeneration can result from cell
division within any of the three cell layers, and generation of
the multinucleate umbrella cells is likely the result of intermediate cell-cell fusion.67
The umbrella cells have a unique, highly specialized surface
membrane containing thickened plaques of asymmetric unit
membrane that represent the primary transcellular urinary
barrier. The asymmetric unit membrane plaques are formed
by the interactions of four membrane proteinsuroplakins Ia,
Ib, II, and IIIwhich are useful markers of terminal urothelial
cytodifferentiation.68 Urothelial cell layers can be characterized by staining against markers of epithelial differentiation.
Symplekin (a marker of tight junctions), uroplakins, and cytokeratin 20 are found exclusively in superficial cells, whereas
other cytokeratins, such as CK7, CK8, CK13, CK17, CK18, and
CK19, are expressed in basal and intermediate urothelium.69
Skeletal Muscle
The contractile unit of adult skeletal muscle is the myofiber, a
highly specialized syncytial cell containing hundreds of postmitotic myonuclei within a continuous cytoplasm. Repair and
maintenance of myofiber is attributed to a pool of undifferentiated myogenic precursors or satellite cells, located beneath
the basal lamina of myofibers.70 In mature skeletal muscle,
these cells are normally in a quiescent state, and they can be
activated in response to muscle damage or disease.71 Satellite
cells, when activated, express myogenic markers and regenerate damaged myofibers. Satellite cells can be defined by their
position and functionally, by the expression of specific proteins such as M-cadherin, c-Met, Pax7, the adhesion molecule
N-CAM, CD34, and the myogenic regulatory factor Myf5.72
More recent studies suggest that after activation and proliferation, a few satellite cells switch from terminal myogenesis
209
Smooth Muscle
In contrast to striated muscle, smooth muscle cells retain a multifunctional capacity for contraction, migration, proliferation,
synthesis of ECM components, and secretion of growth factors and cytokines. Each phenotypic state is characterized by
expression of a unique set of structural, contractile, and receptor proteins and isoforms that correlate with differing patterns
of gene expression.75 A striking feature of smooth muscle biology is the considerable heterogeneity in the origin of smooth
muscle cells. During embryogenesis, their precursors arise
from three different lineages: mesenchymal cells, neural crest
cells and epicardial-derived cells.76 This confers the regional
specificity required of them to adapt to tissue-specific needs
and is reflected in their varying gene expression patterns that
can be used for tissue engineering purposes.
Stem Cells
Adult Stem Cells
Adult stem cells such as bone marrow stem cells have been
used effectively in clinical practice for replacement after ablative therapy in malignancies. These adult stem cells were
thought to have the potential for transdifferentiation, or the
ability to cross tissue lines and regenerate other tissue types.
More recent studies have shown, however, that these cells are
unable to acquire other phenotypes. The presence of twice the
normal amount of DNA content in transformed adult stem
cells suggests cell fusion rather than transdifferentiation, casting serious doubts on their plasticity.77-79
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part
I: Basics
iffer from hES and hEG cells in that they do not require feeder
d
layers, are not immortal, and do not form teratomas when
implanted in an immunocompromised animal. Several such
cell lines have been established from hEG-derived embryoid
bodies, and mixed cells and clonally isolated lines have been
shown to express various developmentally distinct markers.87
Pluripotential stem cells derived from hES cells and hEG cells
can differentiate into any tissue,82,87 regenerate rapidly, and be
used even when native bladder tissue is unavailable. Smooth
muscle differentiation of mouse embryonic stem cells83 and
hematopoietic and neural differentiation of hES cells have
been reported.84,85 hEG cell derivatives have facilitated neurologic recovery in paralyzed rats with experimentally induced
motor neuron disease.88
Using markers of differentiated smooth muscle such as actin
(SMA-) and myosin heavy chain (SM-MHC), Lakshmanan
and associates89 selected EBD cells derived from hEG cells,
and characterized and co-cultured them with human urothelial and smooth muscle cells on commercially available porcine
SIS. These hEG-derived cells were found to be positively chemotactic in co-cultures with human bladder smooth muscle
and urothelium.90 Frimberger and colleagues91 showed that
hEG-derived cells cultured on SIS had the ability to regenerate bladders in a nude rat model of partial cystectomy. Viable
hEG-derived cells were identified in vivo for 4 weeks using
lipophilic dyes. Factors affecting in vivo survival and differentiation of these cells remain to be elucidated.
Urinary Rhabdosphincter
Strasser and associates98 reported the first clinical study of cell
therapybased treatment of sphincter insufficiency using muscle-derived stem cell transplantation in patients with stress urinary incontinence. More recently, these investigators reported
randomized clinical trials comparing the effectiveness of ultrasound-guided injection of autologous myoblast and fibroblast
with standard endoscopic injection of collagen for treatment of
stress urinary incontinence.4,99,100 Their results confirmed the
efficacy and safety of cell-based therapy to improve the structure and contractile function of sphincter.
In the first North American clinical trial of cell-based therapy for incontinence, transurethral or periurethral injection
of autologous muscle-derived cells was used to treat stress
urinary continence in eight women.101 Three patients received
a repeat injection after 6 months. The injection of musclederived cells in this pilot study showed no short-term or
long-term adverse events. A multicenter study to investigate
a muscle-derived cell dose-response is now ongoing.
Kajbafzadeh and colleagues102 investigated autologous
muscle precursor cell injection in recovery of external urethral
sphincter function in five children with the exstrophy-epispadias
complex and urinary incontinence. During 4 months of follow-up, incontinence score improved in four children; a girl
with very short urethral length and fibrosis had no change in
continence status. This study suggested a potential new therapeutic approach for incontinence therapy in patients with the
bladder exstrophy-epispadias complex.
Ureter
Matsunuma and coworkers5 investigated the efficacy of
the ureteral decellularized matrix as a scaffold material for
a tissue-engineered ureter, and the effect of bone marrow
derived mononuclear cells on the neovascularization of the
scaffold in a canine model. Urothelial cells were obtained from
canine bladders, cultured, and seeded onto the inner surface of
the ureteral decellularized matrix before transplantation into
the subcutaneous space of nude mice or the omentum of nude
rats. To facilitate neovascularization and survival of urothelial cells in the implant, bone marrowderived mononuclear
cells were seeded around the matrices before transplantation.
This study showed that the ureteral decellularized matrix
is a useful scaffold for a tissue-engineered ureter, especially
chapter
Urethra
Bhargava and colleagues2 developed a tissue-engineered buccal mucosa for use in substitution urethroplasty. In this study,
oral keratinocytes and fibroblasts were isolated from the epidermis and dermis of buccal mucosa. These cells were seeded
on the de-epidermized dermis to create a full-thickness buccal
mucosa. Histologically, the tissue-engineered buccal mucosa
closely resembled the native oral mucosa and was suitable for
clinical use.
Penile Tissue
Kwon and coworkers3 reported the possibility of replacing an
entire cross-sectional segment of both corporeal penile bodies with autologous engineered tissues in rabbits. Autologous
corpus cavernosal smooth muscle and endothelial cells were
harvested, expanded, and seeded on the acellular collagen
matrices. An entire cross-sectional segment of rabbit phallus was excised and interposed by engineered matrices. The
211
experimental corporeal bodies showed intact structural integrity on cavernosography, and histologically sinusoidal spaces
and walls lined with endothelial and smooth muscle cells
were observed in the engineered grafts. Grafts without cells
contained fibrotic tissue and calcifications with sparse corporeal elements. This study showed that autologous engineered
corporeal collagen matrices can form corpora cavernosa tissue
structures in a rabbit model.
CONCLUSION
There is undoubtedly a need for urologic tissue substitutes,
either engineered or regenerated, or a combination thereof.
The amalgamation of advances in biomaterial science and cell
biology, with pediatric urologists as catalysts, should prove to
be an exciting and rewarding time for research in this nascent
field.
REFERENCES
For complete list of references log onto www.expertconsult.com
1: Embriology
and the Urinary Tract
PAR T
chapter
BASICS
KIDNEY
c h a p te r
II
I
16
Diagnosis
The diagnosis of renal ectopia may be suspected antenatally,
especially if hydronephrosis is also present. Routine abdominal and pelvic ultrasound for another indication may result in
an incidental diagnosis of renal ectopia. Vesicoureteric reflux is
associated with an incidence of 30% for unilateral renal ectopia
and 71% for bilateral renal ectopia,9 and routine investigations
after urinary tract infection may result in the diagnosis.
If obstruction is suspected on ultrasound, drainage may
be assessed using a Tc 99m MAG3 renal scan, but the areas
of interest must be appropriately selected. Occasionally, com
puted tomography (CT) or magnetic resonance (MR) urography may provide additional information.
Additional malformations of the contralateral kidney or
cardiovascular, respiratory, urogenital, or skeletal systems are
common (Table 16-2).10,11 Genital malformations in women
may cause problems during menstruation, conception, and
pregnancy.
Outcome
Patients do not require intervention for renal ectopia, unless
they develop a complication. The natural history of vesicoureteral reflux in ectopia seems to be similar to vesicoureteral
reflux in normal kidneys with spontaneous resolution to be
Incidence
Location
Notes
Pelvic
Most common
Iliac
Rare
Thoracic
Rarestapproximately 1:16,000
Crossed
Rareapproximately 1:7000
Across midline
213
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part
II: Kidney
Figure 16-1 Pelvic kidney. Intravenous urography shows renal calyces of a kidney lying within the pelvis.
ABNORMAL FUSION
During ascent, if the two developing kidneys come into contact in the midline, a horseshoe kidney results. If the lower
pole of one kidney comes into contact with the upper pole of
the contralateral kidney, cross-fused renal ectopia may result.
Retrocaval ureter
Genital
Female (75%)
Bicornuate, unicornuate, or absent uterus
Duplicate or rudimentary vagina
Mayer-Rokitansky
Male (15%)
Undescended testis (5%)
HORSESHOE KIDNEY
Horseshoe kidney is the most common fusion abnormality.
The reported incidence is 1:400 to 1:1800 with a male-to-female
ratio of 2:1.14,15 A genetic basis for the anomaly has been postulated.16 Inherited defects such as cystic renal disease occur
with the same incidence as in normal kidneys.
Hypospadias (5-10%)
Anatomy
Duplicate urethra
Cardiac
Various anomalies
Skeletal
Scoliosis
Hemivertebrae
Adrenal
Rare
Others
Fanconi syndrome
Conjoined twins
anticipated, although this may be less likely in girls.12 Pyeloplasty for PUJ obstruction may be necessary, and this may
require a transperitoneal approach, either open or laparoscopic
depending on the precise position of the kidney.
Renal stones may be treated with extracorporeal shock
wave lithotripsy and percutaneous nephrostolithotomy with
good results. Access to a pelvic kidney for percutaneous
nephrostolithotomy may be difficult, but there are reports
of laparoscopic guidance to help with a transperitoneal
approach.13
Diagnosis
The diagnosis is usually made during routine investigations
of the urinary tract. Ultrasound may show the abnormality of
position and the connecting isthmus. Isotope studies usually
chapter
215
Figure 16-2 Thoracic kidney. CT scan (with intravenous contrast agent) shows the right kidney lying within the thoracic cavity.
Figure 16-3 Horseshoe kidney. CT scan (with intravenous contrast agent) shows renal tissue with an isthmus crossing the midline.
reveal a functioning isthmus (Fig. 16-4). Intravenous urographic appearances are often classic with renal malrotation
and medially pointing lower pole calyces. The upper ureters are often displaced laterally by the parenchymal bridge.
Vesicoureteric reflux has been reported in 80% of cases,18 with
30% overall having recurrent urinary tract infection. Micturating cystogram may suggest the diagnosis. Gadoliniumenhanced MR urography can show excellent anatomic
information (Fig. 16-5).
Associated Abnormalities
Associated cardiovascular, genitourinary, skeletal, and
neurologic abnormalities are reported in approximately
80%of cases.19 There is an increased incidence of horseshoe
kidney in trisomy 18 (20%) and Turner syndrome (7%). Later
in life, there is an association with abdominal aortic aneurysms.20
Outcomes
Horseshoe kidneys are often asymptomatic,21 and outcomes
depend on associated urologic problems. Xanthogranulomatous pyelonephritis has rarely been reported.22
PUJ obstruction, more often left-sided, is the most common indication for surgical intervention. This obstruction
may arise as a result of an intrinsic PUJ problem, impaired
drainage secondary to the isthmus, or occasionally crossing
vessels.23 Depending on the position of the horseshoe, the
PUJ may be approached retroperitoneally, either anteriorly or
through the flank. A transperitoneal approach is occasionally
necessary, and this has now been described using laparoscopic
techniques. It is no longer considered necessary to divide the
isthmus.4 Good results have been reported using ureterocalicostomy for reconstruction, rather than a routine pyeloplasty,
allowing dependent drainage.24
Renal calculi can be seen in 20% of cases. Extracorporeal
shock wave lithotripsy may be used with similar success rates
216
part
II: Kidney
DMSA
Renal
RT
Anterior
Scan
LT
Anatomy
If fusion occurs, the upper pole of the crossed kidney fuses to
the lower pole of the normally positioned kidney. The kidney
usually remains incompletely rotated with the pelvis anterior.
Diagnosis
Most fused kidneys remain undetected; when fused kidneys
are detected, it is because of pyelonephritis (60%), loin mass
(33%), or incidental discovery (7%) on routine screening for
urinary abnormalities.37 CT or MR urography may allow better definition of the exact anatomic picture (Fig. 16-7).
Associated Abnormalities
There is a high incidence of associated malformations, particularly if there is only one ureter. Malformations of cardiac,
musculoskeletal, genital, gastrointestinal, anorectal, and renal
systems are reported, occasionally as part of the VACTERL
(vertebral, anal, cardiac, tracheal, esophageal, renal, and limb)
association.
chapter
217
Figure 16-6 Crossed renal ectopia. A, Cross-fused ectopia. B, Crossunfused ectopia. C, Unilateral crossed ectopia. D, Bilateral crossed
ectopia. (A-D, From Ritchey M. Anomalies of the kidney. In:
Kelalis PP, King LR, Belman AB, eds. Clinical Pediatric Urology. 3rd ed.
Philadelphia: Saunders; 1992.)
CONCLUSION
Anomalies of kidney position and fusion are rare. Most of
these anomalies remain asymptomatic throughout life. For
patients affected by imperfect drainage, recurrent infection, or
urolithiasis, renal function rather than position should dictate
management.
REFERENCES
For complete list of references log onto www.expertconsult.com
renal ectopia. (Courtesy of Andrew Kirsch, Clinical Professor of Urology, Atlanta, GA.)
CHAPTER
17
HISTOLOGY
Gross examination of a typical MCDK reveals multiple, variable sized cysts in a bunch-of-grapes type of cluster with
very little intervening stroma, a loss of reniform configuration,
and an absence of a calyceal collecting system (Fig. 17-1). The
renal artery and vein are usually hypoplastic and sometimes
absent.8 The ureter may be absent, but is usually atretic. In cases
of unilateral renal agenesis, this atretic ureter may be the only
clue to a regressed MCDK. The cysts were previously thought
to be noncommunicating. Felson and Cussen5 reported communications to exist in histologic studies of MCDKs, however,
an observation that has since been confirmed by several investigators.9,10 Glassberg and Kassner11 and Dewan and Goh12
performed intracystic contrast injection studies to show the
connections radiologically. Twenty of 22 MCDKs (including
5 with the hydronephrotic variant) reported in the literature
were found to have connections between the cysts after undergoing intracystic contrast injection studies (Figs. 17-2 and
17-3). Glassberg and Kassner,11 as had Griscom and associates13 previously, found one or more pits (or orifices) at the
hilar aspects of the cysts. These pits communicate with the
tubular structures between the cysts.
Microscopically, the kidneys have features of abnormal
metanephric differentiation. The AAP Section on Urology
Committee on Terminology, Nomenclature, and Classification
chapter
219
Figure 17-2 Hydronephrotic variant of a multicystic dysplastic kidney (A), with the corresponding intracystic contrast agent injection showing
communication between cysts (B).
ETIOLOGY
The etiology of MCDK disease is unclear. Many investigators
have proposed that obstruction is the primary factor involved
in the development of dysplasia.17,19 Felson and Cussen5 in
1975 viewed the multicystic kidney as an extreme form of
hydronephrosis that occurs secondary to atresia of the ureter
or renal pelvis. Cystic dysplasia of an entire upper pole can be
seen in kidneys with duplicated collecting systems, especially
associated with ureteroceles. Bilateral cystic dysplasia also
may be seen secondary to posterior urethral valves. Animal
220
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II: Kidney
models involving ligation of the ureter during early gestation have shown the induction of dysplasia.19-22 Multicystic
dysplasia secondary to obstruction has not been simulated in
an animal model, however.
Shibata and Nagata23 performed detailed morphologic
studies of fetal dysplastic kidneys to show that early in utero
obstruction causes urine retention in the developing nephrons, leading to multiple cyst formation. They reported that
nephron induction with filtrating function occurs before the
development of cysts; early fetal urinary tract obstruction
causes cystic formation in the developing nephrons, which
subsequently disrupts nephron induction and tubular development. Shibata and Nagata23 also cited the importance of
further investigation into abnormalities in the activity of transcription factor PAX2 and antiapoptosis protein BCL2 in the
pathogenesis of renal dysplasia.24
In contrast, Hildebrandt25 attributed the frequent association of an MCDK with ureteral or renal pelvis atresia to failure
of union of the ureteral bud and the metanephric blastema, and
the subsequent abnormal induction of the metanephric blastema by the ureteral bud. Matsell and colleagues15 have shown,
however, that there is no complete block in union because areas
of normal nephrogenesis with collecting ducts may be seen in
MCDKs. They instead propose that it may be abnormalities in
branching of the ureteral bud that are responsible for progressive local histopathologic changes. This proposal is supported
by previous findings of abnormal metanephric development
(i.e., dysplasia) with ectopic ureteral orifices (i.e., ureteral budding) reported by Mackie and Stephens.26
Osathanondh and Potter27 proposed that an ampullary
abnormality in which there is premature termination of
ampullary divisions results in a decreased number of generations of tubules, with the last generation being cystic. These
abnormal tubules fail to induce metanephric differentiation.
The occasional normal or near-normal nephron is the result of
a rare normal ampulla and collecting tubules.
More recently, Spencer and Maizel28 discovered that alterations in epithelial (ureteral) and mesenchymal cells by inhibition
of glycosylation of the extracellular matrix could induce dysplasia without obstruction. The results of these experiments with
chick embryos support the theory that dysplasia is the result
of a disruption in normal epithelial-mesenchymal interaction
during the induction of renal tubules. The important extracellular matrix constituents include fibrous proteins (collagen and
elastin) and adhesive glycoproteins (fibronectin and laminin)
embedded in a gel of proteoglycans (syndecan). In normal
nephrogenesis, there is loss of fibronectin and collagen types I
and III, which are replaced by other constituents, mainly laminin and syndecan. This process occurs because of interaction
between the ureteric bud and the metanephric mesenchyme.
Any alteration in the normal interaction can result in dysplasia.
To support this theory further, Radotra and associates29
from India published a study in 2004 that examined the
immunohistochemical expressions of adhesive glycoproteins,
laminin, and fibronectin in 25 autopsy specimens of renal
dysplasia and normal age-matched control cases. This study
found that compared with normal nephrogenesis, there was
significantly less expression of laminin and more expression of fibronectin in the extracellular matrix of dysplastic
kidneys.
More recent studies have focused on finding the genes
involved with renal development whose abnormal expression
is responsible for renal dysplasia. Various genes have been
identified, including BMP4, FOXC1, KAL, EYA1, and AGTR2;
mutations in these genes have been identified in ectopic budding of the ureter from the wolffian duct and the subsequent
urogenital anomalies.30 One of the most studied is PAX2, a
CLINICAL FEATURES
MCDK disease is one of the most common causes of an abdominal mass in infants.13,32-35 The incidence of MCDK disease is
estimated to be 1:3100 to 1:4300,36 a much higher number than
was reported in the era before routine antenatal ultrasound.
Previously, the diagnosis was most often made in infancy in
the presence of a palpable abdominal mass, which is found
in 22% to 37% of cases.35-37 It is difficult to ascertain what percentage of prenatally diagnosed MCDKs would have been
identified by palpation during routine neonatal examination
had the diagnosis not been made previously. Diagnosis may
be made at 15 weeks of gestation on routine prenatal screening
ultrasound; mean age of diagnosis is 28 weeks (range, 21 to
35 weeks).38,39 MCDK is more common on the left, with a
slightly greater incidence in boys.33,40,41 Postnatal presentation
includes palpable abdominal mass, flank pain, urinary tract
infection (UTI), or hypertension. The October 2000 database
of the AAP Multicystic Kidney Registry contains 903 patients
(525 boys and 378 girls). The number of left-sided lesions was
slightly higher than the number of right-sided lesions (471 leftsided lesions versus 417 right-sided lesions; 2 were bilateral,
and 13 were not stated); 685 were diagnosed by antenatal ultrasound, and 103 were detected as a flank abdominal mass.42
Most cases of MCDK are sporadic, although there have been
case reports of families who exhibit an autosomal dominant
inheritance pattern of MCDK.43
Autopsy study of prenatally detected bilateral MCDKs
reported a frequency of 19% to 34%.36,44,45 Reports from case
series of bilateral postnatal MCDKs indicate an incidence of
2% to 8%.46,47 This condition is incompatible with life, and
infants affected usually have other syndromal congenital
malformations, including Potter syndrome, Turner syndrome,
Alagille syndrome, Waardenburg syndrome type I, Goldenhar
syndrome, DiGeorge syndrome, Joubert syndrome, trisomy X,
and Meckel syndrome.48-56
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221
EVALUATION
Most MCDKs are detected early in the antenatal period because
of routine use of fetal ultrasound. Abdominal masses in neonates, infants, and children are most commonly of urologic
origin, most likely hydronephrosis or MCDKs.85,86 Gloor and
colleagues87 showed that greater than 50% of infants with an
antenatal diagnosis of urinary tract abnormalities had either
hydronephrosis or MCDKs. Distinguishing hydronephrosis
222
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II: Kidney
from MCDK disease is essential because the approach to therapy and indications for surgery differ in each. If not detected
on antenatal ultrasound, an MCDK may manifest in infancy
or childhood as abdominal fullness or an abdominal mass. It
may be discovered later in life during an evaluation for UTI,
hematuria, hypertension, or other concurrent congenital or
genitourinary abnormality.
Ultrasound in combination with renal scintigraphy yields
an accurate diagnosis of MCDK disease in 93% of suspected
cases.88 In the rest, confusion lies in distinguishing hydronephrosis from a cystic dysplastic kidney with a single
predominant cyst. Postnatal ultrasound evaluation of the
kidneys should be performed to confirm the prenatal findings. Generally, there is a loss of a normal reniform configuration with minimal, if any, parenchyma and cysts of varied
sizes that are haphazardly arranged without a distinct larger
central or medial cyst. A central medial cyst suggests the presence of a renal pelvis and could represent either the hydronephrotic form of MCDK disease or UPJ obstruction. When
there is an identifiable renal sinus, the diagnosis is more likely
hydronephrosis. Stuck and coworkers88 have characterized
ultrasound features of MCDK disease: the presence of sharp
interfaces between multiple, randomly arranged, and variably sized cysts, the largest cyst with nonmedial location; a
lack of an identifiable renal sinus; and an absence of renal
parenchyma.38,88
Suspicious ultrasound findings should be correlated with
renal scintigraphy findings of the absence of renal function.
Occasionally, renal scintigraphy may show a functional segment associated with an MCDK in a duplicated system.65
Ultrasound may obscure the normal parenchyma because
of the overgrowth of the multicystic dysplastic segment.
Parenchymal imaging agents such as Tc 99m DMSA have
traditionally been used. This agent is absorbed and retained
by proximal tubular cells, providing an excellent picture of
functional parenchyma or defects indicating nonfunctioning
parenchyma. Because the Tc 99m DMSA label is retained and
not excreted, the inability to assess the excretory phase of
renal function makes it impossible for Tc 99m DMSA to distinguish accurately an MCDK from hydronephrosis caused by
UPJ obstruction.89,90 If Tc 99m DMSA shows nearly complete
or complete absence of function, the diagnosis is much more
likely to be an MCDK rather than UPJ obstruction. Keep in
mind that MAG3 is an excellent agent to evaluate function, in
particular when evaluating for obstruction with a furosemide
renogram and when function is thought to be present, but in
general Tc 99m DMSA is the agent of choice when trying to
identify if any functional tissue is present at all.91,92 Aggressive
evaluation and treatment of the only functioning kidney are
vital.
Traditionally, complete evaluation of an MCDK has also
included a VCUG. Contralateral VUR has been reported to
be associated with an MCDK in 15% to 28% of cases in the
literature.36,63,66-69 Early detection of contralateral VUR is
important in the prevention of pyelonephritic scarring and
deterioration of renal function in the only functioning renal
unit.67 Blane and associates93 reported that ultrasound alone
cannot be relied on to screen selectively for VUR based on
their study that found normal ultrasound findings in 74%
of refluxing units. Ismaili and associates94 challenge routine
VCUG, however, and assert that VCUG is unnecessary as
routine screening in patients with MCDK. In their study of
76 newborns with antenatally detected MCDK, Ismaili and
associates94 found that two successive normal neonatal renal
ultrasound scans can rule out any clinically significant contralateral anomalies, making VCUGs unnecessary. Only four
(7%) of the infants with two normal renal ultrasound scans
had contralateral VUR; all were grade I-II and resolved spontaneously by age 2.
Siegel and Feldenberg95 evaluated the clinical course of
35 patients with MCDKs to predict which patients were
at greatest risk for significant damage to the contralateral
solitary kidney independent of the results of a VCUG. The
patients were divided into simple MCDK (no associated genitourinary anomalies) and complex MCDK (bilateral dysplasia
or associated genitourinary anomalies not including VUR). In
the simple MCDK group, all patients had an excellent clinical
outcome with no damage to the contralateral kidney. Presence
or absence of VUR was not a predictor of UTI. In the complex
MCDK group, the patients had a higher rate of contralateral
kidney damage; however, associated structural genitourinary
anomalies were stronger predictors of prognosis than the
presence or absence of UTI or VUR.
Fetal renal artery Doppler studies have been investigated
to determine if postnatal renal function can be predicted in
morphologically abnormal prenatal kidneys. Gill and colleagues96 studied renal artery Doppler waveforms of five
fetuses suspected to have unilateral MCDK disease with the
contralateral kidney of each serving as control. Renal artery
flow was absent in the suspected moieties, but present in the
contralateral unaffected moieties. Postnatal scintigraphy was
used to confirm nonfunction in the cystic kidneys. One kidney,
with a duplex system, had a cystic upper moiety and a hydronephrotic noncystic lower moiety. Doppler waveforms were
detected in the lower, but not in the upper, segment. Postnatal
evaluation with duplex Doppler studies of the renal artery
and vein also showed abnormal waveforms. Duplex Doppler
ultrasound may serve as an adjunct in diagnosing MCDK disease and perhaps may replace postnatal renal scintigraphy.96
The diagnosis of an MCDK is suspected on renal ultrasound (loss of reniform configuration, multiple cysts, nonmedial location of largest cyst, absent pelvis, minimal to absent
renal parenchyma) and confirmed by renal scintigraphy (lack
of function). Postnatal imaging of the contralateral kidney
with ultrasound is important to detect abnormalities; however, it remains controversial as to whether routine VCUG is
necessary if the renal ultrasound scan is normal.
NATURAL HISTORY
Long-term data are now available for several large studies of
patients with MCDK. These data have provided information
about the natural history of the disease.
Infection
There has been no definitive correlation between MCDK and
increased risk of UTI. The concern for increased incidence of
infection is mainly due to the higher rate of abnormalities in
the contralateral kidney.
In the study by Aslam and Watson63 of 202 patients with
MCDKs, 20 patients had UTIs; none required hospitalization or parenteral antibiotics, and no patients developed
renal scarring. Only seven of these patients had documented
VUR. In another series of 43 patients with MCDKs managed
conservatively, only 4 patients had UTIs, and no patients had
contralateral renal scarring.83
Hypertension
Hypertension has been reported in patients with MCDK, and
the risk of hypertension has often prompted parents to choose
nephrectomy over conservative management. Studies have
chapter
suggested that the mechanism of hypertension is ischemiainduced renin secretion in the juxtaglomerular apparatus
of mature glomeruli and interlobular arteries in the scarred
areas of the dysplastic kidney.97 In a large-scale review of
the literature, Narchi98 analyzed 29 studies of patients with
MCDKs and found that only 6 of the 1115 children developed
hypertension; the probability of a child with unilateral MCDKs
developing hypertension is 5.4 per 1000 (95% confidence interval 1.93 to 11.7 per 1000), which is similar to the risk in the
general pediatric population.99 Critics point out that there
was no uniform definition of hypertension and minimal longterm follow-up of most of the patients; there have also been
several studies that showed a subtle increase in blood pressure in children with a solitary kidney from other causes.100
In the Aslam and Watson63 study, however, after 10 years of
follow-up, there was still no child who developed hypertension. A survey of physicians reported that 15% have treated
hypertension related to MCDKs,101 suggesting that hypertension associated with MCDKs may be underreported,102 perhaps because of the previous lack of antenatal screening with
ultrasound.
The literature on surgical causes of hypertension does not
report MCDKs as a significant cause of pediatric hypertension.103,104 Numerous small series have shown resolution of
hypertension after nephrectomy.105-109 Webb and coworkers109
noted poorer rates of resolution of hypertension after nephrectomy with increasing age, possibly resulting from hypertension-induced damage of the contralateral, originally healthy
arteriole. Cases of hypertension associated with MCDKs and
cured by nephrectomy are reported in the literature. The
true risk of hypertension cannot be assessed, however, given
sporadic case reports. Routine surgical treatment of MCDKs
based on the risk of hypertension cannot be substantiated, but
when hypertension is diagnosed in a child with an MCDK,
prompt surgical excision is recommended to ensure the best
chance of cure.
Malignancy
In a review of the literature, Perez and associates70 found
multiple reports of malignancy arising in MCDKs, including
renal cell carcinoma (5 cases),110-114 malignant mesothelioma
(1 case),115 and Wilms tumor (11 cases).6,116-122 Renal cell carcinoma is common, with 25,000 new cases reported each year.58
This fact, in conjunction with Beckwiths119 observation that
renal cell carcinoma may be difficult to distinguish from multicystic renal carcinoma, makes one question whether there is
truly an increased risk above that of the normal population.
Wilms tumor has a more solid association with MCDKs,
as shown by Perez and associates70 in a thorough review.
The dilemma arises in ascertaining the frequency with which
Wilms tumor arises in MCDKs. Noe and Raghavaiah123 used
a 5% incidence of nodular renal blastema in MCDKs and a 1%
incidence of Wilms tumor from nodular renal blastema124 to
calculate a 0.05% risk of Wilms tumor in MCDK disease. This
finding was corroborated by Perez and associates,70 who used
the risk of Wilms tumor, risk of MCDKs, and yearly birth
rate to estimate the risk of Wilms tumor arising in MCDKs to
be 3:10,000 to 10:10,000 (0.03% to 0.1%). They estimated two
to eight new cases of Wilms tumor in children with MCDKs
each year if there are 6000 to 8000 children with MCDKs in a
given year. In a 30-year review, however, only six such cases in
the United States have been reported, suggesting the true risk
of Wilms tumor in children with MCDKs should be significantly lower than the calculated rate of 0.03% to 0.1%.70
Beckwith125 reported no increased risk of Wilms tumor
in dysplastic kidneys in his experience. According to a more
223
Regression
Pedicelli and colleagues noted spontaneous regression in 809
MCDKs.129 In a retrospective review, Rottenberg and colleagues130 reported 55 cases, of which 40% (22) of the MCDKs
regressed completely at a mean of 21 months, and 33% (18)
decreased in size as shown by ultrasound evaluation. Kessler
and associates37 reported retrospectively on 14 of 23 (61%)
patients with spontaneous regression at a mean of 10 months.
A prospective study of the natural history of MCDK showed
complete regression in 21% (7 of 33) and a decrease in size in
61% (20 of 33) at 24 months.131 As of October 2000, the AAP
Multicystic Dysplastic Kidney Registry had follow-up data on
622 patients at 1 to 3 years after diagnosis. Of these, 286 (46%)
MCDKs were smaller, 26 (4.2%) were larger, 211 (33.9%) were
unchanged, and 99 (15.9%) had disappeared completely.42 At
10 years of follow-up, Aslam and Watson63 showed that 33%
had involuted at 2 years of age, 47% at 5 years, and 59% at
10 years (Figs. 17-4 and 17-5).
Prenatal regression also can occur and may be mistaken
for unilateral renal agenesis.35,45 Many have proposed a
common embryologic insult resulting in differing degrees
of malformations, ranging from renal agenesis to dysplastic
kidney to MCDK disease.32,57,58 Ashley and Mostofi132 showed
19 of 157 cases of unilateral renal agenesis in the presence of
an ipsilateral ureter, suggesting the former presence of a renal
unit. The etiology of unilateral renal agenesis remains multifactorial, however.
Regression does not imply cure or eliminate the risk of
morbidity associated with MCDK disease. Some studies have
shown that the risk of hypertension and malignant degeneration is not eliminated with regression.109,114 Gough and
associates133 reported on four patients with regression by
ultrasound criteria who underwent exploration to remove any
possible residual tissue according to the parents wishes. All
four patients were found to have substantial residual masses
proved by histologic examination at the time of surgery.
Involution is accomplished by progressive decompression
of cystic fluid, leaving behind the thin, dysplastic parenchyma,134,135 although Avni and colleagues39 have reported
the absence of tissue at exploration. In addition, there is no
224
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II: Kidney
e vidence that size predicts the risk of hypertension or malignant transformation.35 Early ultrasound detection of malignant degeneration proves to be difficult in a small, involuted
kidney. Screening for UTI, microhematuria, and the urine cytologic appearance is unreliable in the presence of ureteral atresia
that separates the kidney from the lower urinary tract.6,35
TREATMENT
Conservative management of MCDK disease is supported
by the high rate of spontaneous regression and low rate of
hypertension, UTI, and malignancy. The regimen for followup study is quite varied. Each visit should include a physical examination, evaluation of blood pressure, urinalysis,
and a urine culture if needed. There is no consensus for the
ideal interval of screening ultrasound. The study by Aslam
and Watson63 proposes that after 2 years, the next clinical and
Figure 17-5 Ultrasound studies of a multicystic dysplastic kidney at birth (A) and at 9 months of age (B) show an almost completely regressed
kidney.
chapter
225
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
18
GLOMERULONEPHRITIS IN CHILDREN
Sharon Phillips Andreoli
HYPOCOMPLEMENTEMIC
GLOMERULONEPHRITIDES
Serologic studies and complement levels are important in evaluating a child with clinical and laboratory findings suggestive
of GN. The third component of complement (C3) is usually
depressed in postinfectious GN, in MPGN, in GN associated
with systemic lupus erythematosus (SLE), and in nephritis of
chronic infection (see Table 18-1).2,5,11 MPGN is divided further
into three subtypestype I; type II, also called dense deposit
disease; and type III. Postinfectious GN and MPGN are primary renal diseases, whereas SLE and nephritis of chronic
infection are systemic diseases that involve the kidney. C4 is
usually depressed in type I and III MPGN and in lupus GN,
suggesting that complement is activated by the classic pathway, whereas C4 is usually normal in type II MPGN and in
postinfectious GN, suggesting that complement activation
is via the alternative pathway in these diseases. The mechanism of complement activation and hypocomplementemia is
complex and seems to be related to increased catabolism and
decreased synthesis. In MPGN, increased degradation is associated with the presence of C3 nephritic factor in 30% to 75%
226
Postinfectious Glomerulonephritis
Epidemiologic studies in siblings of children with confirmed
postinfectious GN have shown that some have urinary abnormalities compatible with mild postinfectious GN.13 Some children with postinfectious GN may be asymptomatic, but most
who come to medical attention have an abrupt onset of an
acute nephritic syndrome that includes hematuria, fluid retention, and hypertension with or without renal insufficiency. The
typical child presents with an acute nephritic syndrome 7 to
21 days after an infection. Hematuria is gross in 30% to 50% of
cases. The degree of hypertension varies; blood pressure may
be only mildly elevated, or the presenting symptoms may be
related to hypertensive encephalopathy in a few cases. Edema
is usually due to fluid retention, rather than the nephrotic syndrome, and pulmonary congestion and cardiomegaly are common in postinfectious GN. Renal insufficiency is usually mild,
but occasionally may be severe. Postinfectious GN typically
occurs in children 2 to 12 years old.
In 80% to 90% of cases, postinfectious GN occurs after an
infection with a nephritic strain of group A beta-hemolytic
streptococcus; postinfectious GN is frequently called poststreptococcal GN. The preceding streptococcal infection is
usually a pharyngeal or pyodermal skin infection. In a few
cases, GN may follow viral, fungal, or other bacterial infections. Hematuria is seen in nearly all cases, and gross hematuria with tea-colored or cola-colored urine is common. The
proteinuria may range from several hundred milligrams to a
few grams per day, and the serum albumin is usually mildly
depressed. Proteinuria sufficient to result in hypoalbuminemia and edema is rare, occurring in less than 10% of cases,
and the edema in postinfectious GN is usually due to fluid
retention, rather than hypoalbuminemia. The C3 is low in 85%
to 95% of cases, and the Streptozyme test is positive when the
preceding infection was a streptococcal infection.
An antistreptolysin O (ASO) titer and the Streptozyme
test are the two tests commonly used to evaluate for previous
streptococcal infection. The ASO titer measures antibodies
only to streptolysin O and increases after a preceding pharyngeal infection, but there is a significantly blunted response
when the preceding infection is pyodermal.14-16 This is thought
to be due to lipids and cholesterol esters in the skin interfering in antigen recognition of the streptolysin O antigen. The
Streptozyme test detects antibodies to approximately five
streptococcal antigens, including streptolysin O, hyaluronidase, DNAase B, NADase, and other less well-defined streptococcal antigens.16 Each test is positive in approximately 16%
to 18% of healthy children. Because of the high positive rate
in healthy children, a positive Streptozyme test in a patient
with hypocomplementemic GN does not confirm that the
nephritis is truly poststreptococcal. Although a positive
Streptozyme test supports a presumptive diagnosis of poststreptococcal GN, a negative Streptozyme test suggests an
chapter
227
in Children
Hypocomplementemic glomerulonephritis
Postinfectious glomerulonephritis
Membranoproliferative glomerulonephritis
Systemic lupus erythematosus nephritis
Nephritis of chronic infection
IgA-related glomerulonephritis
IgA nephropathy
Henoch-Schnlein purpura
Systemic lupus erythematosus nephritis
Membranous glomerulonephritis
Rapidly progressive glomerulonephritis
Postinfectious glomerulonephritis
Membranoproliferative glomerulonephritis
Systemic lupus erythematosus nephritis
Henoch-Schnlein purpura
ANCA-positive glomerulonephritis
Pauci-immune rapidly progressive glomerulonephritis
Wegener granulomatosis
Polyarteritis nodosa
Anti-GBM antibody disease
Goodpasture syndrome
ANCA, antineutrophil cytoplasmic antibody; GBM, glomerular basement
membrane.
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Membranoproliferative Glomerulonephritis
MPGN is also known as mesangiocapillary GN. MPGN is
divided into three subtypestype I, type II (dense deposit disease), and type III. Type I and type III are similar in their clinical, laboratory, and pathologic characteristics; kidney biopsy
specimens from children with type II MPGN show distinct
pathologic features, as described later.22 In pediatric patients,
70% to 80% of the cases of MPGN are types I and III, and 20%
to 30% are type II.22 MPGN is very rare in toddlers and preschool-age children and is most common in adolescents. The
age at onset of type I disease is slightly older compared with
that of type II disease. In a large study of adult and pediatric
patients with MPGN, the median age of presentation of type I
disease was approximately 21 years versus 11.5 years for type
II disease.22 Other conditions associated with type II MPGN
include partial lipodystrophy and ophthalmologic abnormalities in the retinal epithelium called basal laminar drusen, which
were more advanced in patients with the longest duration of
type II disease.23
Many children with MPGN present with nephrotic syndrome with or without gross hematuria, whereas a small
percentage present with RPGN.6,22,24 Many children eventually found to have MPGN are first found to have hematuria
and proteinuria during a routine physical examination.
Hypertension is present in approximately one fourth to one
third of children early in the course of the disease.7 Although
clinical and laboratory findings cannot predict the subtype, it
has been suggested that type III MPGN may be more likely
to manifest with asymptomatic hematuria and proteinuria
compared with types I and II.8
Urinalysis usually shows hematuria and proteinuria.
Hematuria may be gross or microscopic. Proteinuria may
range from a few hundred milligrams to several grams per
day, leading to hypoalbuminemia, edema, and hyperlipidemia
characteristic of the nephrotic syndrome. Unless the child has
RPGN, blood urea nitrogen and creatinine levels at presentation are usually normal to slightly elevated. C3 is depressed in
70% to 90% of cases, and a low C3 is important in establishing
a preliminary diagnosis of MPGN.22 The depressed C3 does
not correlate with prognosis, disease activity, or progression
of the renal disease. As described earlier, the mechanism for
chapter
deposit (arrow) with mesangial interposition and mesangial deposits characteristic of membranoproliferative glomerulonephritis type
I. (From Andreoli SP. Chronic glomerulonephritis in childhood:
membranoproliferative glomerulonephritis, Henoch-Schnlein purpura nephritis, and IgA nephropathy. Pediatr Clin North Am. 1995;42:
1487-1504.)
229
230
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II: Kidney
Clinical Symptom
Rash
Affected (%)
Range (%)
68
14-94
Fever
78
54-94
Arthralgia
75
44-100
Cardiac disease
40
19-56
Neurologic disease
30
3-48
Renal disease
82
28-100
chapter
the use of ventriculoperitoneal shunts rather than ventriculoatrial shunts, these infections are uncommon. Currently,
chronic infections with hepatitis viruses, human immunodeficiency virus (HIV), and syphilis are more important in the
United States, whereas malaria, parasitic infection, and HIV are
more common in developing countries. Although not invariably the case, the symptoms of the primary infection are usually the predominant clinical manifestation, and glomerular
disease is a secondary issue that may be noted only incidentally.
In nephritis of chronic infection, hematuria and proteinuria of
some degree are usually present. The serum C3 level is usually
depressed by uncertain mechanisms, but it is presumed to be
due to activation of the immune system as a result of chronic
deposition of antigen with in situ immune complex formation
or deposition of circulating immune complexes. Rheumatoid
factor also may be positive, presumably as a result of the formation of antibodies resulting from chronic immune stimulation.
The pathology of nephritis of chronic infection varies
and may range from mild mesangial proliferation with or
without focal crescent formation to RPGN in severe cases.
Immunofluorescent studies are usually positive, reflecting
the presumed underlying immune complex pathophysiologic mechanisms of the disease. Immune complex deposits
evident on electron microscopy are quite variable because
deposits may be located in the mesangial areas or in subendothelial or subepithelial locations. Therapy for nephritis of
chronic infection is directed at treating the underlying infection because eradication of the infection should eliminate
further renal injury.
IMMUNOGLOBULIN ARELATED
GLOMERULONEPHRITIS
Several different renal diseases are associated with predominant deposits of IgA in the kidney, including IgA nephropathy, HSP, and SLE (see Table 18-1). IgA nephropathy has been
described as the most common GN leading to chronic kidney
disease worldwide.9,59 HSP is a common vasculitic lesion in
children with a peak incidence at 4 to 5 years of age. Most
patients with HSP do not develop chronic kidney disease, but
complications from HSP nephritis may not become apparent
until adulthood. A long-term follow-up study showed that
many pregnancies in women who had HSP nephritis during
childhood were complicated by proteinuria or hypertension or
both.60 Complications of pregnancy occurred even in women
who had no active signs of renal disease before pregnancy.
The relationship of HSP nephritis and IgA nephropathy is
uncertain. It has been suggested that IgA nephropathy is HSP
nephritis without the rash.61,62 A report describes the development of IgA nephropathy in one identical twin while the other
developed HSP after adenoviral infection in each.61 The renal
pathologic features in HSP nephritis and IgA nephropathy
are very similar, and clinical characteristics of severe renal
disease are similar in IgA nephropathy and in HSP nephritis.
The clinical manifestations, laboratory and pathologic findings, pathophysiology, and potential treatment strategies for
IgA nephropathy and HSP nephritis are discussed in this section; GN associated with SLE, which also may be associated
with predominant IgA deposits, is reviewed in the section
Hypocomplementemic Glomerulonephritides.
Immunoglobulin A Nephropathy
IgA nephropathy was first described in the late 1960s by the
French pathologist Berger63; IgA nephropathy has also been
called Berger disease. IgA nephropathy affects males more
231
commonly than females and is rare in blacks.64 In pediatric patients, the most common clinical presentation of IgA
nephropathy is recurrent episodes of painless, gross hematuria occurring within 1 to 3 days after an upper respiratory tract
infection. The gross hematuria generally resolves over the
next several days, but recurs after additional viral or bacterial
infections. This presentation of IgA nephropathy differs from
postinfectious GN in the short latency period between the
infection and the onset of hematuria, in the absence of features
of an acute nephritic syndrome, and in the recurrent nature
of the gross hematuria with illness over the course of several
years. Microscopic hematuria with or without proteinuria may
persist between episodes of gross hematuria. IgA nephropathy also may manifest with asymptomatic microscopic hematuria with or without proteinuria. A few children with IgA
nephropathy present with hypertension, nephrotic syndrome,
or RPGN.
IgA nephropathy was originally thought to be a benign
GN, but long-term follow-up has shown that many patients
eventually develop chronic kidney disease.65-69 It is estimated
that 20% to 40% of children and adults with IgA nephropathy
develop progressive glomerulosclerosis, interstitial fibrosis,
and chronic kidney disease.9,59,65-69 Various clinical, laboratory, and histologic findings are associated with a higher risk
for progressive disease, and it is this subset of children who
should be targeted for potential therapy. Urinary loss of podocytes is associated with progressive disease in children with
IgA nephropathy and HSP nephritis.70
Hematuria is nearly always found on urinalysis, whereas
the degree of proteinuria varies, ranging from normal to several grams per day. Multiple studies in adult and pediatric
patients have shown that persistent proteinuria is the best
laboratory indicator of renal disease that is likely to progress
to chronic renal failure. The magnitude of proteinuria correlates with the presence and degree of segmental sclerosis,
crescent formation, and interstitial changes on biopsy specimens and with deposition of IgA adjacent to the GBM and
in the mesangium.65,66 The serum C3 level is normal in IgA
nephropathy, differentiating it from postinfectious GN and
MPGN. Although the serum C3 level is normal, signs of complement activation are found in many patients with sensitive
assays that detect fragments of activated C3.71 Renal function
is usually normal at presentation, but a few children have a
mildly depressed glomerular filtration rate.
Screening blood tests for IgA nephropathy, including tests
for circulating IgA-containing immune complexes and IgAfibronectin aggregates in patients with IgA nephropathy, and
increased levels of IgA have been suggested to correlate with
IgA nephropathy. Each of these abnormalities is noted in a
variable number of patients with IgA nephropathy, however,
and these tests lack sufficient sensitivity to be of any diagnostic or prognostic value. The only mechanism to diagnose IgA
nephropathy with certainty is a kidney biopsy.
The histologic features of IgA nephropathy range from
minimal and minor changes to focal or diffuse mesangial
proliferation; segmental sclerosis and crescent formation
may be seen in severe cases (Fig. 18-7).5,66,67 The presence of
segmental sclerosis on a biopsy specimen is associated with
proteinuria; interstitial fibrosis and tubular atrophy also are
seen in severe cases and are associated with development
of chronic kidney disease. IgA nephropathy was so named
because immunofluorescent studies show predominant IgA
deposition in the mesangium with lesser amounts of IgG and
IgM (Fig. 18-8). In severe cases, IgA extends to the GBM. GBM
deposition of IgA also is associated with proteinuria and the
development of chronic renal disease in some studies.65 C3
is usually deposited in a distribution similar to that of IgA.
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chapter
Henoch-Schnlein Purpura
The typical clinical features of HSP include rash, gastrointestinal disease, arthritis, and renal disease. Several other organs,
including the central nervous system, cardiopulmonary system, and musculoskeletal system, also may be affected by
leukocytoclastic vasculitis characteristic of HSP. Most children
do not have severe renal disease and do not experience serious sequelae after HSP, but a few children do develop serious renal disease, which accounts for the major morbidity of
HSP.91,92 HSP typically occurs in younger children with a peak
age incidence of 4 to 5 years. Although HSP is less common in
older children and adolescents, older children with HSP seem
to be at higher risk for severe renal disease. Renal disease in
unselected patients with HSP has been estimated to range
from 20% to 50%.92 Typically, children who develop renal disease have hematuria with or without proteinuria within the
first 2 to 3 months from the onset of the rash.
More recent studies have shown that genetic polymorphisms may predispose to the development of HSP or have a
role in the evolution to HSP nephritis, or both. In a study of
57 patients with HSP, no significant differences were found in
the allele or genotype frequencies for two vascular endothelial
cell growth factor (VGEF) polymorphisms between patients
with HSP and control patients, but the high VGEF producer
allele was increased in patients with HSP nephritis compared
with healthy controls.93 Polymorphisms of the interleukin-1
gene were not different in patients with HSP compared with
controls, but each of the 5 patients who developed severe
nephropathy carried the rare T allele compared with 16 of the
remaining 44 patients.94
Other studies showed that the TT genotype of the C-509T
polymorphism of the transforming growth factor- gene was
significantly more common in children with HSP compared
with control children, and the TT genotype was more common in children with severe HSP.95 Polymorphism of the
renin-angiotensin system also has been associated with the
development of HSP and possibly the development of renal
disease.96 Patients with familial Mediterranean fever have a
higher incidence of HSP, with approximately 5% of patients
with familial Mediterranean fever developing HSP.97 Other
studies have shown no association with uteroglobin gene
polymorphism in childhood HSP.98 Similarly, polymorphisms
in thrombophilia genes, including methylenetetrahydrofolate
reductase, prothrombin, and factor V genes, did not differ
in patients with HSP and controls.99 Although more studies
are needed, these early studies suggest that there may be a
genetically determined susceptibility to risk and severity of
HSP nephritis.
Hematuria is the first indication of renal involvement in
HSP nephritis, and most children with renal involvement have
isolated hematuria. Some children have low-grade proteinuria
in addition to hematuria, however. Urinary abnormalities in
children with hematuria with or without low-grade proteinuria generally resolve spontaneously, and such children are at
low risk for progressive renal disease and late complications.
A smaller percentage of children with HSP nephritis have
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II: Kidney
MEMBRANOUS GLOMERULONEPHRITIS
Membranous GN is frequently called membranous glomerulopathy or membranous nephropathy because there is little to
no inflammation detectable on light microscopy. Membranous
GN is much more common in adult patients than in pediatric
patients. In the International Study of Kidney Diseases in
Children, less than 1% of children with nephrotic syndrome
were found to have membranous GN.107,108 Most children pre
sent with nephrotic syndrome and have microscopic hematuria.109,110 Asymptomatic proteinuria and gross hematuria are
less common presentations. Most children are normotensive,
but 20% to 30% have some degree of hypertension.
Membranous GN may be idiopathic or secondary.
Secondary forms of membranous GN are associated with
collagen vascular diseases such as SLE and autoimmune diseases such as Crohn disease. Secondary forms of membranous
GN also are associated with drug exposure or more commonly
with chronic infections, such as hepatitis B, syphilis, malaria,
and other parasitic infections. Similar infections are associated
with nephritis of chronic infection, and hypocomplementemia
may be seen in secondary cases of membranous GN, suggesting an overlap between nephritis of chronic infection and
membranous GN associated with chronic infection.
At presentation, renal function is usually normal, but
some children develop a progressive course and eventually develop chronic renal failure.110 Complement levels are
normal, and serologic studies are negative, unless the child
chapter
235
REFERENCES
For complete list of references log onto www.expertconsult.com
P A R T
III
19
Obstruction of the upper urinary tract presents a significant clinical challenge to pediatric urologists, not as much
in surgically managing these conditions, but in determining
which patients may be benefited by therapy, and whether
there may be more effective means of improving the function of obstructed kidneys. The ultimate key to unraveling
these questions lies in an understanding of the mechanisms
and pathophysiology of congenital urinary obstruction. This
chapter reviews the basic pathophysiologic themes of upper
urinary tract obstruction with an emphasis on the effects of
obstruction on the developing kidney. These pathophysiologic mechanisms are similar to those affecting the kidney in
lower urinary tract obstruction.
Definition of Obstruction
More problematic is the definition of obstruction, which continues to elude the pediatric urologic community. Koffs8 definition was a valuable contribution to the conceptualization of
obstruction when he wrote that obstruction is any restriction
to urinary outflow, that left untreated will cause progressive
renal deterioration. This definition needs to be expanded in
the context of congenital obstruction, which may affect normal development of the kidney, limiting normal increases in
function, but not producing a decline in function.9 A childs
kidney needs to increase its function significantly in the first
years of life, and obstruction may constrain its normal maturation. If a kidney at birth is functioning at a lesser degree than
normal associated with a potentially obstructive lesion, the
loss of function may have already occurred before a time
when it could be measured. This makes the condition no less
obstructive, and raises the concern for potential further loss of
absolute or potential function. The abnormally low function
may be viewed as an indication of impaired maturation (i.e.,
no function has been lost, but the normal level of function
has not been achieved). How one acts in these situations is not
determined by defining it as obstruction, but by the clinical
context.
237
238
part
Etiology of Obstruction
Embryonic Development
of the
Ureter
Hydrostatic pressure is generated in the developing fetal kidney as urine accumulates between 9 and 12 weeks of gestation with subsequent distention of the developing renal pelvis.
Chwalla membrane is found at the distal end of the ureteric
bud, and its rupture during this period of gestation allows the
accumulated urine to enter the bladder.23 The purpose of this
membrane is unclear, but during gestation it usually develops
between days 35 and 37, then disappears between days 43 and
49. Chwalla membrane has been hypothesized as either a protective mechanism for excretions from the metanephros or as a
temporary structure appearing as the urogenital sinus resorbs
the common nephric duct.24 The lumen of the ureter appears
to fuse and become a solid cord between 28 and 35 days, during which the lumen is not apparent histologically. It then
undergoes subsequent recanalization, beginning at 42 days
gestation in the middle portion of the ureter (i.e., metanephric
cord), then progresses distally and proximally. The most distal
portion of the UVJ and the most proximal portion of the UPJ
are the last parts of the ureter to recanalize. Folds, kinks, or
muscular invaginations in ureteral formation also may persist
during recanalization.13,25,26
It is appealing to hypothesize that intrinsic UPJ obstruction may result from incomplete canalization of the proximal
ureter. Whether this is a universal pattern in the mammalian
kidney is uncertain, and more recent studies of ureteral development would call this into question.27 Other possible mechanisms include obstructing valvular mucosal folds, proximal
ureteral polyps, and functional abnormalities of ureteropelvic
muscular contractions.26,28-32
Light microscopy at the obstructive UPJ shows increased
collagen deposition at the proximal or distal ureter, an inflammatory cell reaction, muscular malorientation, and thickened
adventitia.10,33,34 It is unclear whether these histologic changes
are the causes of, or subsequent to, obstruction. Evidence has
emerged suggesting abnormal innervation of the UPJ as a
basis for disordered function and obstruction.35-39 Although
this idea may be seen as a parallel of the aganglionic character of Hirschsprung disease in the gut, it is unclear which is
cause or effect. Similar questions have been raised about UVJ
obstruction, which may share a similar etiology. Inflammatory
mechanisms also have been postulated, although whether this
is cause or effect is unclear.40
These uncertainties are challenged further by the observed
resolution of the effects of these obstructions, particularly
with regard to neonatal UVJ obstruction.41-43 Such resolution
suggests a delayed maturational process. In these patients,
it may be postulated that segmental peristaltic function has
not matured, and the system is overwhelmed by the volume of urine output, resulting in proximal ureteral dilation.
Resolution eventually comes with catch-up of the functional
capacity of the transport system. The converse also may be
seen, which may provide some insight into the underlying
mechanism of obstruction. There are reports of children with
mild hydronephrosis who subsequently develop marked
dilation at a later age, some with symptoms. This progression would suggest a system that was an effective (although
just barely) transport system up to a certain volume per unit
time, but becomes dysfunctional at the higher volumes with
increasing age and size of the child; this may explain cases of
presumed acquired UPJ obstruction in children.
chapter
19: Congenital Urine Flow Impairments of the Upper Urinary Tract: Pathophysiology and Experimental Studies
239
eral ureteral obstruction at 55 days gestation. The kidney was markedly growth impaired and irregular, and had a fibrous feel. Histology
showed reduced glomerular number, disordered renal architecture,
almost no medullary development, dilated tubules with primitive
fibromuscular collages, and a greatly increased interstitium. (From
Peters CA. Obstruction of the fetal urinary tract. J Am Soc Nephrol.
1997;8:658.)
240
part
absence of prior infection. Apparent developmental impairment of specific compartments of the nephron, particularly
the proximal tubules, has been reported, pointing to specific
sensitivity to these pathologic changes. Other changes noted
include tubular atrophy or dropout in more severe cases and
occasional glomerular sclerosis and interstitial fibrosis.65
PATHOPHYSIOLOGIC MECHANISMS
Several components of the upper urinary tract are affected by
obstructionthe collecting system, including the ureter and
pelvis, and the renal parenchyma. Within the renal parenchyma,
the compartments that are significantly affected can be divided
into the glomerulus, including renal vascular regulation, the
proximal and distal tubules, the collecting ducts, and the interstitium. Each component interacts with the others in feedback
systems, and each responds to the obstruction in specific and
general ways. By examining these elements, a clearer picture of
obstructive pathophysiology may emerge (Fig. 19-3).
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19: Congenital Urine Flow Impairments of the Upper Urinary Tract: Pathophysiology and Experimental Studies
241
Pathophysiologic Mechanisms
Apoptosis
BAD-GF1
Macrophage mediated in PT
CRG/UUO
Osteopontin
Angiotensin II
TNF
Bax
Caspases
Interstitial fibrosis
Osteopontin
ALK5 TGF signaling
Inflammation
Krox 24, IRF-1, MCP-1
A2A and receptor/PDE4
TGF-1 inhibits via smad7
Vascular/neural
GFR due to NO
Dopamine vasoactive
Cell-cell communication
Connexins
Integrins and
leukocyte infiltration
EMT
TGF-1 smad2/3
Angiotensin II
Figure 19-3 Diagram of mediators of obstructive nephropathy with their site and category of action. See text for abbreviations.
Further investigation is needed to begin to understand the
mechanisms of ureteral and renal pelvic response to obstructive processes.
from postnatal studies to fetal systems. Fetal filtration is provided by the placenta, and the filtration function of the fetal
kidney is quite different from that of the postnatal kidney. In
fetal life, the kidney receives about 5% of cardiac output, in
contrast to 20% postnatally. Differences in oxygen tension,
hormonal levels and sensitivity, and homeostatic mechanisms
have been well documented.87 The fetal kidney is a developing entity. Its regulatory systems are incomplete and evolving. Its capacity and patterns of response to any challenge
are forming, yet this is the kidney exposed to obstruction, at
the point where it has only started to develop its ability to
respond to a challenge such as obstruction. The postnatal kidney has already formed much of its repertoire of responses, so
experimental evidence drawn from postnatal renal responses
to obstruction may not reflect fetal renal responses at all. With
that caveat, and a developing body of fetal studies, however,
some conclusions regarding fetal renal obstruction may be
drawn.
RESPONSE PATTERNS
Three classes of response to obstruction may be identified
in each of the four renal segments. Obstruction in the fetal
kidney produces alterations in growth regulation, tissue differentiation, and specific injury responses. Connecting these
responses are potential changes in the integrative systems of
renal physiology, principally its hemodynamics and innervation. The ultimate result can be abnormal development and
abnormal function. Response patterns in the developing kidney, as with many biologic systems, also can be seen as compensatory. These compensatory mechanisms may be beneficial
242
part
25
Obstruction
95 days
20
(+/ 1 SEM)
15
Normal
10
5
0
60
Obstruction
60 days
80
100
120
140
Growth Regulation
Growth regulation determines the number of cells, the number of glomeruli, and the length of tubules or collecting ducts.
Growth is the balance between cell proliferation and cell
death (apoptosis), a tightly regulated dynamic in the developing kidney, and obstruction clearly affects this in all segments
of the nephron. Fetal sheep ureteral obstruction early in gestation produces small kidneys (Fig. 19-4).60 These kidneys
are not atrophic (i.e., having lost mass), but have not grown
normally. Later in gestation, this effect was much less pronounced, and with partial obstruction, kidneys were larger
than normal, indicating growth acceleration. Growth regulation is complex, mediated by a multitude of growth factors
that typically play specific roles at specific times in particular
cells during renal development. Globally, however, growth
factor expression levels are markedly higher in the early fetal
kidney,88 perhaps indicating why it seems more susceptible
to growth alterations than the later gestation and postnatal
kidney. Early in gestation, growth activity of the fetal kidney
is extremely high relative to later in gestation. Each unit of
renal mass increases its mass more quickly than it does later
in gestation.
The mechanisms by which obstruction alters growth remain
incompletely defined. There is some evidence that hydrostatic
pressure alters cell proliferation. There are parallels in various
cell types in which stretch induces growth.81,89,90 This is seen
in muscle cells as noted earlier, and in renal epithelia associated with cyst formation.91,92 Impaired growth may be a more
nonspecific effect in which markedly elevated pressures cause
sufficient cell damage to reduce their ability to proliferate or
may stimulate apoptotic signals and subsequent cell death.93
Stretch may exert its growth effects by changing the balance
between cell death and proliferation. In cultured renal epithelial cells exposed to severe stress, programmed cell death is
induced (apoptosis).94,95 Concurrently, there is an increase in
the production of the growth factor HB-EGF. This response
may be to limit cell death; when artificially expressed at
high levels, HB-EGF reduced cell death in stretched renal
epithelia.
Proliferation
Apoptosis
Tubular atrophy
Int. fibrosis
As with all aspects of the spectrum of obstruction, the character of the cell, tissue, or organ response depends on the differing degrees of obstructive effect. The particular responses
of renal epithelia to mechanical forces and the regulation of
apoptosis may not be uniform across species, however, as
reported by Kiley and colleagues,96 who showed that EGF is
a protective factor for neonatal rat renal epithelia, but is proapoptotic in mice. Generalizing any conclusions to humans
becomes difficult.
Several experimental systems have shown obstruction
to alter renal regulation of apoptosis.96-100 Increased renal
tubular apoptosis has been described in human dysplastic
kidneys,101-103 and some of the molecular signals have been
defined in early neonatal ureteral obstruction.104-107 Apoptosis
is highly regulated by several proteins, including bcl-2 and
clusterin. bcl-2 acts to inhibit apoptosis and is reduced in
obstructed kidneys. As with most biologic systems, there is a
natural balance to this, and bcl-2 is counteracted by Bax, a proapoptotic molecule expressed in renal epithelium. The determinants of that balance are the critical factors in the net result,
not simply the expression level of bcl-2. Clusterin is a protein
that acts to protect cells against apoptotic processes by maintaining normal intercellular communication. In obstructive
models, clusterin is upregulated in a variable way, presumably
as a response to counter apoptotic processes. In association
with increased apoptosis, decreased levels of various growth
factors may be seen, particularly EGF, which has been investigated in obstructive nephropathy.98 Administration of EGF to
obstructed animals has been shown to reduce apoptotic activity and reduce medullary loss (Fig. 19-5).96,108
Multiple factors influence the relative levels of cell proliferation and death, particularly the cellular environment. Normal
connections with the interstitial cells of the kidney are necessary
to prevent apoptosis in renal epithelium, a pathway mediated
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19: Congenital Urine Flow Impairments of the Upper Urinary Tract: Pathophysiology and Experimental Studies
Differentiation
Development of any organ is the result of growth and differentiation; the obstructed fetal kidney may be growth impaired,
but, more importantly, it may have abnormal differentiation.
The regulation of cell differentiation in the fetal kidney is
highly complex and only now being understood on a cellular
basis.119 Alterations in normal differentiation produce abnormal function in the postnatal kidney, and this may range from
the absence of measurable function in a dysplastic kidney
to minimal disturbances of function associated with subtle
changes in tubular morphology or cellular function.
Controversy continues to exist regarding the relationship
between obstruction and renal dysplasia; this is due in part
to various definitions of renal dysplasia, which emerged
from controversy regarding the etiology of abnormal kidneys
associated with reflux and infection.56 The controversy was
renewed as fetal intervention for severe urinary obstruction
began, with one camp arguing that dysplasia was an embryonic event resulting from abnormal renal induction and was
irreversible. The opposing side contended that dysplasia was
243
due to obstruction, and might be at least partially reversible. An ingenious experiment by Berman and Maizels120,121
showed that ureteral obstruction in the chick embryo did not
produce dysplasia based on strict histologic criteria, whereas
physical disruption of the developing renal mesenchyme produced the appearance of dysplasia. Not all of the obstructed
kidneys had hydronephrosis, however, raising the question of
how effective the obstruction was.
Beck,58 using fetal sheep, showed markedly altered renal
architecture with early gestation (58 days out of 140 days)
unilateral ureteral obstruction. Several investigators have
reproduced these findings (see Fig. 19-1).59,60,62 The important
observation is that obstruction undoubtedly alters normal
patterns of development. Whether it should be called dysplasia, obstructive dysplasia, or dysgenesis is arbitrary
and perhaps irrelevant. Not all renal dysplasia is due to
obstruction, but it is clear that it can be, and some of it is. In
a boy with severe valves and dysplastic kidneys, one might
invoke two problems (i.e., valves and embryonic dysplasia),
although it seems equally likely that the renal failure is due to
the obstructive process.
Alterations in renal differentiation are the result of disordered cell interactions in most cases. The process of normal
nephrogenesis is a complex interplay of cell signaling, growth,
death, and change. Some of the key factors in this interaction
have been described, and specific alterations in their expression patterns can be induced with obstruction.122-124 In markedly abnormal kidneys, such as multicystic dysplastic kidneys,
expression patterns of key signaling molecules are disordered,
such as PAX-2, an embryonically expressed protein that is
critical in nephrogenesis.102 Obstruction of fetal sheep kidneys acutely induces altered expression of several embryonic
signaling molecules.125 More prolonged postnatal obstruction
in rodents undergoing nephrogenesis induced changes in a
class of important renal signaling molecules, Wnt-4, Wnt-7b,
and Wnt-11.126 The pattern observed was one of abnormal
persistence of expression of Wnt-4, or reactivation of Wnt-4 if
obstruction was induced after the completion of nephrogenesis, suggesting induction of fetal or immature cellular signaling systems, out of the normal maturational pattern.
Although the cause-and-effect connection has yet to be
proven, the association is compelling. The end result of
reduced glomerular number has been shown in multiple
experimental systems with early obstruction. In fetal sheep,
this produced a 40% to 60% reduction in glomeruli at term with
early gestation obstruction.60 Neonatal partial obstruction in
the pig produced almost 30% reduction in glomerular number
with no apparent reduction in glomerular filtration rate when
measured acutely.127 In obstructed neonatal rats, glomerular
reduction was proportionate to the duration of obstruction,
with a 40% reduction after 5 days of obstruction.128
Normal patterns of nephrogenesis can be markedly disordered in the setting of obstruction. This also may lead to
complete lack of glomerular development in severe cases,
which would preclude further development of that nephron.
Individual cells require the appropriate signals to differentiate
normally to function, and if this is disordered during fetal life,
postnatal function may be impaired.
Differentiation patterns of other elements of the nephron
may be affected by obstruction as well. In the proximal and
distal tubules, normal expression and function of ion transporters, critical to tubular function, may be disrupted by obstruction. In the collecting duct, expression of aquaporin-2 (AQP-2)
is affected by postnatal obstruction, producing changes in the
ability of collecting duct cells to regulate water homeostasis,
and contributing to postobstructive diuresis. Permanent loss
of normal aquaporin expression and regulation, as might
part
occur with early obstruction, may be the cellular basis for the
nephrogenic diabetes insipidus seen in some cases of obstructive nephropathy.129-133 This effect has been suggested in a
fetal model of vesicoureteral reflux, although not proven in a
model of fetal obstruction.134
Part of normal renal development includes maturation of
interstitial fibroblasts; some of these cells are transformed into
renal epithelia in the process of nephrogenesis,116,135 whereas
others disappear. Obstruction has been shown to induce an
abnormal transdifferentiation of these immature fibroblasts
to myofibroblasts, which may have a significant role in
production of abnormal ECM.136,137 Myofibroblasts are typically found to express -smooth muscle actin, which is seen
to persist in neonatal obstruction beyond the time of normal
disappearance.138 Similar abnormal expression of -smooth
muscle actin has been shown in fetal renal obstruction.139
Other markers of cellular immaturity have been shown in
fetal and neonatal obstruction, such as vimentin.140 This finding indicates not only a disruption of normal differentiation
in renal interstitium and epithelium, but also a disturbance of
the normal cell-to-cell signaling that regulates these cells.
Injury Responses
Alterations in growth and differentiation are important factors
in the response of the fetal kidney to obstruction, but they interact with a wide variety of responses that may best be termed
injury responses, in that they are abnormal or exaggerated
normal responses to a stimulusin this case, obstruction.
These injury responses have been studied largely in postnatal animals, and their relevance to fetal urinary obstruction
remains uncertain. Some specific studies of fetal obstruction
have been performed. These injury responses include fibrosis (scarring), inflammation, and altered cell proliferation as
noted earlier.
Tissue Fibrosis
Fibrosis is a common and damaging process in the kidney
and may be evident as glomerulosclerosis, interstitial fibrosis, or parenchymal scarring. It is a common final pathway
of renal injury in various conditions, including diabetic
nephropathy, hypertensive nephropathy, and several glomerulopathies.141-143 Increased connective tissue has long
been described in obstructed kidneys, but only more recently
have the mechanisms of tissue fibrosis in obstruction been
examined. Fibrosis is the result of increased net deposition of
various connective tissues, including collagens, fibronectin,
laminin, and many others around normal cells. The increased
ECM may distort normal physical arrangements and intercellular signaling, and cause loss of function, or it may produce
abnormal function itself by changing the physical properties
of the tissue, as in the bladder. Recognizing the importance
of intercellular communication within the kidney, it is readily apparent that disrupting the physical arrangements of the
various cell types may impair function and normal developmental processes.
ECM homeostasis is a highly regulated balance of synthesis and degradation, with the latter mediated by local tissue
enzymes, the matrix metalloproteinases (MMPs) (the designation as metalloproteinases reflects the presence of metallic
cofactors essential for enzyme activity, usually zinc). The degradation of the ECM is itself regulated by a balance in which
the activity of the MMPs is inhibited by tissue inhibitors of
metalloproteinases (TIMPs). The net degradative activity
(proteolytic balance) determines the rate of ECM breakdown,
which in combination with even stable ECM synthesis can
80
ECM (%)
Glomeruli (%)
60
Volume fraction (%)
244
Tubular
lumen (%)
*
* *
40
+
++
* * *
20
+ + +
Male
Female
Normal
* p = 0.0014
+ p = n.s.
Male
Female
Obstructed
** p = 0.0029
++ p = n.s.
chapter
19: Congenital Urine Flow Impairments of the Upper Urinary Tract: Pathophysiology and Experimental Studies
245
Integrative Responses
Hemodynamics
Vascular regulation is the key to normal renal function, and
it is well recognized in adults that obstruction affects renal
perfusion through several mechanisms. The classic studies of
Moody and associates173-175 showed an initial increase in renal
blood flow with complete unilateral ureteral obstruction and
subsequent progressive diminution over time. The mediators
of these changes are several, and include the prostaglandin
system, nitric oxide (NO), and others. Although these elements may have a role in fetal obstruction, complete obstruction is rare, and usually associated with a severely dysplastic
kidney.
The fetal kidney is a vascular organ, and obstruction is
certain to play a role in vascular regulation. Few investigators
have examined this aspect of fetal obstruction. More recent
studies by Mure and coworkers176 have shown that with complete fetal obstruction, renal perfusion declines in proportion to
parenchymal loss. In partial obstruction, however, Bogaert and
associates177,178 reported that despite several weeks of partial
unilateral ureteral obstruction, renal blood flow was preserved,
as indexed to renal weight. Bogaert and associates179 also
have shown that NO may be an important modulator of renal
vascular function in the fetal kidney. In many systems, NO is
paired with and balanced against the activity of angiotensin II,
further developing the role of renal angiotensin II in normal
246
part
Renal Innervation
Renal nerves are a neglected component of renal physiology,
perhaps because of the difficulty in studying their function,
but there is strong evidence that they play major roles in various renal functions. There is evidence of their modulation by
obstruction in the regulation of renin expression in the neonatal obstructed kidney,184 and the hemodynamic response to
obstruction. It also is possible that renal innervation is crucial
in the crosstalk that occurs between the two renal units. In
nearly all experimental models of unilateral obstruction, the
contralateral kidney shows evidence of change. In fetal life,
this change has been shown by contralateral compensatory
hypertrophy with unilateral early gestation obstruction.185 It
also is suggested by observations that the response of a kidney
to obstruction depends on the condition of the other kidney.
When both kidneys are obstructed, the kidneys are more likely
to be hydronephrotic, rather than cystic or dysplastic. A solitary obstructed kidney acts as bilaterally obstructed kidneys.60
Renal innervation may play a role in this crosstalk, and potentially modulate individual renal responses to obstruction.
FUNCTIONAL EFFECTS
The end result of disordered growth, differentiation, and
injury response is abnormal function; there is a wide spectrum
of functional impairment. Function also must be seen in a time
scale because renal disease may be progressive. Progression
of renal disease may occur after the initial insult has been
removed, owing to loss of functional renal mass or owing to
ongoing injury response such as fibrosis. No studies of fetal
obstruction have examined postnatal function over time.
Several models of chronic obstruction in fetal sheep have
examined renal function in utero. Glicks study186 of in utero
severe UPJ obstruction examined prenatal function, and determined that obstructed kidneys were markedly impaired in
terms of glomerular filtration rate and sodium handling
(increased fractional excretion of sodium) compared with controls. Histologically, these kidneys were significantly abnormal
with diffuse structural changes, despite in utero decompression.186,187 In a model of fetal obstruction with decompression
in utero, Ward and coworkers188 reported reduced creatinine
clearance and higher fractional excretion of sodium. With
varying degrees of obstructive severity, Peters and colleagues60
identified increased sodium clearance and reduced free water
clearance in more severe obstruction. Bussieres and associates189 used a model of partial bladder outlet obstruction and
assessed creatinine clearance in utero. They reported reduced
clearance depending on the onset of obstruction. In contrast,
Bogaert and colleagues178 found no change in renal function
with partial bladder outlet obstruction in utero. It is difficult to
assess the significance of these data with respect to postnatal
function because of the low level of normal clearance present in
the fetus, the lack of standardization of the severity of obstruction, and the absence of postnatal functional evaluation.
In the pouch (fetal) opossum, ureteral obstruction produced marked reduction in creatinine clearance when examined at adulthood, even when unobstructed at full term.
Several animals had only partial obstruction and hydronephrosis, but had minimal reduction in clearance associated
with significant reduction in renal weight.190
There are several congenital models of apparent ureteral
obstruction described in rodents. Boineau and colleagues191
chapter
19: Congenital Urine Flow Impairments of the Upper Urinary Tract: Pathophysiology and Experimental Studies
RECOVERY OF FUNCTION
A significant challenge in obstructive nephropathy is predicting the functional reversibility of an obstructive lesion. If differentiation has been disordered, can any functional recovery be
possible? It is unknown how much of the dysplastic change
induced by congenital obstruction might be altered with relief
of obstruction. This would require a realignment of the differentiation process that has been disordered. Although some
element of further normal development may occur after relief
of obstruction in fetal or neonatal life, several studies have
shown this to depend on the duration of obstruction.187,215
In a model of neonatal ureteral obstruction and decompression in the rodent, Chevalier and colleagues215 showed apparent functional recovery associated with the presence of ongoing
hyperfiltration injury and later functional loss. Even with a
40% persistent reduction in glomerular number with unilateral
obstruction, overall glomerular filtration rate was maintained,
confirming compensatory hyperfiltration. This finding raises
the concern of the real functional severity of the obstructive renal
injury, relative to what is measured, and the potential for slowly
progressive injury undetected by conventional methods.215
With variable partial obstruction, reversibility is determined by
obstructive severity and duration.207 Similar clinical findings
have been reported as well when correction is delayed.216
Indicators of potential reversibility continue to be sought.
Most of these use filtered or secreted compounds in the urine
that may reflect renal glomerular or tubular function.217,218
There has been variable success in predicting the level of functional reserve, and this may reflect simply a lack of correlation
or perhaps the presence of biphasic patterns of these markers
in the urine of obstructed kidneys. With progression of renal
impairment, the levels of any markers may initially rise and
then decline. Any given level may be on either side of the peak
and reflect either worsening injury or failing of the kidney,
each with a different recovery potential. With the emergence
of technologies to analyze the urinary proteome, new optimism is present that clinically useful indicators of progressive
obstructive uropathy may be identified.
More recent reports suggest the utility of a fingerprint-type
approach in which the specific identity of the biomarkers
is less relevant than the pattern that is unique to significant
obstruction.219 This study showed a very high prediction
of unilateral obstructions that required surgery. These were
largely very severe cases that would not be controversial.
The real challenge would be to identify the patient whose
247
CLINICAL APPLICATIONS
Although a practical understanding of the pathophysiology
of congenital obstructive uropathy eludes us for now, with
improved understanding of the critical elements of this condition, we will be able to manage our patients better. This improved
management will come in diagnosis, prognosis, and treatment.
At present, one of our greatest diagnostic frustrations is an
asymptomatic child with prenatally detected hydronephrosis
and apparently normal function on renal scan. Is this child at
risk for functional loss? Is there already some functional loss that
is not being detected on current studies? Markers of obstructive
nephropathy, based on the pathophysiologic mechanisms, may
help us determine this. TGF-1, implicated in renal fibrosis and
obstruction, is elevated above normal values in the urine of children with UPJ obstruction, but not correlated with long-term
outcomes.221 Similarly, N-acetyl--glucosaminidase (NAG), an
indicator of tubular injury, has been shown to be elevated in UPJ
obstruction, but long-term functional correlates remain to be performed.218 Other markers may present themselves as we learn
more about the response of the fetal kidney to obstruction.
As with diagnosis, prognosis is determined by ongoing
response and should be able to be indicated by assessing the
pathophysiologic mechanisms of obstruction. Finally, our
therapy for obstructive uropathy will be improved by understanding the pathophysiology of obstruction in ways that are
just emerging in medical technology. Locally delivered gene
therapy to alter specific molecular processes ultimately may
permit inhibition or reversal of pathologic responses in the
obstructed kidney.109,222,223 Introduction of EGF to obstructed
animals has been reported to reduce the histologic effects of
obstruction.98,108 Induction of local expression of aquaporins
in the tubules of the kidney may permit normalization of
water metabolism in the previously obstructed kidney.
At present, an opportunity for enhanced treatment is available through the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.153,224,225 Although this
treatment may not be applicable in neonatal life, inhibition of one
of the key factors in several aspects of obstructive renal pathology may provide for less renal injury and longer functional
life of the obstructed kidney in an older child. Angiotensinconverting enzyme inhibitors are being used for patients with
diabetic and hypertensive nephropathy, and perhaps should
be explored for obstructive nephropathy.148 Gene therapy with
antisense genetic segments for AT1 have been shown to protect
against cardiac hypertrophy in hypertensive rodents.226
Obstructive uropathy in a child is a complex, dynamic process involving a wide variety of embryonic and developmental regulators of cellular function, growth, differentiation, and
communication, which produces a wide spectrum of pathology that we deal with daily. Understanding those mechanisms
is essential to permit any advancement in the clinical management of the many children with these conditions.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
20
only in terms of workload required and delivered at a particular time. This term is expressed by urine flow rate and
distal intravesical pressure, both of which vary constantly in
a dynamic fashion.
Many experimental models are based on a complete
occlusion (via constricting ligature) system. A comparative
situation occurs in pediatric urology with ureteral atresia and resultant multicystic dysplastic kidney. Universal
agreement exists that these two situations represent complete ureteral obstruction. We believe the term complete
ureteral obstruction should be restricted to these situations. In clinical cases of pediatric hydronephrosis, there is
always a patent lumen, and complete ureteropelvic obstruction
does not exist. In that situation, we prefer the term ureteropelvic urine transport inefficiency. We believe that the
ureteral transport inefficiencies represent a continuous
spectrum of severity, rather than two arbitrary categories.
We and others have seen cases improve spontaneously and
unpredictably decompensate. The severity of hydronephrosis
for an individual patient is often dynamic rather than static.
Evidence strongly suggests that although measurement of
(1) differential renal function, (2) renal parenchymal volume,
(3) degree of dilation, and (4) ureteropelvic physiology is
extremely important, these measures often do not correlate
well with each other. These measurements all are used to predict the childs future, however. They attempt to answer the
following questions:
1. Will the child experience further progressive irreversible
loss of renal function?
2. Will the child experience further progressive loss of renal
parenchymal volume?
3. Will future complications of pyelonephritis, stones, or
hypertension occur?
4. Will the child develop pain or hematuria in the decades to
come?
5. If renal function is currently diminished, will it improve,
remain static, or deteriorate?
Although current status is useful to predict the future, it
is far from infallible. Aggressive proponents of a particular
testing system or strategy of management also are wise to
remember that there is a major difference between established
current political consensus and determining long-term scientific validity.
HISTORICAL PAPERS
The basic definition, accurate gross pathology, and fundamental pathophysiology of hydronephrosis were published well
before 1935. Particularly noteworthy are the fundamental
writings of Rayer,5 whose Trait des Maladies des reins, was
published in Paris in 1837. Rayer5 noted and illustrated the
following pathologic features of hydronephrosis:
chapter
FUNDAMENTAL PATHOPHYSIOLOGY
Hinmans series of elegant papers7-16 on experimental hydronephrotic studies in various animal models are probably the
most important publications in understanding of the pathogenesis of hydronephrosis. His 1919 paper involved a rat
model with unilateral ureteral ligation of variable duration,
and deligation followed by ipsilateral ureterocystostomy (of
249
ligated ureter), followed by immediate or delayed contralateral nephrectomy. Ligation of 2 weeks duration resulted in
return of most of the function to the previously obstructed
kidney. Ligation of 3 weeks duration resulted in return of 50%
of renal function. With ligation duration of more than 3 weeks,
the animals survived only with delayed or partial contralateral nephrectomy. Hinmans studies showed that the duration of complete ureteral obstruction significantly affects the
severity and reversibility of renal damage. In 1922, Hinman
also showed that infection in addition to obstruction caused
more severe and rapid kidney damage than obstruction alone.
In 1925, he added that after complete ureteral obstruction in
rabbits, there is progressive development of hydronephrosis
and the degree of hydronephrotic atrophy is uniformly proportional to the duration of the obstruction.11
In 1925, Hinman12 showed that partially obstructing the
renal artery by a rubber band combined with ureteral ligation
produced more severe and rapid renal deterioration than ligation alone. He concluded that anemia and nutritional factor resulted in parenchymal degeneration. Hinmans son
reviewed his work 38 years later and concluded that the rate
and degree of hydronephrotic atrophy is closely linked with
the nutrition of the tissue.16
Hinman12 also studied the blood supply in his hydronephrotic model by a series of postmortem barium sulfate angiograms in normal and progressively more severe contralateral
Figure 20-1 Broedels drawings depict progressive hydronephrosis of increasing severity, including
(1) increases in the size of the renal pelvis, (2) changes
in the calyceal architecture, and (3) progressive renal atrophy. (From Geraghty JT, Frontz WA. A study
of primary hydronephrosis. J Urol. 1918;2:161-188.
Reprinted in Urol Clin North Am. 1998;25:164.)
250
part
hydronephrotic kidneys. These images revealed a progressive thinning of the arterial tree, and elongation and narrowing of individual renal arterial branches. All of these studies
confirmed the role of ischemia in hydronephrotic renal atrophy. Hinman also introduced the concept that proportion of
renal mass to the body weight is very uniform for animals of
the same species. He proposed a ratio of 9.1 g of renal tissue
per kilogram of body weight in cats and 7 g/kg in dogs.
In 1922, Hinman7 stated that the continual formation
of urine after ureteral obstruction even when complete is
essential to the production of hydronephrotic atrophy is selfevident. In other words, even with complete obstruction,
urine continues to be delivered from nephrons to the collecting system and then reabsorbed by various mechanisms. In
1929, Morrison17 provided experimental confirmation of continued urine formation and reabsorption by dye studies.
Finally, Hinman13 reviewed a compensatory physiologic
mechanism that he labeled renal reserve power. This concept had several factors. First, normal animals had more renal
function than necessary for survival. This was first shown by
De Paoli,17a who performed total nephrectomy on one side
and partial nephrectomy on the other side and had animals
survive. Also, Hinmans review included the thesis that
remaining residual renal tissue could enlarge and increase
function.
DEVELOPMENT OF ULTRASONOGRAPHY
The modern history of hydronephrosis is dominated by one
development, maternal ultrasonography, which allowed safe
detection of antenatal hydronephrosis. Before this technologic
advance, congenital hydronephrosis presented throughout
childhood (and adulthood) with various symptoms, including
flank pain, recurrent febrile urinary tract infections, abdominal mass, urolithiasis, and hematuria. Today, most children do
not present with these sequelae of long-standing chronic ureteral transport inefficiency, for which treatment is more clearly
defined. Instead, most children with antenatal hydronephrosis
are evaluated much earlier in the clinical course of the disease.
In much the same way that prostatic-specific antigen has dramatically changed the clinical management of prostate cancer
through earlier detection in clinically asymptomatic patients,
a concept known as lead time, the widespread use of ultrasound resulted in earlier detection of asymptomatic children.
The consequences of lead-time detection of hydronephrosis are far-reaching. The numbers of children with postnatal
hydronephrosis have dramatically increased in parallel with
the increased application of ultrasound. More importantly, the
natural history of the hydronephrotic kidney has now come
under question. Whether hydronephrosis represents a natural
state in the dynamic development of the newborn genitourinary tract, transitional hydronephrosis,23 or is the result of
the underlying pathologic disease process (e.g., UPJ obstruction, vesicoureteral reflux [VUR]) has become more difficult
INCIDENCE
We reviewed the available literature in an attempt to appreciate the scope of the prevalence of pediatric hydronephrosis in
the United States. Our findings should be viewed in the context that they are predominantly derived from single institutional data, retrospective studies, and flaws associated with
meta-analysis. Certain patterns emerge, however, which are
consistent among various studies.
As of the 1996 census data from the National Center of
Health, there were more than 600,000 maternal ultrasound
scans performed each year in the United States.24 Suspected
antenatal hydronephrosis is found in 0.2% to 2% of all
maternal ultrasound scans; this leads to a detection rate of
approximately 1200 to 12,000 new cases of suspected antenatal
hydronephrosis each year. The false-positive detection rate is
reported to be 9% to 22%.25 Various series have shown that
approximately 66% to 75% of postpartum ultrasound studies
confirm antenatally detected hydronephrosis. We have not
included cases of ultrasound-detected hydronephrosis that
were not found prenatally or cases in newborns who were
normal in the immediate postpartum period, but subsequently
were found to have hydronephrosis as an infant.
Of patients in whom hydronephrosis persisted in the postpartum period, the most common immediate radiologic investigations obtained were voiding cystourethrogram (VCUG)
and nuclear renography. In a study by Gunn and colleagues,1
23 of 40 (57%) infants with significant upper tract dilation
were shown to have a hypoplastic adynamic segment by
nuclear renography. This is the most common cause of dilation of the upper tract, accounting for nearly 60% to 80% of all
persistent hydronephrosis.26 In a follow-up series by Morin
and associates,3 23 of 63 (36%) patients with antenatally and
postnatally detected hydronephrosis had abnormal VCUGs.
VUR as an etiology of hydronephrosis accounts for 25% to
35% of postnatally diagnosed hydronephrosis.27
UPJ problems occur most commonly in boys28,29 especially
in the newborn period, when the ratio exceeds 2:1.30,31 Leftsided lesions predominate, and in neonates more than two
thirds occur on this side. Bilateral UPJ obstruction is present
in 10% to 40% of cases.32,33 In our experience, most bilateral
cases are asymmetric with one side being more severe than the
other. The great variation in incidence is probably explained
by variable criteria of diagnosis on the less severe side.
In this age of routine prenatal ultrasound, the study by
Thomas34 is particularly practical. This study showed the incidence of detectable in utero dilation to be 1 in 60 pregnancies,
with 1 in 500 having a significant urologic problem, of which
about half are problems with ureteropelvic urine transport
inefficiency (Fig. 20-2).
EMBRYOLOGY
Life begins as a single cell. This cell quickly forms a basketballshaped sphere called a blastocyst. Gastrulation (ingrowth of
tissue) results in two cavities (amniotic sac and yolk sac) and a
suspended disc, which becomes the future embryo. Three layers
are quickly formed in the embryoan outer ectoderm, a middle
chapter
Antenatal hydronephrosis
(0.1-2.0%)
Postpartum
(hydronephrosis)
(6675%)
Postpartum
(normal)
(25 33%)
Abnormal studies
(VCUG, nuclear renography)
(33 57%)
Hypoplastic
adynamic segment
(80%)
VUR reflux
(17 48%)
251
Figure 20-2 Incidence of antenatal hydronephrosis, results of postnatal studies, and causes. MCDK, multicystic dysplastic kidney; PUV,
posterior urethral valves; VCUG, voiding cystourethrogram; VUR,
vesicoureteral reflux.
mesoderm, and an inner endoderm. The endoderm forms the
lining of the subsequent inner system, which later communicates directly with the atmosphere (e.g., gastrointestinal tract,
respiratory tract, urinary tract, and female genital tract).
By 4 weeks of gestation, primitive organs called primordia
have been formed. These include the cloaca (from endodermal
tissue) and mesonephros (from mesoderm tissue). At 4weeks,
the ureteral bud forms as an outpouching of the mesonephric
duct just before it joins the cloaca. The ureteral bud grows
in a cranial direction and penetrates the metanephric blastomere. An important process of induction occurs at this
point. Induction indicates that adjacent tissues influence each
otherdevelopment of a biochemical crosstalk. The ureteral bud induces the metanephric blastomere to transform it
from an indifferent mesenchyme to form the specialized nephrons. By progressive generations of dichotomous division, the
ureteral bud is induced to form the ureteral pelvis, calyces,
and collecting tubules. At about 6 weeks, the midureter is a
solid cord that recanalizes in both directions.35
Some authors have suggested that the ureteropelvic and
ureterovesical areas are the last to recanalize. By this theory,
Chwalla membrane may play a role because most ureteral
hypoplastic adynamic segments occur at these two sites.36
Other authors indicate this solid cord recanalization process
does not involve ureteropelvic areas.37 A more plausible
explanation is that in human fetuses histologic differentiation
of ureteral mural smooth muscle begins at the bladder and
proceeds toward the kidney where such muscle is evident by
16 weeks of gestation. It is logical to us that premature arrest of
ureteral wall musculature development leads to an aperistaltic
hypoplastic ureteral adynamic segment at the UPJ region.
By the 10th to the 12th week of gestation, urine can pass
from the glomerulus to the urinary bladder. By the 14th week,
the ambiguous kidneys are capable of concentrating urea and
removing sodium. By the 18th week of gestation, virtually
all of the amniotic fluid is made of fetal urine. Most prenatal
ultrasound protocols begin surveillance just before the midpoint of gestation (16 to 20 weeks), which corresponds to these
developmental milestones.
FUNDAMENTAL BIOPHYSICS
All of these systems basically involve flow of fluid through
biologic conduits and storage in vesicoelastic containers.
These are biohydraulic systems. Many infallible hydraulic
laws are applicable to all hydraulic systems, including the following laws: Poiseuilles, LaPlaces, the first law of thermodynamics (conservation of mass and energy), and the concepts
of power/work as applied to a hydraulic system such as the
upper urinary collecting system. The major determinants governing flow of fluids through hollow conduits and their interrelationship were described in a mathematical expression by
Poiseuille, an 18th century French physician:
Flow =
P r4
8n1
252
part
Cardiopelvic
Detrusor
atmospheric
70
60
50
40
30
20
10
lo
lo
ca
p
m
Bo
fil
t
w
m
ca
p
P
Pr elvi
s
ox
b
U
re olu
te
s
r
D com
is
p
ta
lb
o
D
et lus
ru
D s st
et
r u or
s
vo
i
U d
re
th
ra
At
m
os
the fluid and the length of the conduit. Poiseuilles law has
many applications in the analyses of our study system, but
three require special emphasis. First, the renal circulation
is totally unique with two arterioles (afferent and efferent).
Minor changes in either arteriole radius amplified by the
fourth power dramatically change the arteriole resistance and
glomerular filtration pressures; approximately 19% increase
in the radius doubles the flow. Also, each nephron is a very
long thin conduit when its length is compared with its width.
Finally, the hypoplastic proximal adynamic ureteropelvic segment as was discussed earlier is narrower than the normal UPJ
and has greater resistance. The UPJ is not just a static conduit,
however, and this is not the only factor in its decreased urine
transport capability.
LaPlace describes the major determinants and interrelationships of storage of fluid in vesicoelastic containers:
P=
T
r2
chapter
18 mm Hg
60 mm Hg
100 mm Hg
10 mm Hg
18 mm Hg
13 mm Hg
10 mm Hg
8 mm Hg
Interstitial fluid
pressure 6 mm Hg
0 mm Hg
sels and tubules of the functional nephron and in the interstitial fluid.
(From Guyton A. Textbook of Medical Physiology. 8th ed. Philadelphia:
Saunders; 1991, p 289.)
After extrusion into the ureter, the urine forms a bolus owing
to a contraction ring that completely coapts the ureteral wall
(Fig. 20-6).43 The contraction ring at the proximal end of the bolus
proceeds along the ureter at a constant velocity. The velocity of
the leading edge of the bolus varies so that the width and length
of the same bolus vary in different parts of the ureter. Weiss44 has
summarized the ureteral physiology. Contraction waves occur
at a frequency of two to six times per minute with the baseline
Filtration pressure =1
100
100
100
18
60
(32)
253
14
43
(28)
19
80
(50)
Normal
Colloid
osmotic
pressure
10
Effect of afferent
arteriolar constriction
10
Effect of efferent
arteriolar constriction
part
KIDNEY
Calyces
Pelvis
URETER
Moving
bolus
Empty bladder
Full bladder
UVJ
Moving
contraction
wave
Speed
V
Pressure
Pressure in
contraction
wave
Pcon
30
BLADDER
254
Bolus
pressure
Ureteric
resting
pressure
Detrusor
pressure
Pbol
Pdet
moving from the renal pelvis to the bladder. UVJ, ureterovesical junction; V, speed of voiding. (From Weiss RM, Coolsaet BL. The ureter. In:
Gillenwater JY, Grayhack JT, Howards SS, et al, eds. Adult and Pediatric
Urology. 2nd ed. St. Louis: Mosby-Year Book; 1987, p 889. Reprinted
from Griffiths DJ, Notschaele C. The mechanics of urine transport in
the upper urinary tract: the dynamics of the isolated bolus. Neurol
Urodynam. 1983;2:155. 1983 Wiley-Liss, Inc. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)
20
10
Normal
Reflux
(From Weiss RM, Coolsaet BL. The ureter. In: Gillenwater JY, Grayhack
JT, Howards SS, et al, eds. Adult and Pediatric Urology. 2nd ed. St. Louis:
Mosby-Year Book; 1987, p 891.)
Micropuncture Data
All the quoted figures in this section on physiology of renal
hemodynamics and glomerular filtration have basically been
gleaned from micropuncture data in various mammals. These
data correlate well with experimental hydronephrosis data
and direct patient measurements of Fung, Kiil, and others.38,53
Normal pressures driving fluid from Bowman capsule down
the nephron are only about 10 to 20 mm Hg (13.6 to 26 cm H2O),
depending on the animal used. Pressure at the distal nephron
and at the ureter in the pelvis is usually constantly 6.5 mm Hg
chapter
60
255
Standard error
N 5
55
50
45
40
35
30
25
20
II
III
6.0
5.0
4.0
3.0
2.0
1.0
L Ureter obstructed
Control
8 9 10 11 12 13 14 15 16 17 18
Time in hours
1.2
IPSILATERAL RENAL BLOOD FLOW WITH
STANDARD ERROR OF MEAN DURING
CHRONIC TOTAL URETERAL OCCLUSION
120
100
80
60
40
0.8
0.6
0.4
0.2
0.0
20
0
1.0
14 13 14 14 13 13 11
Control 1
3 4
Days
4
2
4 6
Weeks
Figure 20-9 Changes in left renal blood flow with chronic total left
8 10 12 14 16 18 20 22
Time (hrs)
20 cm H2O
40 cm H2O
256
part
Proportion of
apoptotic cells (%)
CORTEX, GLOMERULI
50
40
30
20
10
0
12
18
24
12
10
8
6
4
2
0
12
18
24
MEDULLA
Proportion of
apoptotic cells (%)
4
3
2
1
0
Renal excision models involve measurement of serum creatinine, GFR (usually inulin), and renal reserve. Following
this, there is a total removal of one kidney and removal of a
known percentage (based on water volume displacement) of
the contralateral kidney with subsequent measurements of
serum creatinine, GFR, and renal reserve. These studies show
it is possible to remove greater than 75% to 80% of the nephrons and not to affect measurable GFR or serum creatinine.
Renal reserve (ability to increase GFR with amino acid load)
is impaired. The message of this model is that GFR measurements alone are not good prognostic indicators of mild or
moderate irreversible significant nephron loss.
12
18
24
6
Duration of elevated
renal pelvic pressure (hr)
Experimental kidney
Control kidney
chapter
257
Intrinsic Pathology
These basic histologic types have been described over the
years by many authors. Cussen68,69 systematically outlined the
anatomic function of these lesions. He first stressed that physical patency exists in all of these cases. The lumen is narrow,
however. The lining is normal, but is surrounded by a reduced
number of leiomyocytes (small muscle cells). The individual
smooth muscle cells are of normal size.70 Starr and colleagues71
also studied these lesions histologically and observed additional findings, including increased collagen between the
muscle bundles, increased elastin in the adventitia, and rearrangement of the orientation of muscle fibers.
Many authors noted predominance of longitudinal muscles,
excessive collagen in and around muscle cells, and attenuated
muscle bundles. Hanna and colleagues, Notely, and others72-75
learned from electron microscopic studies of pathologic UPJs
that there is excessive collagen fibers and ground substance
between and around the muscle cells. As a result, muscle cells
are widely separated, and their points of connection or nexus
are attenuated. Gosling and Dixon76 also noted electron microscopic histologic abnormalities at the UPJ.
In hundreds of cases over the years, we have almost always
grossly observed the following practical points:
1. The described intrinsic lesions occur in almost 100% of
cases.
2. The lumen is small but physically patent.
3. The mural wall is thin.
4. The elasticity of the wall tested by placing both pincers of
a nontoothed Iris forceps in the lumen is significantly reduced compared with the distal normal ureter in the same
patient.
Our final conclusion is that there is an interference with
peristalsis propagation across the UPJ and interference with
urine bolus formation in the proximal ureter. This is best
labeled as a hypoplastic adynamic ureteral segment at the
UPJ. As we show later, this segment of conduit actively transports urine, albeit at low workloads (i.e., low urine volumes
into lower bladder pressures), but cannot efficiently adjust to
increased workloads (high urine volumes or higher bladder
pressures) in an effective manner.
Other authors have described, beginning with Ferjon77
in 1894, flap valve as an etiologic cause at the UPJ. More
recently, Maizels and Stephens observed similar lesions.78 We
have occasionally observed the benign mesodermal polyp as
described by Gup.79
Extrinsic Pathology
Extrinsic pathology refers primarily to the aberrant crossing vessels, fibrous band adhesions, kinks, and anomalous
takeoffs. Mayo80 probably offered the first lively description
258
part
Figure 20-12 CT scan of the left kidney with two aberrant renal vessels entrapping the ureteropelvic junction, creating hydronephrosis.
chapter
Horseshoe Kidney
Horseshoe kidney occurs in about 1 per 500 live births.
Approximately 15% of these cases have an associated ureteropelvic urine transport efficiency problem. This is at least 15 to
20 times the association rate in a normal kidney; there seems
to be an intrinsic tendency for ureteropelvic urine transport
problems to occur in horseshoe kidney. At times in the past,
the isthmus itself was thought to be a secondary extrinsic factor, and simultaneous symphysiotomy was performed. The
consensus now is that division of the parenchyma is almost
never necessary. The diagnosis is still important to make
preoperatively because it affects the incision and approach
if open pyeloplasty is performed, and the individual vascular configuration affects the technical details of repair. We
259
Ectopic Kidney
Renal ectopy refers to a kidney outside the renal fossa. It
is a rare finding, occurring in 0.01% to 0.08% of patients.105
According to Gleason and coworkers,106 sites include pelvic (55%), crossed (32%), lumbar (12%), and thoracic (1%).
Approximately half of such kidneys are hydronephrotic.
Hydronephrosis is due to various causes, including UPJ
problems (37%), VUR and lower tract problems (26%), and
hypoplastic adynamic segments at the ureterovesical junction (15%). All cases require lower tract imaging and accurate anatomic (not just functional) upper tract imaging. We
currently prefer CT urograms with simultaneous ureteral
fluoroscopy. Surgical correction requires special consideration.107-109 Position, incision, and approach must be individualized; in most cases, a modified Gibson incision allows
an extraperitoneal approach. Open pyeloplasty is usually
260
part
CLINICAL PRESENTATION
The clinical presentation changed dramatically after the advent
of widespread maternal ultrasound screening in approximately 1978. Before prenatal ultrasound, children primarily
presented with symptoms. Presentations include febrile urinary tract infections, abdominal masses, pyuria, pain, hematuria, and gastrointestinal symptoms. The hematuria may
follow trivial or mild abdominal trauma. Fifty percent of all
palpable abdominal masses are renal, and almost 50% of those
are hydronephrosis. Other, less common presentations include
failure to thrive, anemia, sudden onset of hypertension, and
urinary extravasation.
UPJ problems are often associated with other congenital
anomalies, including imperforate anus, contralateral multicystic kidney, congenital heart disease, VATER syndrome,
(Vertebral, Anus, Trachea, Esophagus, Renal), and esophageal
atresia. In patients with the established diagnosis, a renal
ultrasound examination should be performed. Now most
cases are asymptomatic and are diagnosed on routine maternal ultrasound screening.
DIAGNOSTIC TESTS
In ordering diagnostic tests, the clinician should ask the following questions:
1. What information do I seek, or what question do I wish to
answer?
2. What is the most accurate test for answering this question?
3. What is the most effective method of answering the
question?
4. Can I answer more than one question simultaneously with
a single test?
5. Is the question really relevant to the patientwill it add to
the selection, safety, and success of the management strategy?
The last 2 decades have given rise to a wide variety of
imaging and other diagnostic procedures. The options are
numerous and confusing. Most authors review diagnostic
tests by methodology. This is a standard approach, but we
prefer to make the technology work for us and for the patient.
We prefer to start with the question we wish to answer:
1. Is there abnormal fluid collection in the fetal kidney?
2. Are the prenatal findings reconfirmed after birth?
3. Are the abnormal findings in the lower urinary tract the
primary cause of the hydro(uretero)nephrosis?
4. Is the urinary tract infected?
5. Is there associated VUR; if so, how severe?
6. What is the anatomic and functional status of the
contralateral kidney and upper urinary tract?
7. Are there calculi proximal to the UPJ; if so, how many,
and what is the possible etiology?
8. Has pyelonephritis scarring damaged the affected
kidney?
9. Has the affected kidney been damaged by ischemia and
atrophy; if so, how severe?
10. Does UPJ lesion occur in the kidney with anomalous
ascent?
11. What is the differential function of the affected and
contralateral kidney; is the function stable, improving, or
deteriorating?
chapter
Renal Pelvis
Calyces
Parenchyma
Slight
dilation
II
Moderate
dilation
Mild
caliectasis
III
Large
dilation
Moderate
caliectasis
IV
Severe dilation
Severe dilation
Thinning
N, normal.
261
Postnatal Ultrasonography
There is very little debate about the type of examination, but there is about the timing of the test and necessity
for re-examination. Transitory neonatal dehydration lasts
approximately 48 hours.84 For minor problems in mild and
moderate cases, imaging should be done after 48 hours. In
severe cases (bilateral, solitary, oligohydramnios, or very
large), we recommend doing the examination earlier.
Although renal ultrasound is an ideal noninvasive method
to detect infant hydronephrosis, the significance of the upper
tract dilation is more difficult to assess because it does not
reveal renal function.26,111 Ultrasound is often operator dependent, and the designation of the grade of hydronephrosis is
often subjective. Ultrasound cannot adequately assess the renal
parenchymal damage resulting from the underlying disease
process. In a study of 255 renal units with reflux, the postnatal
sonogram was normal in 177 (70%) of the examined cases.112
part
Counts
Time
1
Counts
Counts
Time
1
Furosemide
Washout
Time
Counts
262
Furosemide
Time
Figure 20-13 Stylized time activity curve in provocative renal renography. A, Normal curve shows the three renogram phases: 1 = perfusion
phase; 2 = cortical transit phase; 3 = excretion/clearance phase. B, Abnormal curves. These curves are typical for obstructive or nonobstructive
dilation with accumulation of tracer in the collecting system. Impaired renal function with cortical retention of tracer can produce a similar appearance, although the peak parenchymal activity would be lower than normal (bottom curve). C, In nonobstructed collecting systems, there is
prompt washout of pelvicalyceal activity after intravenous furosemide. D, In cases of obstruction or impaired renal function, poor or no washout
is seen. (From Roarke MC, Sandler CM. Provocative imaging: diuretic renography. Urol Clin North Am. 1998;25:227.)
chapter
Distal
Collecting
tubule
tubule
10 mmHg 0 mmHg
30
n
23
35
125
100
20
14 cm H2O
10
14
Individualized
flow rate (1.3
12.5 mL /min)
Fixed
10 mL /min
flow rate
in when the timing is started, and the mathematical differences in determination of 50% clearance point. Timing may
be started when the furosemide is given, or when its affect
can be visualized on the activity curve. The former has the
disadvantage of disregarding individual response time to the
drug, and the latter is subjective, particularly in equivocal
cases in which the precise amount of radiopharmaceutical is
unclear. Mathematical variation includes linear extrapolation
to determine the 50% point on construction of a computerretrieved exponential best-fit curve.
Most institutions report half-times of less than 15 minutes
to be normal and more than 20 minutes as being obstructed
(see previous discussion). Values between 15 and 20 minutes
are equivocal. As mentioned previously, we strongly believe
that this single test is not definitive in distinguishing obstructive from nonobstructive cases (see later discussion on
correlation).
50
Flow (mL/min)
40
263
20
10
5
2
1
Figure 20-15 Approximate urine flow rates (mL/min) in each section of the nephron. Flow is plotted in a semilogarithmic scale illustrating the significant differences in flow in the proximal versus distal
nephron. (From Guyton A. Textbook of Medical Physiology. 8th ed. Philadelphia: Saunders; 1991, p 303.)
264
part
40
40
30
20
10
0
10
20
30
Peak renal pelvic pressure
post diuresis (cm H2O)
40
30
20
10
10
20
30
Time (min)
Furosemide
diuretic urine flow rates. (From Fung LC, Khoury AE, McLorie GA,
etal. Evaluation of pediatric hydronephrosis using individualized
pressure flow criteria. J Urol. 1995;154[2 Pt 2]:671-676.)
chapter
265
PRENATAL MANAGEMENT
Since the routine application of maternal-fetal ultrasonography,
virtually every pediatric urologist in the world has acquired a
new type of patientthe pregnant mother. As mentioned in
the section on diagnostic testing, accurate prenatal diagnosis
must determine the presence, severity, and progression of the
lesion. Accurate pathologic anatomy and physiology must
be rendered as soon and as accurately as practically possible.
Emphasis must be on family education, term counseling, and
presentation of options.
Evaluation must include the following:
1. The significance of detectable urinary tract dilation in
utero varies significantly from incidental to catastrophic.
2. An excellent prognosis is more common than a good
prognosis, which is more common than a poor prognosis,
which is more common than a catastrophic prognosis.
3. Kidneys are paired organs, and unilateral disease (with a
contralateral kidney) never constitutes immediate
life-threatening disease, and in utero invasive procedures
or early delivery is never indicated.
4. Fetal renal pelvis size does not correlate with significance.
Dilation of 3 to 11 mm (seen at 26 to 28 weeks of
gestation) occurs in 18% of fetuses and very seldom
results in operative problems postnatally. Dilation of
more than 12 mm resulted in postnatal surgery in 34% of
patients managed in a very conservative group.
Dilation greater than 20 mm is clinically significant, but
does not always require postnatal operative intervention. If postnatal operative intervention is required, it is
usually very successful with few long-term sequelae.
5. In cases of very severe (SFU grade IV) unilateral lesions
leading to unilateral renal loss with a normal contralateral
kidney, an excellent quality and length of life can be
achieved with one kidney. Highly intelligent people daily
voluntarily donate one of their kidneys to another person.
6. The concept of a hopeful versus hopeless kidney
must be explained to the family. A hydronephrotic
kidney (even severely) is hopeful and is capable of
delivery of future long-term meaningful renal function.
A severely hypoplastic kidney is hopeless. It is important
also to explain timing and accuracy of establishing
distinguishing diagnosis.
7. In establishing perspective, it is important to remind
families that billions of people have lived on the
earth, and that all have encountered or will encounter
significant disease.
8. In cases of bilateral hydronephroses, the prognosis
primarily depends on the status of the favorable kidney.
Frequently in bilateral UPJ obstruction problems, there is
significant asymmetry in severity.
9. Some cases have obvious indications of severity. These
include bilateral (or solitary kidney) dilation of greater
than 20 mm, bilateral evidence of hypoplastic dysplasia,
progressive bilateral dilation with ultrasound evidence of
oligohydramnios, and pulmonary hypoplasia.
10. Perinatal imaging is not 100% accurate.
266
part
INTRAUTERINE INTERVENTION
Since its debut accompanied by national magazine coverage,
intrauterine surgery has had limited applications in terms of
total number of patients successfully treated on a worldwide
basis. Careful detailed long-term follow-up studies at Boston
Childrens Hospital indicated that only 20% of patients with
prenatally detected urinary dilation are candidates for such
treatment. Nevertheless, centers of excellence, such as the Fetal
Treatment Center at the University of California in San Francisco, remain progressive, committed, innovative, and able to
publish significant feats of technical excellence.
Families considering such treatment should be aware of
reported complication rates of 45% associated with shunting procedures. These are from reporting centers. It is safe to
assume that complication rates in nonreporting centers are
even higher. Complications include preterm labor, hemorrhage, chorioamnionitis, urinary ascites, catheter migration,
and catheter failure.36 The medicolegal status is complicated
and frequently concentrates on rights of the fetus and
mother. Ethical dilemmas involving responsibility are complex. Controlled studies show that long-term benefits are
lacking. Tertiary medical centers with the emotional commitment, technical expertise, and experience would have
problems not treating suitable patients. The decision is often
made whether the mother and fetus are referred or not to such
a committed center.
TERMINATION
In our opinion, no single subject divides Americans more than
therapeutic abortions. Physicians and families, for religious,
personal, and philosophical reasons, often have dramatically
opposed views. The widespread use of this procedure may
affect the future of pediatric urology more than any other
future event. Use of therapeutic abortion is more common
in European countries and has already affected practice
patterns. Paradoxically, it is often most commonly used in
countries whose citizens are primarily Roman Catholic (e.g.,
France) despite the Churchs traditional, steadfast, and total
opposition. More recent presentations at international meetings have indicated routine use of late-term abortion for
severe genitourinary problems. We believe that the physician should declare his or her personal beliefs to the family. Nevertheless, there are extreme circumstances in which
neonatal life is essentially impossible (e.g., bilateral hypoplasia, severe oligohydramnios, and pulmonary hypoplasia), in
which termination, whether therapeutic or spontaneous, is
inevitable.
POSTNATAL MANAGEMENT
Careful physical examination to include or exclude all conditions or widespread differential diagnosis is indicated. These
conditions include myelodysplasia, sacrococcygeal teratoma,
cloaca and urogenital sinus problems, lower tract dysfunction with imperforate anus, prune-belly syndrome, and
hydrometrocolpos. Lower tract problems including anterior
and posterior urethral valves, bladder diverticulum, ectopic
ureterocele, or ectopic ureter and primary reflux are included
or excluded by VCUG (see earlier section on VCUG versus
nuclear cystogram). Postnatal ultrasound is done at 3 to 5 days
of age (e.g., after 48 hours) except in cases where VCUG shows
a significant lower tract problem, and management has to be
advanced because of the severity of the pathology.
After VCUG and postnatal ultrasound, patients are assigned
to various management groups as follows:
1. Examination, VCUG, and ultrasoundall normal.
Many authors stop further follow-up at this point.
Other authors suggest a second ultrasound 3 to 7 months
later.
2. Examination normal, VCUG shows primary VUR,
ultrasound shows hydronephrosis.
Patients are followed as outpatients on prophylactic
antibiotics, and primary VUR is managed appropriately.
3. Examination normal, VCUG shows other primary disease such as posterior urethral valves, ultrasound shows
hydronephrosis.
Appropriate management is instituted.
4. Examination normal, VCUG normal, ultrasound shows
one normal kidney and one hydronephrotic kidney.
Defer imaging to at least 1 month of age, or longer if low
birth weight.
5. Examination normal, VCUG normal or shows minimal
reflux, ultrasound shows mild bilateral hydronephrosis.
Favorable prognosis (SFU grade II or better).
Treat as above.
6. Examination normal, VCUG normal or shows minimal
reflux, ultrasound shows solitary or bilateral hydronephrosis with the better kidney SFU grade III or worse, particularly if both kidneys are SFU grade IV.
Serial daily serum creatinine beginning at day 2 of life.
If renal function worsens, treat as neonatal renal failure
(see subsequent discussion).
chapter
SURGICAL TREATMENT
Similar to imaging, modern advances have resulted in many
surgical options for correction of a pediatric UPJ. The main
decisions that have to be made when surgery is indicated are
the following:
267
We use a Foley catheter with a Y connector for infusing color confirmation (see later section on use of splints).
Endotracheal intubation, relaxation, ventilation, and no nitrous
oxide are mandatory. The child is flexed using the anatomic
location of the kidney as the midpoint, and we use the kidney
rest and flexion capability of a Skytron 6000 (Skytron, Grand
Rapids, MI) surgical table. The child is placed in a prone position with suitably sized transverse thoracic and midthigh rolls.
A transverse skin incision is made just under and parallel to
the 12th rib with one third of the incision over the paraspinal
muscle and two thirds lateral to the skin. The subcutaneous
tissues are extensively mobilized to permit a longitudinal incision over the midlumbodorsal fascia and paraspinal muscle.
The three circular muscles (external oblique, internal oblique,
and transversus abdominis) are slid laterally to separate from
each of three longitudinal muscles (erector spinae, quadratus
lumborum, and psoas). We find bipolar cautery invaluable.
Closure is with a single muscle fascia layer bringing the
lumbodorsal fascia back together again. We use interrupted
modified figure-of-8 (Maxon, Ethicon) sutures for this. We
have often done bilateral procedures successfully under the
same anesthesia without position changes or redraping. Pain
is minimal, morbidity is reduced, and mobilization is almost
immediate.
Anterior Approaches
268
part
Figure 20-18 Schematic depiction of standardized technique of open pyeloplasty as proposed by Hynes and Anderson. A, Lines of cuts to excise
the hypoplastic adynamic ureteral segment. B, Ureteral spatulation to face the renal parenchyma and placing preliminary sutures. C, Completed
procedure. (From Novick AC, Streem AB. Surgery of the kidney. In: Walsh PC, Retik AB, Vaughan ED, et al, eds. Campbells Urology. 7th ed. Philadelphia: Saunders; 1998: 3044.)
Other alternatives include Foley V-Y plasty and the spiral flap
of Culp and Scardino, all of which have their advocates and
perhaps special individual anatomic indications. With use of
a preoperative CT urogram, we are usually aware of aberrant
vessels preoperatively.
Selection of Patients
Even strong experienced advocates do not recommend these
procedures in neonates, infants, or young children.129 In
preadolescent children, the choice is more controversial. In
adolescents, the anatomy is similar to adults. Massive hydronephrosis or crossing aberrant vessels or both in multiple
reports decrease success. Preoperative imaging may direct
the safest place for ureterotomy. Figenshau and Clayman129
and other authors empirically place the cut in a lateral position. Long avascular strictures, total obliteration of the
lumen, and periureteral fibrosis are contraindications for the
procedure.127,130-134
Success of Endopyelotomy
The success rate of endopyelotomy seems to be independent
of the approach (retrograde or percutaneous antegrade) (Table
20-2). Similarly, the type of incision, whether using Accucise (Applied Urology, Laguna Hills, CA), a balloon with
chapter
Percent Successful
90
74
Vessels present
33
30
269
Robotic Surgery
Robotic-assisted pyeloplasty attempts to overcome the technical hurdles of laparoscopic surgery. One of the authors
(W.C.F.) routinely uses the daVinci Robotic System (Intuitive
Surgical, Sunnyvale, CA) in a minimally invasive approach
to pyeloplasty. Robotic pyeloplasty directly mimics our open
technique. The UPJ is exposed transabdominally through a
retroperitoneal or transmesenteric approach. Complex intracorporeal movements, such as dissecting, suturing, and knot
tying, are easily mastered.140 The daVinci system has 15 times
optical magnification in a three-dimensional viewing environment. The robotic instruments are placed through 5- or 8-mm
trocars allowing for 6 degrees of freedom.141 The pyeloplasty is
performed in the same manner as first described by Anderson
and Hynes21 in 1949. A renal pelvis stay suture is introduced
extracorporeally and can be repositioned easily during the
ureteropelvic anastomoses. Finally, a 4.7F double-J ureteral
stent is easily placed intraoperatively through a 14-gauge
intravenous catheter punctured into the abdominal wall under
direct vision. The short-term outcomes of our robotic-assisted
pyeloplasties (e.g., decreased hydronephrosis, preservation of
renal function) are indistinguishable from our open series. The
long-term efficacy of this approach is not yet supported by the
literature, however.
We contend that robotic surgery should be considered a
direct translation of open surgery and does not represent an
evolution of laparoscopy. Because robotic surgery does not
use laparoscopic skills (as described earlier), it represents
an extension of the open surgery branch of the surgical
270
part
COMPLICATIONS OF SURGERY
Parents must be informed about potential, general, and specific complications of the procedure. For prevention of general complications, several safety measures must be followed
meticulously. First, all of these procedures require endotracheal anesthesia. We do not perform such procedures (even
balloon dilation) with a laryngeal airway. In open procedures
(particularly posterior lumbotomy), we avoid nitrous oxide
to minimize the dilation of the intestinal tract. Any procedure
requiring position changes (e.g., posterior lumbotomy pyeloplasty) requires stethoscope auscultation confirmation of
good airway entry into both lungs after each position change.
In small infants, we either use a central line (internal jugular
or subclavian) or have two well-performing peripheral intravenous access lines. An appropriate-sized cautery plate is
positioned, and great care is taken not to get it wet during the
preparation of the wound. In positioning patients, great care
must be taken to ensure no pressure points are compressed.
Irrigation instilled into the urinary tract for any open endoscopic procedure must be nonelectrolyte (i.e., water).
The complications of surgery for UPJ problems are similar
regardless of whether the approach is intraluminal, extramural, open, or endoscopic. Although certain techniques have a
predilection for certain complications, there seems to be little
doubt that some techniques generally have higher complication rates than others. Similar to any other operation, complications can be general or specific.
Pulmonary complications can be minimized by using
endotracheal anesthesia even for endourologic procedures.129
Because many of these procedures involve an unusual position, air entry in both lungs must be confirmed before and after
position changes. Significant hemorrhage occurs primarily
from adjacent aberrant vessels. Accurate preoperative and
intraoperative diagnosis minimizes these complications.
For endourologic procedures, the prospective patient (or
parent) is advised regarding the following:
1. Ureteral imaging techniques for preoperative diagnosis.
2. We advise CT urography.
3. Most incisions are made laterally.
4. Particular care is taken in anomalous kidneys.
5. Plan Balternative emergency open intervention
with catastrophic hemorrhageis established before the
procedure.
6. Prophylactic and therapeutic preoperative and
intraoperative antibiotics minimize infection.
Specific Complications
Obstruction
Obstruction occurs primarily at the operative site, but also
occurs at the ureterovesical junction. Obstruction occurs most
commonly in balloon dilation in children (rate of 20%).129 In
collective series of endopyelotomy (total of 86 patients), the
overall failure or complication rate was 14%. Distal ureterovesical problems are more common in endoscopic procedures
involving multiple instrumentation of the ureterovesical
junction. A series of 70 neonates with open pyeloplasties at
the Childrens Hospital of Philadelphia had no postoperative obstruction. Other authors report a postoperative
Leaks
Leaks into the retroperitoneum and wound from nonstented
open pediatric pyeloplasties have been reported. Reoperation after prolonged hospitalization can occur in 4.8%.144 This
problem has been virtually eliminated in our experience (and
others) by routine use of internal double-J stents. Urine leakage into the thorax occurs primarily with antegrade endourologic procedures.129
RESULTS OF MANAGEMENT
In this section, we review the results of management of UPJ
problems in children by the following methods of treatment:
intrauterine intervention, postnatal serial observation, standard open pyeloplasty, endopyelotomy, and ureteropelvic
dilation. Laparoscopic pyeloplasty has been reported in children, but multiple center reports of a reasonable number of
patients are unavailable to make a meaningful judgment.
Comparison of results is difficult for various reasons. First,
there is not a standard method of premanagement staging of
severity. The most widely used criteria are the SFU classification for hydronephrosis and split GFR based on nuclear medicine studies. Second, there is no standard follow-up interval,
such as 5 or 10 years. Finally, in contrast to the oncology field,
where survival and disease-free survival are easily comprehended and documented, there are no standard criteria of
success.
Intrauterine intervention, as explained earlier, is applied
only to more severe bilateral (or solitary) kidney problems
with oligohydramnios and pulmonary development problems. The results must be compared with an oncology series,
which includes only the highest grade and highest stage
patients. Also, these procedures are applied to all causes of
chapter
271
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
21
HISTORICAL PERSPECTIVE
Megaureter has been synonymous with dilated ureter,
megaloureter, wide ureter, big ureter, and hydroureterall
descriptive terms that lack true meaning.1,2 The normal ureteral diameter in children rarely exceeds 5 mm. This was first
reported by Cussen in 19713 and later supported by Hellstrom
and associates in 1985.4 Cussens work3 was based on autopsy
investigation of the urinary system in infants and children.
He found that a childs ureter consistently measured less than
5 mm. Hellstrom and associates4 reviewed excretory urograms
in 100 boys and 94 girls. They directly measured ureteral size
from the imaging studies and uniformly found the ureter to be
less than 6 mm in diameter.
In an attempt to improve communication and refine
the understanding and the significance of megaureter, a
working party of pediatric urologists was created.5 They
presented their findings and recommendations in 1976 at an
international pediatric urologic seminar in Philadelphia. An
agreement was made on standardization of nomenclature
and classification of the megaureter. The group defined the
megaureter as primary when it was a lesion intrinsic to the
ureter and as secondary when it was a reaction of the ureter
to a process elsewhere. This group created the ABC clas-
sification of a megaureter: A represented a refluxing ureter;
B, obstructed ureter; and C, nonrefluxing, nonobstructed
ureter. This classification was reported by Smith and colleagues in 1977.6 King7 subsequently modified this classification in 1980 by adding a fourth group that consisted of the
refluxing, obstructed megaureter (Fig. 21-2). He maintained
the primary and secondary subclassifications. Kings classification now is most often referred to when describing a
megaureter.
ANATOMY
To understand pathophysiology, it is important to have a
framework of normal anatomy. Anatomically, the ureter is
divided into three distinct regions: (1) the ureteropelvic junction, (2) the middle spindle, and (3) the ureterovesical junction.
The ureterovesical junction is subsequently divided into the
juxtavesicoureter and the terminal ureter. The terminal ureter
separates into intramural and submucosal segments.8
272
PATHOPHYSIOLOGY
Obstructed Megaureter
Using Kings description, pathophysiology is dictated by ureteral classification. The primary obstructed megaureter has
generated the greatest degree of interest and investigation.
Endoscopically, the obstructed ureteral orifice has a normal
appearance and inserts appropriately on the trigone. Caulk
in 192316 and Swenson and associates in 195217 equated the
obstructed megaureter to that of the enlarged megacolon
seen in Hirschsprung disease. This pathophysiology has been
refuted, however, on the basis of histologic evidence showing
ganglia present in the distal, primarily obstructed megaureter
in a distribution similar to that of a normal ureter.18
Several different histologic abnormalities have been associated with the primary obstructed megaureter, and these
chapter
273
megaureters: those with dense collagen infiltration of the terminal ureter, distal circular muscular hypertrophy, and various degrees of distal muscular dysplasia.
Electron microscopy has elucidated further the pathologic
process of the obstructed megaureter. Several investigators
have identified an increase in collagen deposition between
the lamina propria and muscle bundles of the distal ureter.23-25
These pathologic changes include muscular derangement and
increased interstitial connective tissue, which are confined to
the ureterovesical junction, sparing the middle spindle and
ureteropelvic junction.26
Dixon and associates27 assessed the histologic structure
of primary obstructed ectopic ureters. They found the terminal ureter was encircled by an additional thick collar of
smooth muscle with normally oriented muscle layers but a
diminished diameter. They speculate this embryologic malformation does not resolve spontaneously and may become
the subgroup of obstructed megaureter that requires early
intervention.
Allowing the megaureter to express its natural history
has confirmed that some forms of obstructed megaureter
improve with time.28-33 This spontaneous improvement
may be due to segmental maturational development of the
distal ureter. Nicotina and associates28 postulate segmental
hypoplasia of the inner longitudinal muscle layer and the
possible pathogenic involvement of transforming growth
factor- (TGF-), which has been shown to affect maturation of smooth muscle cells. TGF- delays muscle cell differentiation and is detectable in 11- to 21-week-old fetuses,
but diminishes thereafter. Nicotina and associates28 found
TGF- in distal ureters of children who had obstructive
uropathy and who were younger than 2 years, but not in
children who were older than 2 years and who had been
operated on for nonobstructive causes. They postulate that
the spontaneous improvement in the obstructed megaureter may correlate with TGF- depletion within the first
2 years of life.
Gene assessment is beginning to shed light on the underlying pathophysiology of obstructive megaureter. Hohenfellner
and associates34 have shown an increase in angiotensin II
type 2 receptors in patients with a primary obstructive megaureter. Further research into gene identification may play a
future role in management of the megaureter. Current investigation into the contractile function of the smooth muscle wall
of the megaureter and its adrenergic regulation may prove
helpful in new options for pharmacotherapy.34-36
Megaureter
NonobstructedNonrefluxing
Primary
Secondary
Diabetes insipidus
Infection
Postoperative
Obstructed
Primary
Secondary
Refluxing
Primary
Secondary
ObstructedRefluxing
Primary
Secondary
Figure 21-2 Clinical classification of a megaureter. (Adapted from King LR. Megaloureter: definition, diagnosis and management. J Urol.
1980;123:222-223.)
274
part
A
Interlongitudinal
Middle
circular
Outer
longitudinal
elongated, tortuous, and dilated. On endoscopic examination, the ureteral orifices are lateral, look like a golf hole
in appearance, and are frequently associated with a diverticulum. The distal ureter is often asymmetrically involved,
showing significant ectasia (Fig. 21-5). Secondary obstruction
may occur with kinking and folding of the redundant ureter.
Primary obstruction has been reported at the ureterovesical junction in a select group.39 Seen microscopically is an
increase in fibrous tissue at the expense of normally developed ureteric muscle. Gearhart and coworkers40 showed that
children with triad syndrome and vesicoureteral reflux have
an increased ratio of collagen to smooth muscle fibers in the
muscularis. This increased fibrous tissue may help explain
the poor dynamic characteristics of the ureter, which lead
to ineffective peristalsis and urinary stagnation.39 Ehrlich
and Brown41 reported the degeneration of nonmyelinated
Schwann fibers and a decreased number of nerve plexuses, which may contribute to decreased ureteral peristalsis.
Ureteric abnormalities tend to predominate in the distal portion of the ureter; this becomes important when considering
operative intervention.
DIAGNOSIS
Refluxing Megaureter
A refluxing megaureter is endoscopically characterized by
a laterally positioned, gaping ureteral orifice. Pressure from
bladder filling and cyclical voiding can be transmitted into
the ureter, resulting in mechanical enlargement of the ureter (Fig. 21-4). Lee and associates37 showed that in addition
to a lateral position, there are inherent changes in a refluxing megaureter that affect its pathogenic state. They found
a twofold increase in the ratio of collagen fibers to smooth
muscle fibers in refluxing megaureters compared with those
of obstructed megaureters and control ureters.38 Lee and
associates further defined collagen fiber types and showed an
increase in collagen types I and III for obstructed and refluxing megaureters. Refluxing megaureters contained a significantly greater percentage of type III collagen, however, than
other megaureters. Type III collagen is a less distensible fiber,
raising speculation that this intrinsic characteristic results
in a stiffer ureter; this may have an important role in the
decreased success rate after operative correction of refluxing
megaureters compared with the success noted in other forms
of megaureters.37
Refluxing megaureter associated with prune-belly
syndrome (triad of Eagle-Barrett) represents a unique
abnormality.39 The gross appearance of these ureters is
EVALUATION
Ultrasonography
Ultrasonography is the primary imaging modality used to
assess antenatal hydronephrosis and is the initial imaging study
obtained for symptomatic genitourinary abnormalities. Ultrasound should have a key role in the assessment of megaureter.
Evaluating the size, shape, tortuosity, and bulbar appearance
of the ureter in conjunction with similar findings of the renal
pelvis can often give the impression of an obstructive process.
The ureter can often be traced from the renal pelvis to its distal
chapter
275
Voiding Cystourethrography
Voiding cystourethrography is essential when evaluating the
megaureter to rule out vesicoureteral reflux. A conventional
fluoroscopic cystogram is preferred over a nuclear cystogram
in that the anatomic appearance of the bladder, bladder neck,
urethra, and ureters is necessary for precise diagnosis and
treatment. The cyclical voiding cystourethrogram is beneficial when an ectopic, sphincteric ureter is suspected. In this
scenario, the ureter can be obstructed when the bladder is
at rest and refluxing only during the voiding phase. Cyclical
evaluation may be required to document the refluxing phase.
Blickman and Lebowitz44 characterize the refluxing obstructed
megaureter as having the appearance of a markedly enlarged
proximal ureter associated with a normal-appearing ureterovesical segment.
Excretory Urography
Excretory urography is waning as a diagnostic modality in
the evaluation of pediatric uropathy. Even with tomography, the information gained is limited. Stool, bowel gas, and
i mmaturity of the neonatal kidney limit its utility. In addition, the degree of hydronephrosis noted does not equate to
severity of obstruction. Rarely, excretory uropathy may have
a helpful role when further anatomic definition is required.45
When anatomic detail is required, furosemide (1 mg/kg) given
3minutes before contrast material enhances the multislice CT
scan and shows promise at defining the pathologic defect better than intravenous urography and ultrasonography.46
Renography
Diuresis renal scintigraphy provides the greatest quantitative
information of functional and dynamic data. With the assessment of several parameters, including renal uptake, excretion,
time to peak activity, and time to half peak after furosemide
washout, the degree of obstruction can be assessed. Two common radiotracers used to evaluate obstruction in pediatrics are
technetium 99m diethylenetriamine penta-acetic acid (Tc99m
DTPA) and technetium 99m mercaptoacetyltriglycine (Tc99m
MAG3).47,48 DTPA is a glomerular agent and has been discouraged from use during the first month of life because of low
neonatal glomerular filtration rates. MAG3 is extracted by the
kidneys and is dependent on effective renal plasma flow, not
glomerular filtration rate. This makes MAG3 a more attractive
agent, especially during the neonatal period.47 MAG3 also provides better interpretation of function with less background
artifact.
Many variables can have a role in data acquisition and
interpretation. For that reason, renal scintigraphy must be
performed in a standardized manner using a protocol that
optimizes hydration, administration of diuretic, and acquisition of time-activity curves.49 When assessing the megaureter
for an obstructive pattern, it is important to have two sets of
activity curvesone over the kidney and the other over the
ureter. Isolating simply over the kidney could produce deceiving results showing an acceptable washout of the radiotracer
276
part
These ureters are elongated, tortuous, and dilated. There is often ureteral asymmetry with the distal ureter showing significant ectasia.
(From Joseph DB. Triad syndrome and other disorders of abnormal
detrusor development. In: Gonzales ET, Bauer SB, eds. Pediatric Urology
Practice. Philadelphia: Lippincott Williams & Wilkins; 1999.)
DIFFERENTIAL TREATMENT
Therapeutic intervention of the megaureter depends on accurate classification. Secondary causes of a megaureter justify
treatment of the primary problem whether it is due to a neurogenic bladder, posterior urethral valves, ureterocele, diabetes
insipidus, or a retroperitoneal process. Specific treatments for
these problems are described elsewhere.
Refluxing Megaureter
Grades IV/V and V/V vesicoureteral reflux (according to
International Study Classification) traditionally has prompted
operative intervention.57 For older children presenting with
symptomatic urinary tract infections, this approach may be
appropriate. Growing experience shows, however, that operative intervention is not required as initial management in neonates with refluxing megaureters, especially when identified
during the workup of antenatal hydronephrosis. High-grade
vesicoureteral reflux in neonates occurs more often in boys
than girls. Improvement during the first year of life can be
anticipated in many of these children.57 There is little reason
to proceed with intervention in these early years, particularly
when an infant has remained symptom-free on prophylactic
medical management. Resolution of high-grade vesicoureteral
reflux in neonates is not unusual.
Williams58 first described the constellation of megacystismegaureter in 1954. Megacystis-megaureter is an association
and not a syndrome because underlying pathophysiology is
well understood.59 By definition, the term megacystis-megaureter
chapter
277
Figure 21-6 A, MAG3 renal scan shows delay in peak activity of the
C
should be applied to a large-capacity, thin-walled bladder
with massive primary vesicoureteral reflux.58,59 Megacystismegaureter occurs in approximately 80% of boys diagnosed
antenatally with bilateral reflux and renal impairment.60 The
cause of the male predominance is unknown. There does
not seem to be any degree of bladder outlet obstruction.
Speculation has been given simply to higher neonatal voiding pressure in boys. Children with megacystis-megaureter
show progressive upper tract hydroureteronephrosis and
bladder enlargement resulting from the recurrent cycling of
urine into the upper tract during a detrusor contraction followed by rapid refilling of the bladder on relaxation of the
detrusor after voiding. Over time, this cyclical event leads
to increased bladder volume and subsequently increased
hydroureteronephrosis.
In children who are toilet trained, double voiding combined with prophylactic antibiotics may be an effective temporizing treatment option. Ten to 15 minutes after the initial
void, the child is encouraged to void again, allowing for an
overall decrease in volume of retained urine. Positive effects
of this technique can be seen first with stabilization of bladder
volume followed by reduction in bladder size and improvement of hydroureteronephrosis. In neonates and toddlers who
are not toilet trained, intermittent bladder catheterization can
be an effective technique to eliminate residual urine, allowing
the child to reach an age at which operative correction would
be deemed beneficial. Ultimately, children with a megacystismegaureter are best served by operative reconstruction.59
Obstructed Megaureter
Before the advent of fetal ultrasonography, the treatment
of the obstructed megaureter was straightforward. A child
would present symptomatically with a urinary tract infection, abdominal pain, or nausea and vomiting.1 Adults also
present symptomatically and usually require aggressive management.68 This form of selection eliminated the guesswork
currently required to determine which children would benefit
278
part
OPERATIVE APPROACH
Temporary Diversion
Temporary urinary diversion may have benefits as indicated
earlier. A practical approach for a severely obstructed unilateral megaureter is to proceed with distal cutaneous ureterostomy. This technique is rapid, has minimal morbidity, and can
often be performed in an outpatient setting. With a child in the
supine position, the ureter is approached from a 2-cm incision
placed within an ipsilateral low inguinal skin crease. A muscle-splitting exposure is used to enter the space of Retzius. It is
helpful to have the bladder half full to facilitate the dissection.
Dissection is continued laterally and superiorly, mobilizing
the peritoneum from the bladder. In most situations, the ureter is easily visualized because of its size. A cautious approach
should be taken before transection because bowel can be confused with a distended ureter, particularly in an infant. If there
is any doubt about the structure that has been mobilized, a
21-gauge needle should be passed, aspirating the contents to
confirm urine. If the ureter is not easily identified, the obliterated umbilical artery provides a suitable landmark for initiating the search.
The obliterated umbilical artery should be transected in the
deep pelvis adjacent to the bladder, and the ureter is found
just beneath that point. The ureter is mobilized, and the decision whether to fashion an end or a loop cutaneous ureterostomy is made. The ureter should be secured to the anterior
rectus fascia with 4-0 or 5-0 absorbable suture and to the skin
with the same. The size of the ureter prevents postoperative
stenosis. Lee and associates75 report a unique form of internal
temporary diversion. They create a refluxing anastomosis
securing the side of ureter proximal to the obstruction to the
Definitive Reconstruction
When definitive urinary reconstruction is necessary, the initial approach to the ureter can be intravesical, extravesical, or
combined. The dilated ureter is often exceedingly redundant
and tortuous. Straightening the ureter is required without
devascularization. The functional capability of the ureter
to transmit urine into the bladder through peristalsis parallels the degree of the hydroureter. Ureteral tapering should
enhance urinary flow into the bladder. The ureter also must
be tapered to achieve a ureteral diameter that allows for a 4:1
to 5:1 ratio of tunnel length to ureteral diameter necessary for
an antirefluxing repair. Enough ureter should be mobilized to
taper the intravesical ureter and a short portion of extravesical
ureter. There should be a gradual transition from the tapered
to dilated ureter to prevent a sharp gradient that can act as
a pseudo-obstruction. Several tailoring techniques exist for
ureteral tapering, including ureteral imbrication and formal
ureteral excision.76-79
Imbrication
Ureteral imbrication is appropriate for marginally dilated
ureters. Two common imbricating techniques include the
Starr and Kalicinski plications.76,77 In the Starr plication,76 a
Lembert suture technique with 6-0 absorbable suture is used
to fold in the redundant ureter over a 10F or 12F catheter
(Fig. 21-7). Kalicinski and colleagues77 established a plication
technique that excludes the redundant ureter from the urinary
system (Fig. 21-8). Also, using a 10F or 12F catheter template,
the excess ureter is isolated along its least vascular portion.
A running 5-0 or 6-0 absorbable suture is passed parallel to
the course of the ureter, separating it from the redundant segment. The redundant segment is then folded over the outside
of the ureter and secured with a second absorbable suture
layer. Using either imbrication technique, the plicated ureter
B
C
Figure 21-7 A-C, Starr technique of ureteral imbrication. The ureter
chapter
Excisional Tapering
Formal excisional tapering of the ureter is beneficial, particularly when encountering extremely bulky ureters or a bilateral
process. Hendren78 pioneered the technique that has stood
the test of time. The ureter is tapered loosely over a 10F or
12F catheter, depending on the childs age and size. Straight
Allis clamps are placed longitudinally along the ureter in the
region of least vascularity. Angled Allis clamps are placed over
the ureter, securing the internal 10F to 12F catheter (Fig. 21-9).
Care should be used to prevent the temptation of excluding
too much redundant ureter, which results in excessive tapering around the catheter. The ureter is closed in a two-layer
technique, first with a running locking 5-0 or 6-0 absorbable
279
Figure 21-8 A, Primary obstructed megaureter secondary to aperistaltic distal segment (arrow). B, The Kalicinski technique of ureteral imbrication. The excess segment of ureter is excluded from the flow of urine. It is folded over the ureter using a 10F or 12F catheter as a guide (arrows).
280
part
Figure 21-8, contd C, Kalicinski plication technique isolating the redundant ureter from the distal flow of urine (arrows). D, The excluded
segment has been folded and secured to the distal ureter.
POSTOPERATIVE MANAGEMENT
In the immediate postoperative period, children should be
maintained on appropriate pain control medications and antibiotics. A full course of antibiotics continues while the ureteral
stent is in place. After all stents and drains are removed, antibiotics are changed to a prophylactic dose until obstruction and
persisting vesicoureteral reflux have been ruled out. Ureteral
stents are not necessary in all tapered ureters; however, initial
benefits include decreased urinary extravasation and a scaffold for the ureter to conform to in the postoperative period.
This helps prevent kinking, which can occur in the redundant
and dilated ureter. The ureteral stent also bypasses the tapered
region, which initially may act as an obstruction because of
postoperative edema. The need for a Penrose drain varies,
depending on the technique used for ureteral tailoring and the
presence of an indwelling ureteral catheter. A Penrose drain
may be helpful when a ureteral catheter has not been placed,
and a substantial portion of tapered distal ureter remains extravesical. When a ureteral stent has been placed, the addition of
a Penrose drain is unnecessary. The ureteral stent allows for
chapter
281
Figure 21-9 A, Angled Hendren clamps are placed loosely over a 10F or 12F catheter, securing the retained portion of the distal ureter. Straight
Allis clamps isolate the segment to be excised. B, Two-layer technique is used to close the ureter, interrupting the distalmost portion and allowing
for excision as needed. Arrows indicate interrupted portion.
COMPLICATIONS
Successful operative outcome in the treatment of megaureter
is customary when the operation is performed at pediatric
institutions by appropriately trained surgeons experienced
in the care of children.73 Although success can be anticipated
when performing a tapered reimplant, the potential complication rate and morbidity are greater than when performing a
nontapered ureteroneocystostomy. The two most likely complications include obstruction and persisting reflux. Success
rates for ureteral imbrication have been reported to be 93%
to 95%,77,81-83 and success rates after excisional tapering are
74% to 90%.73,81,83-92
Postoperative complications may not simply be due to
technical error. Inherent ureteral characteristics and bladder
dysfunction affect a successful outcome. Increased collagen
282
part
CONCLUSION
An asymptomatic megaureter is more commonly encountered as a result of the routine use of fetal ultrasonography.
The natural history of megaureter is now unfolding with
REFERENCES
For complete list of references log onto www.expertconsult.com
S E C T I O N
22
Vesicoureteral reflux (VUR) is a dynamic eventthe retrograde flow of bladder urine into the upper tracts. It occurs
normally in the young of many animal species, but is considered abnormal in humans, a feature of disordered anatomy
and function at the ureterovesical junction (UVJ). In clinical
practice, the term vesicoureteral reflux describes a common primary disorder of childhood associated with urinary infection
and renal scarring, or reflux nephropathy. Although the
reflux event usually disappears during growth, the disorder
is of clinical concern because of the morbidity from ascending
urinary infection and the associated nephropathy that can lead
to hypertension and renal function insufficiency.
Clinical and experimental studies have been directed at isolating the causal relationships between the pathophysiologic
components of the VUR disorder: the reflux event, the urinary
infection, and the associated nephropathy. Nevertheless, some
of the issues surrounding these associations remain contentious. The VUR disorder overall is not so simple; it cannot be
explained by a simple organic abnormality. It is a heterogeneous condition with diverse features, suggesting that compound factors may operate in the genesis of the reflux and its
relationships with urinary infection and nephropathy.
Most clinical studies have concerned older children with
acquired renal scarring. Experimental studies have been
directed at the pathophysiologic effects of the reflux event
after birth and the mechanisms for the acquired nephropathy.
It is now clear that the contribution of congenital nephropathy in association with VUR has been underestimated.
Nevertheless, most children presenting in clinical practice do
so after urinary infection, and half already have renal scarring. Most of them are girls, and data from those identified in
infancy suggest that most had normal kidneys at birth.
This chapter considers the clinical disorder, the genesis of
VUR, and the pathophysiologic interrelationships. The roles
of urinary infection and lower tract function are questioned.
Clinical management issues are not addressed. The aim is to
provide a broad understanding and to stimulate curiosity and
activity in evidence-based investigation of the outstanding
anomalies that surround this complex disorder.
Prevalence
The number of children with VUR at any one time is difficult to
ascertain, and the prevalence rate depends on the population
sampled. The early studies of small numbers of newborn and
premature infants did not show any VUR.3,4 Bailey5 in 1979
estimated a prevalence of 0.4% to 1.8% in the general pediatric
population. A more recent meta-analysis of reviewed publications suggests the prevalence may be 9% in healthy normal
children.6 This larger percentage can be explained by several
factors. The data are heavily skewed by the inclusion of a publication reporting an atypical 30% incidence.7 That study comprised infants and children who were hospitalized for various
conditions, some of which are now known to be associated
with urinary tract abnormalities. Repeat micturating cystography in the reflux-positive children on the following day did
not show reflux in most children. It is well known that rapid
filling of the neonatal and infant bladder can generate a flicker
of transient reflux that is not sustained. There is no good evidence for a generally accepted prevalence rate of VUR that is
greater than 1% to 2%.
Investigation of 1005 infants with a prenatal renal pelvis
dilation greater than or equal to 4 mm identified VUR in 6.9%
(equal numbers of boys and girls), an incidence of 0.44% of the
population screened by prenatal ultrasound.8 In infants investigated after an established and specific diagnosis of prenatal
hydronephrosis, the incidence increases to 15% to 25%, which
reflects a prevalence rate of 0.02% to 0.2% of all live births.9
Prenatal screening identifies only a few of all children who
present with VUR at some stage.
Investigations after clinical presentation with urinary
infection show reflux present in 30% to 50% depending on
age and gender.10-15 A survey of 1460 neonates for bacteriuria
indicated that VUR and urinary infection may affect only 0.6%
of asymptomatic neonates, however.16 Prevalence rates relate
predominantly to the white population. VUR is rare among
North African black children presenting with urinary infection or after a diagnosis of prenatal hydronephrosis.17,18
The true incidence of reflux at birth most likely is the same
in boys and girls, although their clinical problems are different. The lower the thresholds for postnatal investigation,
283
284
part
Age (yr)
Series
Infants
(<1)
Rolleston et al
(1970)27
No.
Males
175
91
85
1.1:1
36
20
16
1.3:1
128
79
49
1.6:1
59
22
37
Papachristou
et al (2006)36
181
98
83
1.1:1
Hansson et al
(1999)13
1953
950
1013
1:1
Silva et al
(2006)19
357
103
284
1:3
Smellie et al
(1975)20
233
46
187
1:4
Lenaghan
etal (1976)24
102
35
67
1:2
Bellinger
and Duckett
(1984)21
392
69
323
1:5
Goldraich
and Gold
raich (1992)22
202
43
159
1:4
Wennerstrom
et al (2000)26
1221
232
989
1:4
Merguerian
et al (1999)23*
240
48
192
1:4
Silva et al
(2006)19
296
64
232
1:4
el Khatib et al
(1990)139
293
49
244
1:5
Bourchier
etal (1984)28
Merguerian
et al (1999)23*
Lama et al
(2000)33
0-2
0-15
Adults
(>15)
Females
M:F
1:1.7
*Radiologic
series.
24 with prenatal diagnosis.
5 sibling reflux (excludes prenatal diagnosis).
Includes 2 sibling reflux (excludes prenatal diagnosis).
Excludes grade V reflux, and patients with obvious dysfunctional voiding.
Includes
Includes
Ureterovesical Junction
The UVJ is structurally and functionally adapted to allow the
intermittent passage of ureteral urine and to prevent the reflux
of bladder urine. To achieve these functions, the ureter enters
the bladder with an oblique intramural passage, which extends
submucosally to open onto the trigone (Fig. 22-1).43
Reflux is prevented by active and passive components.
The natural tonus of the ureteral muscles maintains an active
closure of the intravesical ureter except during the efflux of
urine.44 The longitudinal ureteral muscles intermingle with
those of the (superficial) trigone and the contralateral ureter so
that contraction elongates the submucosal tunnel. The adventitia fuses with a fibrous sheath (Waldeyer) circumferentially,
allowing the intramural ureter to move within the hiatus during
bladder filling. Recent studies in the fetus and newborn have
challenged some of these concepts, but the precise age-specific
anatomy is not yet defined.45As the bladder fills and becomes
distended, there is progressive obliquity of the intravesical ureter; the trigone is progressively stretched, increasing resistance
in the intravesical ureter and causing increased pressure within
the distal end of the ureter. During micturition, when the trigone is stimulated, the intravesical ureter is pulled downward,
and the ureteral walls are compressed against the supporting
vesical wall as a passive reinforcement of the valvular mechanism. These actions anchor the ureter, retaining its correct
configuration and preventing lateral displacement of the ureteral orifice. The mechanism requires a complex of muscular
components that includes ureteral and vesical muscle bundles
and an elaborate neural influence. Neurohistochemistry has
defined a dual autonomic innervation by cholinergic and noradrenergic nerves, and there is evidence for neuropeptides that
may act as neuromodulators.46-48 Immunohistochemistry has
revealed further abundant innervation at the UVJ and numerous nitric oxide synthase immunoreactive nerves that may
have a regulatory role, as evidenced from separate biochemical
and functional studies.49
chapter
285
Table 22-2 Presenting Features in Infant Series with Primary Vesicoureteral Reflux Diagnosed after Prenatal
Hydronephrosis
Series
Sheridan et al (1991)29
No.
Patients
Males
Females
M:F
% Units Grade
IV-V VUR
Congenital
Nephropathy
19
16
5:1
29% patients
(1992)30
39
30
3:1
50
33% patients
Marra et al (1994)31
27
23
6:1
68
44% units
(1997)32
Burge et al
Yeung et al
155
117
38
3:1
46
28% units
McIlroy et al (2000)8*
69
37
32
1:1
32
10% patients
Nguyen et al (2000)34
34
28
5:1
64
41% units
Lama et al
(2000)33
34
25
3:1
75
85% units
Brophy et al (2002)35
40
34
6:1
38
13% units
(2006)37
43
31
12
3:1
39
24% patients
Ismaili et al
study of infants with low-threshold prenatal hydronephrosis (anteroposterior pelvis diameter 4 mm).
4 sibling reflux.
VUR, vesicoureteral reflux.
Note: The figures for the incidence of congenital nephropathy should be treated with some caution. Every effort has been made to exclude the infected patients
using the information provided by the authors.
*Screening
Includes
Waldeyer sheath
Deep trigone
Ureteral
orifice
Ureteral
longitudinal
muscles
Ureter becomes
superficial
trigone
Verumontanum
nerve supply, a disordered extracellular matrix, ureteral muscle atrophy, and dysplasia at the ureterovesical junction such
that symmetric contraction of the smooth muscle coat is not
achievable (i.e., there is no active valvular mechanism). Some
of the material examined had been subject to prior infection,
however.56,57
The importance of the functional element in preventing
reflux is supported by the finding of absent interstitial cells
of Cajal in refluxing ureters. These cells are thought to act as
pacemakers for coordinated muscle activity.58
Tanagho and colleagues44,54 emphasized that poor development or a deficiency of the trigone and ureterotrigonal
musculature is the predominant cause of reflux. It allows
lateral displacement or migration of the ureteral orifice and
inevitable reduction in intravesical length.
The lateral displacement of the ureteral orifice reaches its
most extreme expression as the classic golf-hole orifice,
which is associated with free reflux and often with dilated
upper urinary tracts. Mackie and Stephens59 postulated that
this displacement represents a primary abnormality of the
ureteral bud resulting in a ureter that arises in a laterally ectopic position (Fig. 22-2). The theory has been controversial and
considered most plausible when applied to duplex systems.
It has now achieved credence with the discovery of specific
genes involved in the induction and orientation of the ureteral
bud and renal development.60,61 The subject has been extensively reviewed,42,62 with evidence indicating that VUR can be
a field defect with displacement of the ureteral bud giving rise
to the abnormal orifice and ureter, while inducing dysplastic
renal development on that side.
There are considerable complex genetic and molecular
interrelationships. The angiotensin II receptor gene type 2
(Agtr2), present in humans and animals, has a diverse and
extensive regulatory role in the urinary tract. Its inactivation
in mice can cause VUR, or renal hypoplasia or dysplasia
or both, with ureteral ectopia as part of a spectrum of
286
part
1O
2O
3B
3O
2B
1B
Figure 22-2 The position of the ureteral orifice is determined embryologically by the point of fusion of the ureteric bud before fusion with
the mesonephros. The ureterovesical junction may arise at any point
between 2 and 3. Position 3distally ectopic nonrefluxing (when this
is situated at the bladder neck or in the urethra, reflux may occur). Position 1normal nonrefluxing. Position 2lateral ectopic refluxing.
Fully normal differentiation of the renal blastema occurs only when
the ureteric bud develops from position 1. (Adapted from Mackie G,
Stephens F. Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J Urol. 1975;114:274.)
c ongenital anomalies of the urinary tract. It seems, however,
that other control mechanisms operate that can correct ectopic ureteral budding, such that an abnormal ureteral bud
in early gestation does not lead to an evident abnormality in
mice at birth. The significance of these observations is currently unknown.61 The mode of inheritance of mutant Agtr2
is sporadic (i.e., there is incomplete penetrance), and no
association has been found between human Agtr2 mutations
and VUR. Instead, multiple genes cooperate to achieve correct development, and a multiplicity of minor genetic aberrations may be required before human VUR is expressed.62
Such complexity may explain the wide variability of the
VUR disorder.
VUR shows a wide spectrum of anatomic and functional
abnormalities. At a mild extreme of the disorder, the reflux
may appear benign and, unless urinary infection intervenes,
exempt from any associated renal pathology. A marginal
incompetence may not indicate a pathologic situation, but
instead the consequence of normal biologic deviance, such as
occurs with other natural physical dimensions. The absence
of identifiable VUR in healthy, normal newborn and premature infants suggests that it is not the norm.3,4 At the tail-end
of normal biologic variation, however, shortness in the intravesical ureter or a marginal immaturity in ureterotrigonal
musculature may bestow a predisposition to VUR. Tanagho
and colleagues44,54 postulated that a minor trigonal deficiency
may result in a marginally incompetent UVJ that permits
reflux only when challenged; a moderate deficiency might
explain reflux that occurs only with the elevated pressures of
micturition, whereas severe deficiency would allow reflux at
low pressure.
Spontaneous Resolution
The spontaneous resolution of VUR during childhood accounts
for its greater prevalence in neonates than older children,66 and
contributes to its scarcity in adults.67 A study following adults
since childhood VUR showed reflux persisting after adolescence in 53 of 221 (24%).68 The grade of reflux influences, but
does not determine, whether or not reflux disappears, the rate
of which may be 85% for radiographically low-grade reflux
and 41% for severe reflux.66 Resolution is more likely, or occurs
sooner, the younger the child is at diagnosis.19,69 In one infant
series, the resolution rate at age 15 months was 70% for mild
reflux and 43% for severe reflux.32 By way of contrast, the
International Reflux Study reported a 28% resolution rate after
5 years and 47% after 10 years for their older population at
the outset with grades III and IV reflux.69,70 Boys have a faster
resolution rate than girls, regardless of grade and age of series
studied.19,71,72
Dynamics
Micturating cystourethrography, introduced in the 1920s,
remains the standard diagnostic investigation for VUR. It
shows reflux from the retrograde egress of radiographic contrast media instilled into the bladder during radiographic
screening. The passage of contrast media may be observed
to pass into the ureter only or to extend to the renal pelvis.
The upper tracts may appear normal or grossly dilated and
distended. These radiologic appearances form the basis for an
internationally accepted five-point classification scheme (see
Chapter 23).73
The diagnostic emphasis on the anatomic features, portrayed by the micturating cystourethrogram, creates a concept that reflux is a passive event, when in reality it is the
consequence of lower urinary tract dynamics. In everyday
life, the reflux of urine from the bladder occurs only when
bladder pressure exceeds ureteral pressure (i.e., in association
with detrusor muscle contraction), and this could be an isolated unstable contraction or a full voiding episode (Fig. 22-3).
Experience with cystography combined with simultaneous
pressure and flow studies has supported this view and shown
it to be true even in the presence of grossly dilated systems
showing apparently low-pressure reflux diagnosed on conventional contrast cystography alone.74-76
The contrast examination is totally artificial in that it fills
a completely emptied and collapsed system from below.
Although excellent at showing anatomic features, such as
upper tract dilation or paraureteral diverticula, it cannot emulate normal antegrade filling. The difference in dilation, upper
tract drainage, and the reflux event (timing and volume)
shown by direct contrast cystography and physiologic indirect cystography in the same patient can be startling. Upper
chapter
RIGHT KIDNEY
40
mm Hg
0
20
10 s
LEFT KIDNEY
mm Hg
40
above, and toward the end of this filling the ureters are full as
the reflux event begins.
The open communication between the pelvicalyceal system and the bladder via the ureters exposes the kidney to
bladder pressures (see Fig. 22-3) and to bladder dysfunction.
Any sustained pressure elevation resulting from poor bladder compliance or prolonged and frequent voiding creates
an obstructive situation. At the extreme, this elevated pressure can cause damage by an obstructive mechanism in the
absence of infection. In the presence of obstruction, or persistent obstructive dynamics, such as occurs with bladder
dysfunction, the kidney is extremely vulnerable to the introduction of infection just as it is in any obstructed system.
Summary
0
20
10 s
BLADDER
40
mm Hg
287
0
20
10 s
pelvis in the presence of left vesicoureteral reflux. The cystometrogram was obtained during micturition in a pig. (From Ransley PG.
Intrarenal reflux: anatomical, dynamic and radiological studies, part I.
Urol Res. 1977;5:61. Copyright 1977 Springer-Verlag.)
part
Immature Bladder
Development of Lower Urinary Tract Function
100
0
10 sec
cm H2O
Continuous stream
IMMATURE NORMAL
200
100
0
10 sec
UNSTABLE
cm H2O
200
100
0
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DYSCOORDINATED
cm H2O
200
100
0
10 sec
INADEQUATE
200
cm H2O
The immaturity of the bladder and the mechanisms controlling it are extremely complex, involving multiple reflex arcs
and input from the higher centers. The development of complete peripheral neuronal integration and volitional control
is essential for attaining coordinated micturition and mature
bladder function.77,78
A normal immature bladder of infancy has the same
low-pressure bladder filling and storage characteristics as a
normal mature bladder. Detrusor overactivity with filling is
rare. During voiding, maximum voiding pressures are higher
than in maturity in boys and girls, although more markedly elevated in boys.78-80 There can be incomplete detrusor/sphincter synchrony during voiding, which results in
an interrupted urinary flow with intermittent high bladder
pressures as the detrusor contracts against a closed or only
partially relaxed sphincter (Fig. 22-4).78,80,81 This immature
incoordination differs from the classic dysfunctional voiding of later childhood in that the immature bladders empty
efficiently leaving little or no residue, and they do not feature
instability.78,80
In a group of 6-month-old infants, half showed urodynamic
evidence of immature voiding, whereas voiding observational
studies in healthy infants have shown immaturity as interrupted voidings in 20% that persists until 2 years of age.79,82
In a normal infant, bladder control develops progressively so
that complete voluntary control of micturition is achieved by
2 to 4 years old.83 In some infants with reflux, bladder function
also normalizes. In others, an abnormal pattern may persist,
or progress in severity, into childhood; such observations
raise questions about the impact of reflux itself in the evolution of bladder function and the nature of congenital bladder
dysfunction.79,84-88
NORMAL
200
cm H2O
288
100
0
10 sec
chapter
60
50
VUR
Persists
Male
Female
289
Bladder
Abnormal
16
month
8
year
16
month
8
year
29%
40%
1 Abnormal
50%
50%
50%
50%
2 Abnormal
100%
66%
90%
100%
40
30
2 Normal
20
10
0
II
III
IV
Grade of VUR
MALE
60
50
40
30
20
10
0
II
III
IV
IV
Grade of VUR
FEMALE
60
50
40
30
20
10
0
II
III
Grade of VUR
Normal
Generalized
abnormalities
Focal
abnormalities
among male and female infants identified by prenatal hydronephrosis. B, Distribution of nephropathy among male and female infants
(study population as in A). (Adapted from Yeung CK, Godley ML,
Dhillon HK, et al. The characteristics of primary vesico-ureteric reflux
in male and female infants with pre-natal hydronephrosis. Br J Urol.
1997;80:319.)
290
part
chapter
291
Summary
Salient points regarding the pathophysiology of VUR are as
follows:
VUR may have a complex genetic basis.
Infants with reflux but without infection display a
spectrum of disordered bladder function.
Congenital reflux with normal kidneys resolves early in
life.
REFLUX-ASSOCIATED NEPHROPATHIES
The term reflux nephropathy was introduced in 1973 to emphasize the association between VUR and the coarse renal scarring
previously known as chronic atrophic pyelonephritis (Fig.
22-7).121 Congenital reflux nephropathy may arise through
several mechanisms affecting the developing kidney and
manifests a spectrum of abnormalities. Genetic defects may
have an impact on renal development at different stages, and
the embryonic renal development is very sensitive to urinary
tract obstruction whether it is transient, prolonged, or permanent.122-124 The induction of dysplasia by ureteral obstruction
is a classic observation in experimental urology.125 Sterile scarring through an obstructive mechanism can contribute significantly to congenital reflux nephropathy, but plays little part
292
part
Figure 22-8 Acquired reflux-associated nephropathy. A, Newly established focal scarring in a young pig (1 month after instituting urinary infection). B, Corresponding appearance with Tc99m DMSA scintigraphy. (Adapted from Risdon RA, Godley ML, Parkhouse HF, et al. Renal pathology
and the 99mTc-DMSA image during the evolution of the early pyelonephritic scar: an experimental study. J Urol. 1994;151:767.)
Pathology
Reflux nephropathy is characterized by its macroscopic
appearance. The definitive features are coarse segmental
scars, involving cortex and medulla, overlying dilated (or
clubbed) calyces. The wedges of fibrous tissue that constitute the scars are sharply demarcated from the surrounding normal renal parenchyma, and scar contraction with
hypertrophy of the unaffected renal parenchyma can cause
an uneven lobular appearance of the renal outline. The
renal poles are often more prominently affected.126 The
major changes are interstitial with chronic inflammatory cell
infiltration and lymphoid follicle formation together with
tubular atrophy and interstitial fibrosis. The full range of
histopathologic detail is elaborated elsewhere.138 In addition, there is a diffuse form of reflux-associated nephropathy
that historically was poorly detected by intravenous urography, but was shown by renal biopsy to feature interstitial
fibrosis, as with focal scarring. It is clinically significant and
is associated with urinary infection, hypertension, and renal
failure.139
In contrast to these forms, some nephrectomy specimens
of reflux-associated nephropathy have shown evidence
of renal hypoplasia or dysplasia, indicating a component
attributable to abnormal renal development.137,138,140 These
chapter
293
Figure 22-9 Acquired reflux-associated nephropathy. A, Early lesion with coalescent microabscesses during acute pyelonephritis in the pig.
B, Corresponding appearance with Tc99m DMSA scintigraphy (<18 hours earlier). (Adapted from Risdon RA, Godley ML, Parkhouse HF, et al.
Renal pathology and the 99mTc-DMSA image during the evolution of the early pyelonephritic scar: an experimental study. J Urol. 1994;151:767.)
Demographics
Hodson141 estimated that reflux nephropathy affected 1 in 300
in the white population. Thirty percent to 60% of children with
VUR have abnormal kidneys, and most of these are present
when VUR is first diagnosed. Conversely, even severe grades
of reflux in boys and girls can be associated with normal
kidneys.
New scars can develop in previously unscarred kidneys.
The International Reflux Study142 reported a 14% incidence
during the first 5 years of follow-up regardless of medical or
surgical management of VUR. New scarring during the subsequent 5 years was rare, however.69 As the reflux resolves with
time, an increasing number of children are left with persistent
scarring in nonrefluxing systems.
294
part
Figure 22-10 Intrarenal reflux and the genesis of focal (segmental) scars. A, Cystogram in a pig with right-sided vesicoureteral reflux shows
intrarenal reflux. B, Same kidney with corresponding segmental scars after the genesis of scarring followed by growth. There is scar contraction.
(From the collection of the late C.J. Hodson.)
A radiologic series of 368 patients with primary VUR presenting clinically, most with urinary infection, showed a similar association of dysmorphic kidneys, with the severe forms
of VUR disorder in patients younger than 1 year.23 In these
infants, the proportions of boys and girls were similar (1:1.63),
and diffuse abnormalities were four times more common than
focal abnormalities. In children presenting after age 5 years,
when girls predominated by 4:1, diffuse abnormalities also
were seen, but the incidence of focal scarring had increased so
that the proportions of children with diffuse and focal abnormalities were similar. These changing figures may represent
acquired scarring or differential areas of growth within an
abnormal kidney, or both.
Intrarenal Reflux
Intrarenal reflux, or pyelotubular backflow, is the retrograde
passage of urine into the collecting ducts and nephrons. It has
a segmental distribution, occurring predominantly at the renal
chapter
295
Figure 22-11 A, Compound papilla with gaping ductal openings present on a concave surface. B, Simple conical papilla with slitlike ductal
openings. (From Ransley PG, Risdon RA. Reflux and renal scarring. Br J Radiol Suppl. 1978;14:1.)
Urinary Infection
The pig model with unilateral VUR surgically induced early
in life has shown that, in the absence of severely impaired urinary flow, renal scarring can occur only in combination with
VUR and urinary infection, even when voiding pressures are
increased by inducing a urethral constriction. In this unilateral model, the contralateral kidney, which was exposed to
urinary infection but without reflux, did not develop scarring
(see Fig. 22-12).126
After institution of urinary infection in the pig model with
VUR, the pathogenesis of the renal scars typically showed
a rapid progression from small discrete abscesses, reflecting
individually affected tubules, to coalescent abscesses, or a
confluent mass. Within 2 weeks, irreversible scarring was
Figure 22-12 Extensive renal scarring acquired in the pig model with
left-sided vesicoureteral reflux, urinary infection, and bladder outflow
obstruction. Both ureters are dilated. The right kidney without vesicoureteral reflux remained normal.
296
part
sult of the intrarenal reflux of infected urine. Note its origin from the
center of the cribriform area and the sharp transition to normal unaffected parenchyma. B, Early scar after resolution of acute inflammation. Subsequent scar contraction and growth of adjacent parenchyma
create the irregular renal outline characteristic of reflux nephropathy. C, Fine linear scars resulting from successful treatment of acute
lesions.
1cm
0.5cm
Figure 22-14 A and B, Tc99m DMSA renal images show a minor lesion in early acute pyelonephritis in the pig (A) and resolution of the imaging
abnormality after 3 weeks of treatment with antibacterial agents (B). C, Posterior surface of the kidney specimen corresponding to image B, showing the residual abnormality; inset shows dimpled scars. (Adapted from Risdon RA, Godley ML, Gordon I, et al. Renal pathology and the 99mTcDMSA image before and after treatment of the evolving pyelonephritic scar: an experimental study. J Urol. 1994;152:1260.)
chapter
297
298
part
mm Hg
100
50
0
1 min
mm Hg
100
50
0
1 min
Figure 22-15 A, Urodynamic trace of a bladder with severely impaired urinary outflow and upper tract dilation in a pig with vesicoureteral
reflux. This shows only one of a series of prolonged contractions with poor urine outflow, which was repeated frequently (upper trace shows intravesical pressure; lower trace shows abdominal pressure). B, Sterile segmental renal scarring from the same pig 2 weeks later.
chapter
299
Summary
Salient points regarding congenital reflux nephropathy are as
follows:
Congenital reflux nephropathy is part of an embryologic
field defect.
Intrarenal reflux of infected urine through compound
papillae is central to the acquired scarring process.
Sterile urine causes scarring only with extreme lower
urinary tract obstruction, and when sustained high pressures are transmitted to the kidney in the presence of reflux.
The fetal kidney is exquisitely sensitive to abnormal
dynamics. This may be a nongenetic mechanism for
congenital nephropathy.
Early treatment of infected renal parenchyma may limit or
prevent scar formation.
SUMMARY
VUR is a harmless dynamic event that possibly occurs in
large numbers of children without ever being recognized,
particularly in boys. It is the product of ureterotrigonal dysfunction or maldifferentiation. It is significant as a component in clinical disorders only when associated with other
urinary tract problems. It can be one component in a primary
maldevelopment of the urinary tract that predominantly
affects boys and may include nephropathy. The effect of VUR
is to expose the kidney to intrarenal reflux, which extends
lower tract dynamics and any urinary pathogens into the
renal tubules to initiate acquired renal scarring. There may
be teratogenic or genetic origins to explain a predisposition
for urinary infection and abnormal lower tract function, the
interaction of which can turn a harmless event into a clinical
disorder with pathophysiologic consequences that predominantly affects girls.
300
part
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
23
DIAGNOSIS
Methods of Imaging
Voiding Cystourethrogram
Retrograde imaging of the bladder and urethra was first
described in 1905. By the 1930s, the modern combination of retrograde contrast instillation, fluoroscopy, and observation during
filling and micturition was developed.1 The VCUG is the principal method of assessing the lower urinary tract in children.2
The VCUG can quantify reflux in a more accurate and prognostically useful way. The most commonly accepted classification
system is the International Reflux Study (IRS) group method,
which separates reflux into five grades (Figs. 23-1 and 23-2).3 In
addition to visualizing the reflux, the VCUG images the urethra
and bladder. Other conditions that can predispose to UTI, such
as diverticula, posterior urethral valves, neurogenic dysfunction (i.e., trabeculated bladder), urethral strictures, and ureteroceles, all can be detected. The plain film, which is routinely
taken before contrast instillation, also can identify incidental
findings, such as stones, vertebral anomalies, and constipation.
VCUG images allow consistent interpretation. There
is near-perfect agreement in their interpretation between
Radionuclide Studies
The practical application of radioisotopes in pediatric urology was limited until the 1960s. The invention of the gamma
scintillation camera and the development of technetium 99m
(Tc99m)based tracers led to the expanded use of radionuclide
imaging.10 Among the better known tracers are diethylenetriamine penta-acetic acid (DTPA), dimercaptosuccinic acid
(DMSA), and mercaptoacetyltriglycine (MAG3).
Because VUR can lead to renal damage; assessment of renal
function is important. Renal scanning using Tc99m-DMSA is
the preferred method of assessing growth and development.
Tc99m-DMSA concentrates in the renocorticotubular cells.
Irregularities in the contour, representing scars, are sharply
delineated. In 1989, Goldraich and associates11 showed Tc99mDMSA scanning was more accurate than intravenous pyelography (IVP) in determining the presence of renal scarring.
Rushton and coworkers12 showed that Tc99m-DMSA scanning
identified areas of scarring and sites of acute pyelonephritis,
establishing that acute pyelonephritis can lead to scarring. The
correlation between Tc99m-DMSA defects and pyelonephritic
lesions (Fig. 23-3) was supported further in an animal study
by Risdon and associates,13 who showed the defect in the
image and histologic changes in piglet kidneys with reflux
and pyelonephritis. In the 1990s, improvements in ultrasonography led to the conjecture that it could supplant Tc99m-DMSA
as a means of assessing renal damage. Although ultrasound is
useful in detecting large diffuse scarring, smaller focal scars
are missed.12
The nuclear cystogram, or isotope cystogram, is the
radionuclide analogue of the VCUG using a tracer such as
301
302
part
Ultrasonography
The complete evaluation of a child with a UTI requires a lower
and an upper tract study.16,20-23 Ultrasonography of the kidneys and bladder is an excellent complement to the VCUG.
Advances in resolution and clarity led to the hope that ultrasonography may be able to identify reflux independently
chapter
B
Figure 23-3 A, Renal scan of patient with acute pyelonephritis at
time of illness shows several photopenic regions in right kidney. The
left kidney is normal. B, Subsequent delayed scan shows persistence
of photopenic region. This area is most likely at risk to develop a renal scar. (From Hilton SvW. The child with a urinary tract infection.
In: Hilton SvW, Edwards DK, eds. Practical Pediatric Radiology. 2nd ed.
Philadelphia: Saunders; 1994, p 522.)
303
304
part
Figure 23-5 Indirect nuclear cystography. A, Posterior image taken at 5 minutes. Note tracer only in kidneys. B, Image at 20 minutes. Note tracer
accumulating in bladder. C, Image at 45 minutes. An increase in activity is noted in the right renal pelvis, and a decrease in activity is noted in
the left renal pelvis. This shows right VUR to the level of the kidney. (From Hilton SvW. The child with a urinary tract infection. In: Hilton SvW,
Edwards DK, eds. Practical Pediatric Radiology. 2nd ed. Philadelphia: Saunders; 1994, p 520.)
false-negative rate: it missed 30% of patients with reflux. This
technique requires that the patient be catheterized, and it cannot image the urethra. A contrast-enhancing suspension based
on galactose (Levovist) has been introduced, but for now this
novel concept is not yet practical.35,36
PIC Cystography
When a VCUG does not show VUR in children who have
recurrent febrile UTIs, management has been controversial. One idea advanced was that VUR may be occult and
missed by the VCUG. It was suggested that directly instilling contrast material at the orifices while under anesthesia
would unmask the occult VUR; this concept is known as
a PIC cystogram (PIC for positioning the instillation of contrast). In 2003, Rubenstein and colleagues38 first described the
procedure and found good concordance with a control group
with a known history of VUR.39 There was 100% sensitivity in
detecting VUR already known by standard VCUG. There was
also 87% specificity in showing VUR in five ureters not previously known to have VUR with an overall accuracy of 91%.
A multi-institutional report by Edmondson and coworkers40
showed that the PIC cystogram detects occult VUR in about
80% of children with febrile UTI who have normal standard
VCUGs. One question that lingers over this novel technique
is whether the instillation pressure of 1000 mm H2O suggests
that the children affected by occult VUR may actually have
an occult voiding dysfunction.
Molecules
chapter
305
Renal Scarring
The frequency of renal scarring with pyelonephritis and reflux
is proportional to the severity of reflux. Jodal69 noted that
children who presented with their first UTI with grades I and
II had a scarring rate of 10% and 17%. This combined total of
27% is significantly lower than the 66% rate of scarring seen in
grades III and higher. Renal scarring is directly related to the
frequency of pyelonephritic episodes. Only 9% with one episode had scarring, whereas 35% of patients with three attacks
had scarring, and 58% with four or more attacks had scarring. Infancy and prior pyelonephritis have been identified as
strong positive predictors of risk for renal scarring. Pylkkanen
and colleagues70 found that infants younger than age 1 year
had the highest risk of scarring and the highest incidence of
congenital urinary tract anomalies.
The youngest children are at the greatest risk for renal
scarring from bacterial pyelonephritis. Contributing factors
are a low intrarenal reflux pressure, immature immune system, and delayed recognition of pyelonephritis or inadequate
treatment.71 It has been proposed that most of the renal scarring observed in older children occurs during the earliest
childhood years as the result of a devastating injury (the Big
Bang).58 If the youngest children are most vulnerable to scar
formation, and adults rarely develop scars, would it be possible to define an age when the likelihood of scar formation
becomes clinically insignificant?
Smellie and coworkers72 in 1998 reported on the outcome
of childhood reflux in 226 patients. Renal scarring was seen
in 38%. No new scars developed after puberty. Naseer and
Steinhardt73 reported on 1062 patients with reflux followed
for 9 years. Renal scarring was present in 13.5% at the time of
diagnosis, and 2.1% developed new scars.26 Only one patient
who developed new scars had a normal kidney initially.
Vernon and associates74 reported on the development of new
renal scars in 3- and 4-year-old children with reflux while on
prophylaxis. The rates of breakthrough infection were similar
between the two age groups: 27% for 3-year-olds, and 31% for
4-year-olds. New renal scars were found in 2.4% of 3-year-olds
and in none of the 4-year-olds. The children who developed
new scars were all younger than 3.4 years old at original
presentation. The authors estimate that there was only a 2.5%
risk of developing a new renal scar in children with a history
of UTI and reflux, but a normal upper tract at presentation at
age 3 years. This risk approached zero by age 4 years. Cooper
and colleagues75 examined the new renal scar rate in patients
being followed for reflux. Over a 14-year period, 51 children
with reflux were taken off of all prophylactic antibiotics.
Reflux persisted in most, with only 19.6% resolving spontaneously off of antibiotics. Only 11.8% developed a subsequent
UTI. No gross renal scars developed, but subtle new scars may
306
part
Familial Reflux
Identical twins have been observed to have reflux.81,82 Reflux
occurs in the siblings of affected children at a significantly
higher rate than that in the general pediatric population.83-87
Although the exact form of genetic transmission is not yet
established, it has been determined that when one child has
reflux, other siblings are at enough risk to warrant evaluation.
The sibling reflux rate has been estimated to be 40% to
50%.85,88 Jerkins and Noe84 studied 104 siblings, and 32%
were found to have reflux. Most of these siblings with reflux
(73%) had no history of UTI or abnormal voiding symptoms.
Aggarwal and Verrier Jones89 in 1989 reported on screening of
first-degree relatives using ultrasound and IVP. Of 52 relations
tested, 23% were found to have reflux. This study was restricted to only relatives who were younger than 2 years or older
than 2 years and with an upper tract abnormality detected on
ultrasound or IVP. Peeden and Noe85 studied 24 siblings and
found a 46% reflux rate. In a dual-center study of 422 families
comprising 622 siblings, reflux was found in 27%.83 Most
(77%) had grade II or III. The rate was 20% in boys and 33% in
girls. Reflux nephropathy was shown by renal scan in 13.6%.
Evaluation of older siblings is controversial because they
account for only a small fraction of all siblings with reflux, yet
can have a significant proportion of renal scarring. Only 5%
of the positive siblings were 10 years old or older, but in this
group 27% had reflux nephropathy.
The natural history of reflux in siblings is similar to that
of the probands.90 Finally, the economic cost of screening
has been investigated. If the rate of detection among siblings
were only 1%, the early discovery and management would
yield cost savings beyond the cost of screening all siblings.
This includes the prevention of the potential consequences
of reflux in these siblings: hypertension, renal scarring, renal
insufficiency, dialysis, and transplantation.91
The recognition of hereditary VUR has led to efforts to
identify and isolate the associated genes. Autosomal dominant
inheritance is most likely, but because of variable penetrance
and expressivity, large multigenerational pedigrees traceable
to linkage analysis have yet to be assembled. Sanna-Cherchi
and colleagues92 noted that single genome-wide studies of
familial VUR have shown a linkage to chromosomes 6p21,
1p13, 10q26, and 19q13.93,94 Despite sufficient power, linkage
of familial VUR to previously reported candidate intervals has
not been reliably replicated. There is substantial heterogeneity, and any mapping strategy would need a large number of
kindreds or proband loaded pedigrees.
Racial Differences
Children of Asian and African ancestry have a lower incidence of reflux.95-97 In a study of the medical management of
reflux, only 6% of the children were African American, and 2%
were Asian.95 In another study of antenatal hydronephrosis,
53% of whom were African American, the incidence of reflux
was zero among the African Americans, and 17.6% in all the
other children.98 Askari and Belman97 found reflux in only
10% of African American girls after a culture-proven infection.
In a study of primary reflux in African American children,
Skoog and Belman99 found a 23% incidence of renal scarring.
Although there are racial differences in the incidence of reflux,
chapter
Vesicoureteral Reflux
Renal agenesis
Horseshoe kidney and renal ectopia
Multicystic dysplastic kidney
Prune-belly syndrome
Megacystis-megaureter syndrome
Hypospadias
Duplication, ureterocele, ectopic ureter
Imperforate anus
Pretransplant evaluation
Complex syndromes with neurogenic and genitourinary
manifestations
Antenatal Hydronephrosis
In a study of 130 neonates with antenatal hydronephrosis,
38% were found to have reflux, and 49% of these were bilateral.100 Burge and associates101 found 18% of infants with
antenatal hydronephrosis to have reflux. Normal postpartum
ultrasound scans are found in 60% to 80% of infants with antenatal hydronephrosis who have VUR.102,103 It is necessary to
perform a cystogram on all infants discovered to have antenatal hydronephrosis, despite a normal postpartum ultrasound
scan. In contrast to older children, there is a different sex distribution. Instead of the usual female predominance (approximately 3:1), among antenatal hydronephrosis patients there
is a higher percentage of boys. Anderson and Rickwood104
found a 91% male predominance. Oliveira and coworkers105
found that 86% were boys. Gordon and associates106 found a
similar rate (84%). The severity of reflux is greater, with grade
III or higher being more prevalent. Elder107 found that 80%
of antenatally diagnosed reflux is at least grade III. These
children may have other genitourinary anomalies, with ureteropelvic junction obstruction being the most common after
reflux.104,106
Associated Conditions
Many conditions are associated with reflux (Table 23-3). The
site of origin of the ureteral bud from the wolffian duct plays
a crucial role in determining the subsequent development of
the ureter and associated kidney. Abnormalities in adjacent
organs, such as the bladder, urethra, rectum, or sacrum, should
suggest the possibility of reflux.
Renal Anomalies
Where there is only one functional kidney, the presence of contralateral reflux should be investigated. True renal agenesis,
a rare occurrence, has a very high rate of contralateral reflux.
More than one third of patients have contralateral reflux.108
Similarly, multicystic dysplastic kidney has a high contralateral reflux rate. Flack and Bellinger109 noted that in children
with multicystic dysplastic kidney and contralateral reflux,
75% of the refluxing kidneys had a normal ultrasound scan.
A cystogram should be performed in all of these patients.
Children with horseshoe kidneys have a higher than normal
307
Hypospadias
Hypospadias is associated with other congenital anomalies
of the genitourinary tract.112,113 Shafir and colleagues113 found
a reflux rate of 19%, and the presence of VUR in conjunction
with complex genitourinary anomalies should not be surprising.114 Routine evaluation of these boys is not widely recommended, however, because most of the reflux seems to be low
grade and not associated with UTI or pyelonephritis. A cystogram should be performed if there are UTIs.
MEDICAL MANAGEMENT
Observation without Continuous
Prophylaxis: Historical Data
During the 1960s and 1970s, early investigators observed large
groups of children with reflux without continuous prophylaxis
and treated each infection as it occurred. The International
Scale had not been adopted at the time of all these investigations, so descriptive terms were often used to differentiate
high-grade and low-grade VUR. The experience of Lenaghan
and coworkers115-117 helped establish the need for continuous
prophylaxis. These investigators followed children for up to
18 years, and UTIs were treated intermittently as they appeared.
In Lenaghans series, the average age of boys at diagnosis was
less than 1 year, and the average age of girls was 7 years. The
overall cessation rate was 42%. Unilateral reflux without ureteral dilation seemed slightly more likely to resolve (65%) than
bilateral reflux (50%), whereas bilateral reflux with dilation
almost never resolved (26%).
Renal damage, as observed on IVP, occurred even after one
infection. New renal damage was more likely in kidneys with
previous scarring, but could occur in normal kidneys. Of the
group with normal kidneys, 21% developed new scars; of the
group with preexisting scars, 66% developed new scars. Most
proven infections occurred within the first 5 years of diagnosis. Of this population, 36% had scars at diagnosis, and 10%
developed hypertension. Most new scars were seen in girls.116
No boys had infections after reflux stopped, and 40% of girls
continued to have episodes of infection after reflux stopped.
Lenaghan116 concluded that intermittent treatment of infection led to an unacceptably high rate of new scar formation
in all children.
Data from the International Reflux Study in Children
(IRSC) showed a high rate of new scar formation in children
observed off of continuous prophylaxis.118 In this series,
new scars occurred in 12.5% of children with normal kidneys, whereas 62% of scarred kidneys showed progression if
the infections were treated only intermittently. Many of the
children with new scars were older than 7 years. Govan and
associates119 observed girls with reflux while not on continuous prophylaxis. During the observation period, 50% of
these children had UTIs, and 20% of this group had pyelonephritis. Scarring did not occur in all renal units despite
having had infections. More scarring occurred in reflux with
ureteral dilation, although 23% of girls with grade I reflux
developed new scars. ODonnell and colleagues120 observed
a cohort of children without continuous prophylaxis, and
infections were treated after they were diagnosed; 35%
developed new scars. A group followed at the same time
while on continuous prophylaxis had only a 9% rate of new
scar formation.
308
part
Contemporary Data
Smellie and associates132 more recently published a series of
52 children (25 girls, 27 boys), 1 to 12 years old, with grades
III and IV bilateral reflux and bilateral renal scarring. They
were randomly assigned to surgical or medical (prophylaxis)
management and followed for 4 years. No new scars were
seen in either group, and glomerular filtration rate remained
unchanged. Recurrent UTIs occurred in 11 (40%) of the medically managed and 6 (24%) of the surgically managed children. Smellie and associates132 concluded that surgery and
medical therapy were equal in protecting renal integrity and
function in this group of children with relatively severe reflux
nephropathy.
Wheeler and colleagues133 more recently published a
meta-analysis of seven randomized, controlled clinical trials
comparing continuous prophylaxis with surgery. This metaanalysis included the trials detailed previously. The overall
risk of febrile and nonfebrile UTI occurring in either group
was the same after 5 years. Similarly, the risk of new renal
scarring was the same in both groups at 5 years of follow-up.
End-stage renal failure and hypertension were poorly reported, and numbers were too small for analysis. They concluded
that if there was a benefit to surgery over prophylaxis, it was
minimal.
309
Patient Compliance
When continuous antibiotic prophylaxis was first proposed, it
was assumed that good compliance would be necessary over
many years.135 Lack of compliance is a reason to abandon this
regimen and suggest surgery. Most noncompliant families
never return, however, either for prophylaxis management or to
discuss surgery.144 Compliance rates ranging from 12% to 90%
have been reported. Skoog and coworkers122 reported a compliance rate of 88%. The IRS reported compliance rates of 90%, but
this was a prospective investigation in patients with high-grade
reflux and renal scars.3 Families entered the study after signing consent forms and knowing that they were to be followed
for many years. Parents are more likely to be concerned under
those circumstances. Arant95 reported compliance rates of only
12% in families whose children had low-grade reflux.
The compliance issues in a large cohort of children who
presented with low-grade reflux (grades I to III) were examined.56,146 One third of patients failed to comply with a longterm regimen. Most of these noncompliant families (80%)
failed to return after the first year. An analysis of socioeconomic factors revealed that there were no predictable underlying factors except maternal age. Mothers older than 36 years
were more likely to continue bringing their children back.
There was remarkable similarity between compliant and noncompliant groups. There were no significant age or sex differences. Factors such as income, level of parental education,
type of medical insurance, type of primary care physician, and
distance from hospital-based specialists all had no bearing
(Figs. 23-6 and 23-7). Affluent and indigent families had similar rates of noncompliance. Prescription programs, which paid
for medication, did not increase compliance. In a cohort of
more than 35,000 patients with VUR followed for 2 years, all
of whom had insurance-provided pharmacy services, Hensle
and coworkers147 reported that only 17% of patients placed on
long-term prophylaxis remained adherent.
Regardless of the circumstances, a certain number of
families are not going to maintain a regimen of prophylaxis, surveillance urine cultures, and repetitive radiographic
examinations over many years. This situation challenges
the clinician to devise strategies to increase compliance or
40
Percentage of children
chapter
30
LFU
Not LFU
28.2
36.8
38.1 37.3
33.7
25.9
20
10
Urban
Suburban
Rural
310
part
70
Percentage of children
60
Grade*
50
40
30
25.4
20
10
LFU
Not LFU
62.3
20
10.3 9.7
2 0.6
Fee-forHMOs
None
Medicaid
service
Figure 23-7 Percentage of children on antibiotic prophylaxis, grouped
by medical insurance, who became lost to follow-up (LFU) and who
remained under observation (Not LFU). Medicaid, state-funded
insurance for indigent families; HMO, Health Maintenance Organization, a managed-care insurance scheme with rigid control of specialist
referrals and assignment to primary care physicians; fee-for-service,
traditional insurance with no restriction on specialist referrals or primary care physician assignment. (Redrawn from Greenfield SP, Wan J.
Vesicoureteral reflux: practical aspects of evaluation and management.
Pediatr Nephrol. 1996;10:789. Copyright 1996 by Springer-Verlag.)
Breakthrough Infection
Breakthrough infection is defined as the development of an
infection with an organism resistant to prophylaxis.144 Breakthrough infections are more frequent in girls, but they can occur
in boys.144,135,149 Breakthrough infection rates vary, depending
on the range of children followed. The IRSC followed children
with only grades III and IV reflux, and many had preexisting scars. The IRSC reported a breakthrough infection rate of
37%.128 If children with all grades are followed, breakthrough
infection rates vary from 10% to 25%.144,124,150 In one series
of 62 children with documented breakthrough infection, 60
were girls and 2 were boys (Table 23-4).144 The grades of reflux
present in these 62 patients were grade I in 2, grade II in 19,
grade III in 24, grade IV in 14, and grade V in 3; 70% had lowgrade reflux. The age distribution was as follows: younger
than 1 year, 3; 1 to 3 years, 14; 4 to 6 years, 24; 7 to 9 years,
15; and older than 10 years, 6. Although most children were
younger, one third were at least 7 years old.
Breakthrough infections may be more common if there is
voiding dysfunction (see later discussion).151 If the organism
is sensitive to the prophylactic antibiotic, one has to question
the compliance of the family with taking daily medication, or
perhaps the quality of the manufactured antibiotic.149 These
infections may be febrile, with lower tract symptoms only,
or entirely asymptomatic. Scarring has been described after
asymptomatic breakthrough infections, but many authorities
state that only febrile infections are significant.121,135 Smellie
and colleagues135 found that two thirds of breakthrough infections associated with new scars were asymptomatic.
No.
Patients
Patient
Age (yr)
<1
No.
Patients
II
19
1-3
14
III
24
4-6
24
IV
14
7-9
15
>10
Age as a Predictor
Shimada and colleagues159 found that new renal scars resulting from breakthrough infection could occur in older children
while being observed on prophylaxis for reflux. In a group
chapter
Radiographic Predictors
Apart from grade, other aspects of radiographic imaging may
help predict who is most susceptible to renal scarring. Using
radionuclide cystography, McLaren and Simpson161 correlated
high renal scar rates with reflux occurring at low bladder volumes. Mingin and colleagues162 showed that breakthrough
infection is more common in children who have an initial scan
with scarring. They retrospectively reviewed the records of
120 infants who were first identified with VUR owing to prenatal hydronephrosis and who were followed for 4 years. Of
the group with an initial scar seen on Tc99m-DMSA scan, 60%
developed a breakthrough infection, whereas only 8% of the
group without an initial scar developed a breakthrough infection. In a study of 38 patients with breakthrough infections by
Szlyk and coworkers,163 however, 10% were found to have a
new scar, and 75% of those had a normal baseline renal scan.
Radionuclide scanning may be able to identify patients at
highest risk, but a normal renal scan does not guarantee that a
breakthrough infection and new renal scar would not occur.
311
Discontinuing Prophylaxis
Some authors have recommended stopping prophylaxis after
a certain age in boys and girls. The rationale is that most, but
not all, new scarring occurs in younger children, as outlined
previously. Belman and Skoog134 suggested stopping prophylaxis after age 7 years, and Winberg157 suggested age 5 years.
Cooper and colleagues75 reported on a series of 51 children
(40 girls, 11 boys) in whom prophylaxis was stopped. Their
ages ranged from 3 to 14 years, and not all children had contrast cystograms, so the grade was not always known when
prophylaxis was stopped. Six children (five girls, one boy)
returned with UTIs. No new scars were seen after infection,
but only renal ultrasound scans were performed, so new renal
scars might not have been seen.
Similarly, Thompson and colleagues172 discontinued prophylaxis in a large group of children with known reflux at a
mean age of 6 years, and one third developed urinary infections. New scars were seen on renal scanning in seven children off prophylaxis, all of whom had grade II or III reflux.
Many children in this study did not have renal radionuclide
scans, so many new scars could have been overlooked.
Georgaki-Angelaki and coworkers173 reported on a cohort of
54 children who had antibiotics stopped and were then followed for 4 years. None had had a breakthrough infection for
2 years before stopping antibiotics. None had hydronephrosis,
voiding dysfunction, or a new renal scar found on previous
renal scanning. The average age was 6 years at the time of
stopping antibiotics. Greater than 90% had grade III reflux
or less. Routine urine cultures were obtained monthly and
after any fever or lower urinary tract symptoms. There were
only eight infection episodes, and no new renal scars were
seen on Tc99m-DMSA scanning. In this aggressively observed
population of older children with low-grade reflux, stopping
prophylaxis was safe.
There are no large, long-term, prospective studies that
establish safe guidelines for discontinuing prophylaxis based
on grade, sex, race, renal scarring, or voiding habits. Until
these subpopulations are better defined, there is a risk to new
renal scar formation if antibiotics are stopped before spontaneous cessation or surgical correction of VUR in boys or girls
of any age through adolescence and with any grade of reflux,
with or without preexisting scarring. In a survey of pediatric
urologists, however, most stated that they would stop prophylaxis in patients with unresolved high-grade reflux at
puberty.174
312
part
Study
Skoog et
al122
Huang and
(1987)
Tsai150
II
III
IV
83
60
46
0
0
(1995)
92
76
62
32
87
63
53
33
69
56
49
Arant95 (1992)
82
80
46
*Grouped
Early Observations
Early studies by Edwards and coworkers,139 before the development of a widely accepted grading system, revealed that
spontaneous cessation does occur in 85% of children whose
ureters are not dilated, and in 40% of children whose ureters
are dilated. These investigators also showed that reflux can
stop at all ages, including midadolescence, and there was no
way to predict when reflux would cease. Twenty percent to
30% of reflux disappeared every 2 years. Mulcahy and Kelalis178 and Hutch179 showed that cessation can occur after age
10 years, even as late as early adolescence. Lenaghan116,117
observed spontaneous cessation in 15-year-olds.
later.144,139 Data have been conflicting regarding the differences between the resolution rates of bilateral versus unilateral reflux. Most studies seem to show, however, that bilateral
high-grade reflux with ureteral dilation apparently resolves
less often than unilateral high-grade reflux.181 The difference
in resolution rates between bilateral and unilateral low-grade
reflux is less marked (Table 23-6).
Kaplan-Meier curves have been used in an attempt to
predict a time course for families. Using this type of analysis,
Wennerstrom and associates181 showed that 50% of children
with grade I reflux should expect resolution within 2.5 years
of diagnosis; with grade II reflux, within 5 years of diagnosis;
and with grades III and IV, within 8 years of diagnosis. They
also found that girls persisted a bit longer than boys grade
for grade. Using Kaplan-Meier estimates, Esbjorner and colleagues182 also found that boys more often and more rapidly
resolved their reflux over time, even if it was dilating (high
grade).
When looking at low-grade reflux alone (grades I to III),
age at presentation and, by inference, age of the child do not
predict the likelihood of resolution. An analysis of a large
number of these patients found that there was no statistical
difference when comparing resolution rates of children of
different ages in these low grades (Fig. 23-8). Certain trends
could be discerned, however. Resolution rates remained high
(>40%) regardless of age. Resolution rates for older children
(children 7 to 9 years old with grade II reflux, 70% resolution rate) could be higher than the resolution rates for infants
(infants <1 year old with grade II reflux, 54% resolution rate).
There also was no significant difference when comparing
unilateral and bilateral reflux, or when comparing boys with
girls grade for grade in these low grades. The standard deviations for the mean times to resolution were so great that these
times were not useful when counseling individual families
(Table 23-7).
Similarly, Connolly and associates184 found that reflux
resolution rates in girls older than 5 years were comparable
to rates seen in infants. In their cohort, the percent of annual
resolution was 20% each year until age 11 years. Most of their
patients had mild or moderate reflux as graded on a
nuclear cystogram. These data suggest that families and clinicians must expect VUR to persist for many years, possibly
until adolescence. Older children have an equally good chance
of resolving their low-grade reflux up to adolescence. Neither
sex nor laterality can help predict resolution. Grade remains
the best predictive parameter. Finally, although some studies
consider grade I reflux resolved, this may not be accurate
or clinically justified. Grmek and Fettich185 found that 20% of
children with initial grade I reflux had grade II (17%) or grade
III (3%) seen on a second VCUG.
McLorie and colleagues186 presented data regarding resolution rates of grades III and IV reflux, although patients
were not stratified for age at the beginning of the observation period. After 2 years of observation, 80% of children
with grades III and IV reflux were still refluxing, and 50%
or more were still refluxing after 5 years. Neither sex nor
laterality had a bearing on resolution rate. These investigators concluded that it was reasonable to recommend surgery
if the reflux had not ceased after 4 years of observation, no
matter what the age.
chapter
313
Table 23-6 Medical Therapy: Percent Chance of Reflux Resolution after Specified Number of Years*
Risk Category, Age
(No. Patients on which
Estimates Are Based)
3 Year
4 Year
5 Year
Grade I
39.3 (24.6-51.1)
1 Year
63.1 (43.2-76.1)
77.6 (57.2-88.3)
86.4 (67.7-94.3)
91.8 (75.7-97.2)
Grade II (n = 250)
28 (24.1-31.7)
48.1 (42.3-53.4)
62.7 (56.2-68.1)
73.1 (66.8-78.2)
80.6 (74.8-85.1)
21.4 (10.8-30.8)
38.2 (20.4-52.1)
51.5 (29.0-66.8)
61.9 (36.6-77.1)
70 (43.5-84.1)
13.4 (4.6-21.4)
25 (8.9-38.3)
35.1 (13.1-51.5)
43.8 (17.1-61.9)
51.3 (20.9-70.1)
10.8 (3.5-17.5)
20.5 (6.9-32)
29.1 (10.2-43.9)
36.7 (13.4-53.8)
43.6 (16.5-61.9)
12.7 (7.0-18.1)
23.8 (13.5-32.9)
33.5 (19.5-45.0)
41.9 (25.1-55.0)
49.3 (30.3-63.1)
7 (3.1-10.8)
13.5 (6.1-20.4)
19.6 (9.0-28.9)
25.2 (11.8-36.6)
30.5 (14.6-43.4)
2.6 (0.7-4.5)
5.2 (1.4-8.8)
7.7 (2.1-13.0)
10.1 (2.8-16.9)
12.5 (3.5-20.7)
16.1 (8.5-23.1)
29.7 (16.4-40.8)
41 (23.5-54.5)
50.5 (30.0-65.0)
58.5 (36.0-73.1)
4.5 (1.0-7.9)
6.4 (2.0-15.1)
7.8 (3.0-21.8)
8.9 (4.0-28.0)
9.9 (4.9-33.7)
*The
Percentage resolved
90
80
13
Reflux Grade
12
2411
50
48
Age (yr)
20
19
35
15
40
30
5
15
70
60
Grade I
Grade II
Grade III
13
46
79
10
Age at presentation
Figure 23-8 Resolution rates of vesicoureteral reflux, stratified by
grade (I, II, and III) and age at presentation. (Redrawn from Greenfield SP,
Ng M, Wan J. Resolution rates of low-grade vesicoureteral reflux stratified by patient age at presentation. J Urol. 1997;157:1410.)
1
children (2%) had a breakthrough infection while on prophylaxis, and eight children (7%) underwent surgery. These infection rates are lower than the rates reported for probands with
reflux who present with UTIs. Parekh and associates187 found
that reflux in siblings seemed to resolve more quickly than in
probands diagnosed after a UTI. In a group of 40 siblings, 84%
resolved with observation, with a mean time to resolution of
16 months. All had grade III or less at presentation except one
child with grade IV reflux.
II
III
<1
37.68 24.5
14.51 9.37
32.88 32.3
1-3
17.69 10.4
26.93 17.57
22.56 13.1
4-6
16.69 8.85
22.51 24.7
22.56 26.8
7-9
26.52 17.68
20.68 11.9
22.56 14.2
>10
14.69 1.96
11.18
314
part
the tunnel of the upper pole ureter remains adequate to prevent reflux. Rarely, there can be upper pole reflux alone. In
this circumstance, the Weigert-Meyer rule is still operative,
but both ureteral orifices are shifted further caudad, so that
now the lower pole ureter occupies a normal position on the
trigone, whereas an upper pole ureter is ectopic to the bladder
neck or below (Figs. 23-9 and 23-10).
Spontaneous resolution of reflux can occur in the setting
of complete duplication, with certain qualifications.189-191
High-grade lower pole reflux with ureteral dilation and
lower pole atrophy has a low resolution rate, and some
authors189,192 advocate early surgical correction in that
a
b
from the lower pole segment (a) of a complete duplication always enters the bladder cephalad to the ureter from the upper pole (b). If there
is reflux into only one segment, it would be to the lower pole because
the ureterovesical junction tunnel is shorter. B, There would be reflux
only to the upper pole of a complete duplication if both ureters are
shifted caudad, so that now the upper pole ureter enters the bladder
neck ectopically, without any normal ureterovesical junction valve
mechanism (b). The ureter from the lower pole is situated normally on
the trigone and so does not reflux (a).
Congenital periureteral diverticula can occur in association with VUR. Diverticula seem to be larger in boys and of
greater consequence. Amar193 published a series of older boys
with large diverticula and suggested that surgery would be
necessary in all. It was thought that higher pressures of voiding in boys contributed to the lack of spontaneous resolution.
It may be that the size of the diverticulum and the position
relative to the ureteral orifice may be prognostic (Fig. 23-11).
A large diverticulum with the ureter entering directly into
it may have less chance of resolving than a smaller diverticulum that seems to involve less of the submucosal valve
mechanism.
Spontaneous resolution of lower grade reflux with associated diverticula does occur. Afshar and coworkers194 showed
in a group of younger children (median age 3 years) that
chapter
315
Intrarenal Reflux
A
2
C
Figure 23-11 This sequence of drawings represents the anatomic
variations of periureteral diverticula. A, In the mildest form, the ureterovesical junction is not disturbed. The ureteral orifice (1) enters
the bladder near the diverticular orifice (2). B, The second drawing
portrays a moderately abnormal ureterovesical junction, wherein the
valve may or may not function over time with growth of the child.
The ureteral and diverticular orifices (1 and 2) are closer to each
other. C, In the most severe form, the ureter enters the diverticulum
itself, and the ureterovesical junction antireflux valve mechanism is
entirely absent. At cystoscopy, only a single diverticular opening may
be seen.
Solitary Kidney
Palmer and colleagues195 followed 21 patients with solitary
kidneys and reflux. The etiologies of the absent kidneys were
multicystic dysplastic kidney, renal agenesis, and ureteropelvic
junction obstruction. Most with low-grade reflux were followed medically and resolved. The indication for surgery was
mainly persistent high grade, and the investigators concluded
that management strategies should be the same as those for
part
11
10
Presentation
9
Number of patients
316
Follow-up
8
7
6
5
4
3
2
1
0
Low
Normal
High
Bladder capacity
rameters in infant boys diagnosed with high-grade vesicoureteral reflux. (From Sillen U, Bachelard M, Hermanson G, et al. Gross bilateral
reflux in infants: gradual decrease of initial detrusor hypercontractility. J Urol. 1996;155:668.)
chapter
317
318
part
chapter
319
Table 23-8 Treatment Recommendations: Boys and Girls with Primary Vesicoureteral Reflux and with Renal Scarring
Treatment
Clinical Presentation
Reflux Grade/
Laterality
I-II/unilateral or
bilateral
III-IV/unilateral
Patient
Age (yr)
Guideline
Preferred
ption
O
No
Consensus
Antibiotic
prophylaxis
1-5
Antibiotic
prophylaxis
6-10
Antibiotic
prophylaxis
<1
Antibiotic
prophylaxis
Girls: surgery
if persistent
Boys:
surgery if
persistent
1-5
Antibiotic
prophylaxis
Girls: surgery
if persistent
Boys:
surgery if
persistent
<1
Antibiotic
prophylaxis
6-10
Surgery if
persistent
Antibiotic
prophylaxis
1-5
V/unilateral or
bilateral
Reasonable
Alternative
<1
6-10
III-IV/bilateral
Preferred
ption
O
Surgery if
persistent
Antibiotic
prophylaxis
Surgery
Surgery if
persistent
Antibiotic
prophylaxis
Surgery
Surgery if
persistent
Surgery
<1
1-5
Bilateral: surgery
6-10
Surgery
Unilateral:
surgery
Surgery if
persistent
*For
patients with persistent uncomplicated reflux after extended treatment with continuous antibiotic therapy.
consensus was reached regarding the role of continued antibiotic prophylaxis, cystography, or surgery.
From Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux
in children. J Urol. 1997;157:1846-1851.
No
320
part
Table 23-9 Treatment Recommendations: Boys and Girls with Primary Vesicoureteral Reflux and No Renal Scarring
Treatment
Clinical Presentation
Reflux
Grade/
Laterality
I-II/unilateral
or bilateral
III-IV/
unilateral
or bilateral
Guideline
Preferred
ption
O
Guideline
No
Consensus
<1
Antibiotic
prophylaxis
1-5
Antibiotic
prophylaxis
6-10
Antibiotic
prophylaxis
<1
Antibiotic
prophylaxis
1-5
Unilateral:
antibiotic
prophylaxis
6-10
Bilateral:
surgery if
persistent
Unilateral:
antibiotic
prophylaxis
Bilateral:
antibiotic
prophylaxis
Surgery if
persistent
Surgery if
persistent
<1
Antibiotic
prophylaxis
1-5
Bilateral:
surgery
Bilateral:
antibiotic
prophylaxis
Unilateral:
antibiotic
prophylaxis
Unilateral:
surgery
6-10
Unilateral:
surgery if
persistent
Bilateral:
antibiotic
prophylaxis
Bilateral:
surgery
V/unilateral
or bilateral
Preferred
ption
O
Surgery if
persistent
Surgery if
persistent
Surgery
*For
patients with persistent uncomplicated reflux after extended treatment with continuous antibiotic therapy.
consensus was reached regarding the role of continued antibiotic prophylaxis, cystography, or surgery.
From Elder JS, Peters CA, Arant BS Jr, et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux
in children. J Urol. 1997;157:1846-1851.
No
CONCLUSION
The major debate at the end of the 20th century was mainly
between clinicians who advocated surgery for all children
with reflux versus clinicians who advocated antibiotic prophylaxis. More recent innovations have changed the context of the debate, especially the approval of minimally
invasive endoscopic therapy agents in the United States.
More significant, however, is the challenging assertion that
most children with reflux may not need treatment at all.
No statistically valid, prospective, randomized studies conclusively show that all children with reflux benefit from
treatment.
Wheeler and colleagues133 published a meta-analysis of
10 randomized controlled trials, and concluded that it was
uncertain that the identification of children with VUR was
chapter
321
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
24
ENDOSCOPIC TREATMENT
OF VESICOURETERAL REFLUX
Prem Puri and Maria Menezes
Primary vesicoureteral reflux (VUR) is the most common urologic anomaly in children; it has been reported in 30% to 50%
of children who present with a urinary tract infection.1,2 The
association of VUR, urinary tract infection, and renal damage
is well known. Reflux nephropathy is the cause of end-stage
renal failure in 3% to 25% of children and in 10% to 15% of
adults.3-5 The hereditary and familial nature of VUR is well
recognized, and several studies have shown that siblings of
children with VUR have a much higher incidence of reflux than
the general pediatric population.6 It also has been reported that
when VUR is discovered in symptomatic siblings, it is usually
of high grade and associated with a higher incidence of reflux
nephropathy.6
The management of VUR in children has been controversial. Since the 1970s, there have been more than 5000
reports on this subject. Numerous studies have prospectively
compared medical and surgical management of VUR. The
Birmingham Reflux Study showed that more than half of
the patients continued to show severe reflux after 5 years of
medical treatment.7 The study from Toronto showed that 93%
of the patients with grade IV and 83% with grade III VUR had
persistent reflux after 2 years of observational therapy, and
70% with grade IV and 50% with grade III VUR had persistent
reflux after 5 years of this therapy.8 The International Reflux
Study Group in Children (European section) showed that 84%
of the children with grade III and IV reflux randomly allocated
to medical treatment still had reflux after 5 years.9 In children
with bilateral reflux, 91% had persistence of reflux after
5 years. In the European arm of the International Reflux Study
at 10-year follow-up, only 52% of VUR resolved in children
with grade III and IV reflux treated with antibiotic prophylaxis.10 In children with bilateral grade III and IV reflux, it had
resolved in only 39%.10 The American Urological Association
report on VUR reported a reflux resolution rate of 9.9% in
bilateral grade IV VUR after 5 years of medical therapy.11 All
these studies showed further that observational therapy carries an ongoing risk of renal scarring. A question that is often
asked in relation to these patients is how long should they be
followed? Should they have antireflux surgery, or should they
embark on a lifetime of chemoprophylaxis?
Several antireflux procedures have been described. Most
entail opening the bladder and performing various procedures on the ureters. The two most popular operations are the
Politano-Leadbetter technique of transvesical reimplantation
of the ureters and the Cohen transtrigonal advancement of
the ureters.12 The principle behind antireflux procedures is
to lengthen the intravesical ureter against a solid detrusor
support to allow compression against the detrusor. Children
undergoing these procedures spend several days in the hospital. These operations are effective, but not devoid of complications, even in the best hands.
In the report of the International Reflux Study Group, in
the European section of the study, 19% of children had persistent VUR, and 5% had ureteral obstruction after antireflux
surgery.13 In the American section of the study, there was
no obstruction, but 9% had persistent postoperative VUR.
322
Surgery in children with high-grade reflux with dilated ureters carries a higher rate of failure and morbidity than surgery
in children with lower grade reflux and nondilated ureters.
The American Urological Association report on VUR reported
persistence of VUR in 19.3% of ureters after reimplantation
of ureters for grade V reflux.11 The rate of obstruction after
ureteral reimplantation needing reoperation reported by the
American Urological Association in 33 studies was 0.3% to
9.1%.11
Since its first experimental description in 1984 in piglets,14
endoscopic correction of VUR has proved to be a highly successful, minimally invasive treatment for this condition.15-22
Several tissue-augmenting substances have been used for
subureteral injections, such as polytetrafluoroethylene (PTFE)
(Teflon), collagen, silicone (Macroplastique), autologous
chondrocytes, calcium hydroxyapatite, and dextranomer/
hyaluronic acid (Dx/HA) copolymer (Deflux). Excellent longterm results have been reported with subureteral Teflon
injections (STING procedure).16,17 Some groups have been
concerned, however, with the use of PTFE as an implant
material because of reported distant particle migration after
periurethral, periureteral, and intravenous injection in animal studies, despite the reported evidence that the minimal
quantities of paste used to correct VUR and the location of
the injection away from major vessels is not associated with
particle migration.23-25
In 2001, Deflux was approved by the U.S. Food and Drug
Administration (FDA) as an acceptable tissue-augmenting
substance for subureteral injection therapy for VUR. Since
then, endoscopic treatment has become increasingly popular for managing VUR, and Deflux is the most widely used
tissue-augmenting substance. Endoscopic treatment has several advantages. In contrast to long-term antibiotic prophylaxis,
it offers immediate cure of reflux at a high incidence, its success does not rely on patient or parent compliance, and the
procedure is virtually free of adverse side effects. Long-term
administration of antibiotics implies the danger of bacterial
resistance with promotion of breakthrough urinary tract infections, and antibiotics are usually needed for years.
In a long-term study, Schwab and coworkers26 reported
spontaneous resolution rates of 13% yearly for grade I to III
reflux and only 5% for grade IV to V reflux. Median time to
resolution under antibiotic treatment was 4.5 years for grade
III and 9.5 years for grade IV reflux. Overall resolution rates
were 83.3% for grade I to 35.5% for grade IV reflux. In their
study in infants with grade IV and V reflux, Sjostrom and
colleagues27 noted a spontaneous resolution rate of 29% in
boys and 4% in girls in the first year and thereafter an annual
resolution rate of only 9% for boys and girls. Despite antibiotic
prophylaxis, 50% of children had breakthrough urinary tract
infections, primarily in the infant year, and more frequently in
girls than in boys.27 The high incidence of breakthrough urinary tract infection in boys can be attributed to uncircumcised
boys typical in European cohorts, but does not explain the
high incidence of urinary tract infection in girls. A randomized study comparing antibiotic prophylaxis with endoscopic
chapter
TISSUE-AUGMENTING SUBSTANCES
FORENDOSCOPIC INJECTION
Dextranomer/Hyaluronic Acid Copolymer
The tissue-augmenting substance most commonly used
for subureteral injection is Dx/HA copolymer (Deflux),
which consists of microspheres of dextranomer in 1% highmolecular-weight sodium hyaluronan solution.18 Each 1 mL
of Deflux contains 0.5 mL of sodium hyaluronan and 0.5 mL
of dextranomer. Deflux is biodegradable, is nonimmunogenic,
and has no potential for malignant transformation. The dextran microspheres (80 to 250 m in diameter) are made from
cross-linked dextran polymers with a network configuration.
This network acts as a carrier that recruits cells from the surrounding tissues. Histopathologic examination after the injection of Deflux has shown giant cells between the dextran
microspheres, with an ingrowth of fibroblasts and vessels, and
the production of varied amounts of collagen around the dex
tranomers. There is a loss of volume of 25% during the first year
after injection. In recent years, several studies have reported
safety and effectiveness of the endoscopic treatment of VUR
using Deflux as a tissue-augmenting substance.19-22,30-34
Polytetrafluoroethylene
Currently, PTFE (Teflon) is one of the most widely used biomaterials in surgery. It belongs to a family of polymers, substances composed of large molecules formed by chemical
combinations of many small ones (monomers) into chains or
networks. PTFE is the best-known fluorocarbon polymer and
is probably the most inert of the plastic materials. It has the
lowest coefficient of friction and is highly crystalline (>94%
crystallinity). The polymer has a high molecular weight, high
density (2.15 to 2.2 g/mL), low tensile strength (17 to 28 MPa),
and a low surface tension (18.5 erg/cm2). Teflon is considered
to be relatively inert chemically, is easily sterilized, and retains
its functional characteristics for long periods. PTFE is usually not rejected by the host and has not been found to cause
any malignancies in humans. Medical applications include
(1) vascular grafts when fabricated into textiles; (2) knitted fabrics for the treatment of aneurysms; (3) heart valves and aortic
implants; (4) shunts in hemodialysis equipment; (5) bone, cartilage, and ligament replacements; and (6) sutures and tissue
replacement patches.
PTFE paste is a suspension of biologically inert PTFE particles in glycerin. The glycerin is 50% of the paste by weight.
After injection, the glycerin is absorbed into the tissues,
and the PTFE implant achieves a firm consistency, retaining
its shape and position at the injection site, and is encapsulated by thin fibrous tissue.14 PTFE paste has been used in
clinical medicine for more than 35 years with little morbidity.35-42 Politano and colleagues37-41 pioneered periurethral
323
Polydimethylsiloxane
Polydimethylsiloxane (Macroplastique) has been used as a
tissue-augmenting substance for the endoscopic correction of
VUR.119-121 The silicone paste is made of 40% solid textured
polydimethylsiloxane particles suspended in 60% hydrogel.
Its physical properties are similar to those of PTFE. There are
no long-term follow-up studies available, however, with this
injectable substance for the treatment of VUR. Distant silicone
particle migration has also been reported after periurethral
and periureteral microparticulate silicone injections. Buckley
and coworkers122 found that small silicone particles migrated
to the lungs, kidneys, brain, and lymph nodes 4 months after
injection into mongrel dogs. Henly and coworkers123 confirmed these results after periurethral injection of particles less
than 70 m in female dogs.
Autologous Chondrocytes
In 1999, Diamond and Caldamone124 reported preliminary
results of endoscopic injection of autologous chondrocytes
to correct VUR in children. Because chondrocytes possess
the ability to form viable cartilage, they have good potential as a stable tissue-augmenting substance. Twenty-nine
children (46 ureters) with grades II to IV VUR were treated.
Each child underwent cystoscopy and ear cartilage biopsy at
the initial setting. Chondrocytes were grown in culture for
6 weeks. Patients underwent subureteral endoscopic injection of autologous chondrocytes. Ultrasonography was performed at 1 month, and radionuclide cystography was done
3 months postoperatively to confirm reflux resolution. When
reflux persisted, repeat treatment with stored chondrocytes
was offered. Initial chondrocyte injection corrected reflux
in 26 of the 46 ureters (57%), whereas secondary injection
was successful in 12 of 19 in whom the first injection did
not work (63%). Overall reflux was corrected in 38 of the 46
ureters (83%) and in 24 of the 29 patients (83%). There were
no significant complications. In another more recent study,
reflux resolved after one chondrocyte injection in 61% in
the early follow-up group and 74% in the late follow-up
group.125 The potential advantages of autologous chondrocyte injection include a sustained antireflux effect from viable
324
part
A
Section
B
Section
Figure 24-1 A, Needle is introduced under the bladder mucosa, 2 to 3 mm below the affected ureteral orifice at the 6 oclock position. The needle
is advanced about 3 to 4 mm into the lamina propria, and the injection is started slowly. B, Correctly placed implant creates a slitlike ureteric
orifice. In children with grade IV or V reflux, the needle should be inserted directly into the affected ureteral orifice, and the injection should be
made under the mucosa.
c hondrocytes, and prevention of bioincompatibility owing to
their autologous nature.
Calcium Hydroxyapatite
Synthetic calcium hydroxyapatite is a sterile apyrogenic injectable slurry of spherical particles in an aqueous-based gel carrier. The particles are spherical in shape and range from 75 to
125 m in diameter. Calcium hydroxyapatite provides longterm bulking with anticipated 25% volume loss. In a multicenter study using calcium hydroxyapatite for endoscopic
correction of VUR, only 46% of ureters were cured at 1-year
follow-up. The primary center at Rochester achieved a 2-year
cure rate in 72% of ureters.126
chapter
325
Figure 24-2 Endoscopic appearance of subureteral injection. A, Injection in progress. B, Correctly placed implant gives an appearance of a nipple
on the top of which is a slitlike orifice.
the mucosa or the ureter may allow the paste to escape and
may result in failure.
The needle is advanced about 4 to 5 mm into the lamina
propria in the submucosal portion of the ureter, and the injection is started slowly. As the paste is injected, a bulge appears
in the floor of the submucosal ureter. During the injection, the
needle is slowly withdrawn until a volcanic bulge of the
paste is seen. The needle should be kept in position for 30 to
60 seconds after injection to avoid extrusion. Most refluxing
ureters require 0.2 to 0.6 mL of Deflux to correct reflux. A correctly placed injection creates the appearance of a nipple on
the top of which is a slitlike or inverted crescent orifice (Fig.
24-2). If the bulge appears in an incorrect place, the needle
should not be withdrawn, but should be moved so that the
point is in a more favorable position. The noninjected ureteric
roof retains its compliance, while preventing reflux. The success or failure of the procedure depends on the accuracy of the
injection technique.
Most patients are treated as outpatient cases. Antibiotic
prophylaxis is prescribed for 12 weeks after the procedure.
Micturating cystography and renal ultrasonography are performed 3 months after discharge. Follow-up renal and bladder
ultrasound scans are obtained 12 months after endoscopic correction of reflux and then every 2 years to monitor the growth
of kidneys and the size of the subureteral implant.
VUR
One
Injection
Two
Injections
35 (100%)
Grade III
540 (93.1%)
36 (6.2%)
4 (0.7%)
580
Grade IV
355 (77.7%)
87 (19%)
15 (3.3%)
457
Total
22 (75.9%)
952
7 (24.1%)
130
Total
Grade II
Grade V
Three
Injections
35
29
19
1101
326
part
Improved
6%
34 injections
2%
Failed
4%
2 injections
12%
1 injection
76%
In a meta-analysis on endoscopic therapy for VUR, the database included 5527 patients.129 After one treatment, the reflux
resolution rate for grades I and II reflux was 78.5%, for grade
III was 72%, for grade IV was 63%, and for grade V was 51%.
If the first injection was unsuccessful, second treatment had a
success rate of 68%, and the success rate of a third treatment
was 34%.
LONG-TERM RESULTS
Numerous multicenter studies of STING have been reported in
the literature.54,71,88 All these studies have shown that STING
is a simple outpatient procedure, effective in correcting all
grades of VUR, and is associated with little morbidity.
In 1998, Puri and Granata54 reported the results of a multicenter survey of endoscopic treatment of VUR using PTFE
paste in 8332 children. Fifty-three pediatric urologists and
pediatric surgeons at 41 centers worldwide answered an
inquiry regarding experience with STING in VUR. Data were
collected from a completed standard questionnaire. From
1984 to 1996, 1921 boys and 6411 girls with a mean age of
4.5 years (12,251 refluxing ureters) were treated endoscopically
with STING. Reflux was grade I in 407 (3.3%), grade II in 3832
(31.2%), grade III in 5213 (42.5%), grade IV in 2218 (18.1%),
and grade V in 581 (4.7%) ureters. In most patients, STING
was performed on an outpatient basis. Most urologists monitored patients with voiding cystourethrography and renal
ultrasonography at 3 months, 1 year, and 3 years. All patients
were followed for 1 to 13 years.
Reflux resolved in 9226 ureters (75.3%) after one PTFE
injection, in 1478 (12%) after two injections, and in 250 (2%)
after three or four injections (Fig. 24-3). VUR improved to
grade I after one or two injections in 743 (6%) ureters, which
needed no further treatment. Subureteral injection failed to
correct reflux in 554 ureters (4.5%), which were then treated
with ureteral reimplantation. Vesicoureteral junction obstruction requiring ureteral reimplantation developed in 41 ureters (0.33%). More than 90% of ureters have been followed
for more than 2 years. At follow-up, reflux recurred in 326
(2.8%) endoscopically corrected refluxing ureters. No clinically untoward effects were reported in any patient because
of the use of PTFE as an injectable material.
A more recent prospective multicenter trial in the United
States using synthetic calcium hydroxyapatite for endoscopic
chapter
Results
No.
88 (53%)
26 (15.7%)
327
VUR
One
Injection
Two
Injections
14 (100%)
Grade III
175 (93.1%)
12 (6.4%)
1 (0.5%)
188
36 (21.7%)
Grade IV
194 (78.2%)
48 (19.4%)
6 (2.4%)
248
10 (6%)
Grade V
11 (64.7%)
5 (29.4%)
1 (5.9%)
17
Total
394
65
Total
Grade II
6 (3.6%)
Three
Injections
14
467
RRUs after a single injection and resolved after a second injection in another 9 (21%). In four (9%) RRUs, endoscopic correction failed, and the patients underwent open reimplantation.
Our data showed that endoscopic treatment of VUR associated
with ureterocele is a simple, effective, and safe procedure.138
Duplex Systems
328
part
Figure 24-4 A, Voiding cystourethrogram shows high-grade left vesicoureteral reflux after failed reimplantation. B, Voiding cystourethrogram
1 year after endoscopic subureteral injection shows an absence of reflux in the same child.
chapter
329
Few studies have reported the incidence of new contralateral reflux after endoscopic correction of unilateral
reflux.21,128,158,159 Some authors have suggested that the
contralateral ureter should be treated prophylactically in
certain groups of patients undergoing unilateral endoscopic
correction of VUR.158 Our own series had a 10% incidence
of new contralateral reflux and did not support prophylactic endoscopic treatment of the contralateral ureter in
patients undergoing unilateral endoscopic correction of
VUR.159 In our series of 662 patients undergoing unilateral
endoscopic correction of VUR, new contralateral VUR was
diagnosed in 67 (10.1%) patients at follow-up voiding cystourethrogram. Half of these had low-grade new contralateral VUR and required no further treatment, and the other
half with high-grade new contralateral VUR underwent
successful endoscopic correction of VUR. There was no particular risk factor identified with the development of new
contralateral VUR.
CONCLUSION
Endoscopic subureteral injection of tissue-augmenting substances has become an established alternative to long-term
antibiotic prophylaxis and surgical intervention in the management of VUR in children. It is a simple 15-minute outpatient procedure. In terms of effectiveness and safety, Dx/HA
is the most reliable and widely used injectable product for the
endoscopic treatment of VUR.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
25
TECHNIQUES
Cystoscopy and Positioning
Cystoscopy may be performed under the same anesthetic
at the time of the ureteral reimplantation (ureteroneocystostomy). Endoscopic evaluation of the entire lower urinary tract
is advised, especially in patients whose preoperative voiding
cystourethrography suggests an unusual anatomic situation.
Cystoscopic evaluation can also reveal unexpected findings
that were not appreciated on preoperative imaging studies.
Aduplex system with a distally located upper pole ureteric orifice may be discovered during cystoscopy. The upper pole ureter opening ectopically at the bladder neck or proximal urethra
may be difficult to identify and easily missed from the intravesical exposure. If duplex ureters are widely separated from each
other at the level of the trigone and bladder neck, the extravesical common sheath reimplantation approach may be unsuitable.
In boys, the posterior urethra should be examined carefully
for any evidence of outlet obstruction, such as posterior urethral valves. The presence of wall thickening and trabeculation
should alert the clinician of a potential voiding dysfunction and
outlet obstruction. If the bladder mucosa is inflamed diffusely,
one must suspect a possible urinary tract infection, which may
increase the likelihood of postoperative complications.
The patient is positioned supine with a slight break in the
table to raise the hips, especially in obese children. Generally,
the legs are gently spread open, and the perineum is prepared
within the operative field. For extravesical ureteral reimplant,
a Foley balloon catheter is inserted into the bladder to control
the filling and emptying during the procedure.
Intravesical Approach
Exposure
A transverse suprapubic skin incision (Pfannenstiel) is made
along a skin crease approximately one finger-breadth above
the pubic symphysis. This incision provides an excellent
chapter
331
Figure 25-2 Tenotomy scissors are used to establish the correct plane
Ureteral Dissection
A refluxing ureter often has a patulous orifice, is positioned
lateral in the trigone, and has a straight course through the
bladder wall. The interureteric ridge is usually poorly developed. The ureter is first intubated with a small, soft feeding
tube (3.5F to 5F). Having a catheter in the ureter helps with
the initial dissection, especially of the intramural portion. Fine
Politano-Leadbetter Technique
First described in 1958, the Politano-Leadbetter technique4 has
been widely used with excellent results. In this technique, the
ureter is brought into the bladder through a new hiatus superior to the original hiatus. The ureter is placed in a submucosal tunnel directed toward the bladder neck. Success rates
of 97% to 99% have been cited,5 although some authors have
reported a slightly higher complication rate compared with
the relatively simple cross-trigonal method.6 Most reimplants
done currently are in the Cohen fashion because it is easier to
perform and has fewer complications.
332
part
Figure 25-3 Bilateral Cohen cross-trigonal ureteral reimplantation. The ureters are dissected and mobilized as described in the text. The more
superior ureter (typically with more severe reflux) is tunneled transversely to the new orifice just above the contralateral ureter. The inferior ureter
is tunneled below the contralateral ureteral hiatus. (From Retik AB, Colodny AH, Bauer SB. Pediatric urology. In: Paulson DF, ed. Genitourinary
Surgery. Vol 2. New York: Churchill Livingstone; 1984.)
Figure 25-4 Appearance of the completed bilateral Cohen cross-trigonal ureteral reimplantation. (From Retik AB, Colodny AH, Bauer SB. Pediatric urology. In: Paulson DF, ed. Genitourinary Surgery. Vol 2. New York: Churchill Livingstone; 1984.)
potential problem is difficulty in retrograde catheterization or
ureteroscopy or both because of the lateral deviation of the
ureters away from the bladder neck. Technical advancements
in flexible endoscopy may minimize this concern.
When the ureter has been mobilized, the original hiatus is
inspected to see whether it requires narrowing. A large, patulous opening at the hiatus can lead to a diverticulum formation and should be reinforced, but during this maneuver one
must be careful not to make it too tight because this would
lead to postoperative obstruction. It is better to err on the
side of leaving it slightly loose rather than too tight because
a small diverticulum at the hiatus of the submucosal tunnel rarely causes clinical problems. If both ureters are being
reimplanted, it is preferable to reimplant the more severely
refluxing ureter above the ureter with less reflux because the
upper ureter generally would have a slightly longer tunnel.
To achieve longer tunnel lengths, the original hiatus can also
be incised superiorly and laterally, using a broader area of the
posterior bladder wall.
Bladder mucosa surrounding the ureteral hiatus is first
undermined for a few millimeters using sharp tenotomy
chapter
333
Obliterated
hypogastric
artery
Ureter
Extravesical Approach
There has been a renewed interest in the use of the extravesical
technique. In the contemporary reports, the results in terms
of reflux correction seem comparable with the results of traditional intravesical techniques.7-9 The main advantage lies in
the fact that patients who undergo extravesical reimplantation experience significantly less postoperative hematuria and
bladder spasm. Some authors have reported an excellent outcome in performing extravesical ureteral reimplantation in an
outpatient setting or with a short overnight hospital stay.
In the extravesical technique, the submucosal tunnel
required for the flap-valve mechanism is created outside the
bladder lumen without detaching the ureter from the original
ureterovesical junction. Bilateral extravesical repair should be
done with caution, however, because urinary retention can
result, presumably owing to denervation of the subtrigonal
nerve plexus during ureteral dissection and tunnel development.10 Retention rates after bilateral extravesical ureteral
Figure 25-6 The ureter is completely mobilized down to the ureterovesical junction, and the bladder muscle fibers are divided to develop
a muscular trough, exposing the back wall of the bladder mucosa.
Having the bladder moderately full causes the mucosa to bulge outward and helps in dissection. The direction of the submucosal tunnel must be chosen carefully, taking into account the fact the bladder
has been rolled to one side, so that the ureter does not angulate and
kink. (From Peters CA, Retik AB. Ureteral reimplantation including
megaureter repair. In: Marshall FF, ed. Textbook of Operative Urology.
Philadelphia: WB Saunders; 1996.)
Exposure
A Foley catheter is inserted into the bladder to control the
bladder distention. When the prevesical space is exposed, the
bladder is rolled to the side to expose the ureter. This maneuver is easier with the bladder empty. The ureter is identified
and dissected from surrounding structures toward the ureterovesical junction. The most reliable way to find the ureter
is first to identify the obliterated umbilical artery and follow
it posteriorly toward the iliac vessels (Fig. 25-5). The ureter is
typically found crossing just below the obliterated umbilical
artery between the bladder and the peritoneum. Dividing the
obliterated umbilical artery also facilitates sweeping the peritoneum superiorly and improves the overall exposure.
There are many small vessels converging near the ureterovesical junction, and they need to be carefully ligated,
cauterized, and divided. After the ureter has been completely
mobilized, the bladder muscle fibers are incised superior to
the ureterovesical junction to develop a submucosal tunnel
(Fig. 25-6). As the muscle fibers are divided, the backside
of the bladder mucosa becomes visible. Having the bladder
moderately full at this point causes the bladder mucosa to
bulge outward, making dissections easier. This trough should
be long enough to provide an adequate width-to-length ratio
334
part
POSTOPERATIVE MANAGEMENT
Careful attention should be paid to ensure that a brisk diuresis is maintained postoperatively. Until the oral intake of fluid
is adequate, a generous amount of intravenous fluid should
be administered. Diet is advanced quickly, with most patients
resuming a regular diet by the next day. In our experience, the
most troublesome postoperative issue after intravesical ureteral reimplantation has been bladder spasm. The pain from
the operative incision becomes minimal in most patients after
1 to 2 days, but the bladder spasms can persist for several
days. Many agents, such as opioids, local anesthetics, anticholinergics, and antispasmodics, have been tried with modest
efficacy.
Figure 25-8 The muscular trough is closed over the ureter using
interrupted absorbable sutures. The new hiatus must be confirmed to
be loose to prevent obstruction. (From Peters CA, Retik AB. Ureteral
reimplantation including megaureter repair. In: Marshall FF, ed. Textbook of Operative Urology. Philadelphia: WB Saunders; 1996.)
SPECIAL CONSIDERATIONS
Duplex Ureters (Common Sheath Reimplantation)
Often VUR is associated with the lower pole ureter of a
duplex collecting system. As predicted by the Weigert-Meyer
rule of ureteral embryology, the lower pole ureter enters the
chapter
Paraureteral Diverticulum
In some instances, reflux is associated with a paraureteral
diverticulum. The presence of a large diverticulum makes it
unlikely that reflux would resolve spontaneously with time.
The diverticulum is dissected together with the ureter, and
the muscular defect is carefully reinforced to provide a secure
back wall of the submucosal tunnel.
MANAGEMENT OF COMPLICATIONS
Early Obstruction
Obstruction at the newly created ureteroneocystostomy site
is the most common complication within the first 4 weeks
after surgery. Rarely, this obstruction may be entirely silent,
being discovered only by worsening hydronephrosis seen on
imaging studies. More often, symptoms such as abdominal
pain, anorexia, or emesis occur. Fever is unusual. The underlying cause is typically edema at the site of anastomosis,
hematoma at the site of dissection, or kinking at the reimplantation site. Transient obstruction may occur secondary
to mucus or blood clots plugging the ureter. In most cases of
early obstruction, an observational approach is warranted,
using supportive measures and serial ultrasound examinations. Rarely, drainage is indicated in patients with fever,
azotemia, acidosis, or electrolyte imbalance. If drainage is
required, percutaneous nephrostomy is preferable to retrograde stenting. Often, the obstruction resolves shortly after
decompression.
Persistent Obstruction
Persistent obstruction can be entirely silent and lead to renal
loss. The cause of such obstruction is typically ureteral ischemia
or improper placement of the reimplanted ureters. Intermittent
obstruction due to J hooking near the ureterovesical junction
can be seen with bladder filling. Percutaneous dilation may
be tried first, but is typically of limited value. Reoperative
reimplantation is the definitive treatment. In this situation,
one must be prepared for various reconstructive options. A
preoperative antegrade or retrograde ureterogram helps to
delineate the level of obstruction and define the appropriate
surgical strategy.
335
A midline incision, rather than a low transverse suprapubic incision, is preferred when dealing with persistent
obstruction in the event a superior dissection is necessary.
The bladder is exposed and opened, and ureteral dissection
is started intravesically similar to the routine reimplantation,
but one must not hesitate to extend the ureteral mobilization
superiorly by going outside the bladder. The ureter must be
mobilized completely, by reflecting colon medially if necessary. When dissecting the ureter, all the periureteral tissues
should be swept toward the ureter, including the gonadal
vessels, to preserve the ureteral vascularity. The fibrotic
ureter must be cut back until a viable ureteral segment is
encountered with a good blood supply. If there is an ample
ureteral mobility to reach the bladder without tension, one
can proceed with ureteral reimplantation using previously
described techniques. If the ureter does not reach the bladder
easily, one should consider additional bladder mobilization
and upward fixation using the psoas hitch technique. The
bladder is tented superiorly toward the ureter, and the new
ureterovesical hiatus is made.
The outer wall of the bladder is sutured deeply to the
psoas muscle using either polydioxanone or polypropylene
(Prolene). The ureter is brought into the bladder through
the new hiatus and reimplanted with a long tunnel similar
to the Politano-Leadbetter technique. If the ureter does not
reach the bladder easily with the psoas hitch alone, one
can consider performing a Boari flap procedure, in which a
rectangular strip of bladder is raised with a broad base and
tubularized to meet the ureter. One potential limitation using
the Boari bladder flap technique is the difficulty in establishing an effective submucosal tunnel. An additional length can
also be obtained by wide mobilization of the kidney from its
bed and suturing the lower pole of the kidney to the psoas
muscle inferiorly.
Another reconstructive strategy is transureteroureterostomy, in which the obstructed ureter is anastomosed to the
normal contralateral ureter. The ureter to be drained is widely
mobilized without devascularization and brought across to the
other side without tension. It should not be wedged beneath
the inferior mesenteric vessels. An end-to-side anastomosis is
performed using fine chromic or other absorbable interrupted
sutures, and the ureter is drained using a soft feeding tube,
brought through the bladder wall. In situations in which the
ureter is too short for any of the previously described reconstructive options, one can consider ureteral substitution using
a small bowel segment or renal autotransplantation. If both
ureters need to be reimplanted and are too dilated for a small
bladder, it is better to perform a transureteroureterostomy and
reimplant only one ureter, rather than reimplant both ureters
with an inadequate submucosal tunnel.
Persistent Reflux
Persistent reflux after ureteral reimplantation is unusual, but
can occur owing to inadequate tunnel length or ureterovesical fistula. Beyond the technical reasons, one must consider
the possibility of unrecognized voiding dysfunction, outlet
obstruction, or neuropathic bladder. Generally, a trial of observation is worthwhile using prophylactic antibiotics because
postoperative reflux often resolves spontaneously within 1 to
2 years. Massive reflux with recurrent pyelonephritis is best
managed with surgical repair, following operative principles
similar to those outlined for persistent obstruction. Preoperative cystoscopy is crucial in assessing the cause of persistent
reflux.
In contrast to the obstructive situation, reoperative reimplantation for persistent reflux can be performed satisfactorily
336
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REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
26
TERMINOLOGY
Owing to previous confusion over earlier terminology, a standard set of definitions used to describe ureteral duplication
anomalies now exists. These definitions were established by
the Urologic Section of the American Academy of Pediatrics
Committee on Terminology, Nomenclature, and Classification.1 A duplex (duplicated) system refers to a kidney with two
pelvicalyceal systems generally referred to as the upper or lower
poles. If the kidney has two ureters that empty separately into
the bladder (double ureters), it is considered a complete duplication. In contrast, in a partial or incomplete duplication, a common single ureter enters the bladder. A bifid system is a form
of duplication with two pelvicalyceal systems joining at the
ureteropelvic junction (bifid pelvis) or before emptying into
the bladder (bifid ureters).
The upper or lower pole ureter describes the ureter draining the upper or lower pole of a duplex kidney. The orifice
associated with the ureter draining the upper or lower pole is
known as the upper or lower pole orifice. A laterally ectopic ureter
inserts lateral to the normal position. A medially or caudally
ectopic ureter inserts medial and distal to the normal position
on the trigone. An ectopic ureter drains to an abnormal site and
generally refers to an orifice located medially or caudally.
A ureterocele is defined as a cystic dilation of the intravesical submucosal ureter. Ureteroceles contained entirely within
the bladder are classified as intravesical ureteroceles, whereas
ectopic (extravesical) ureteroceles contain a portion permanently
situated at the bladder neck or in the urethra. A single-system
ureterocele is associated with a kidney with only one ureter. A
duplex-system ureterocele is associated with the upper pole of a
kidney with a complete ureteral duplication.
EMBRYOLOGY
The ureter forms from the ureteral bud, which arises as a
diverticulum from a ventral bend or elbow in the mesonephric
(wolffian) duct at the end of the 4th week of gestation. This
bend occurs as the mesonephric duct comes off the posterior
wall crossing the metanephros from lateral to medial to reach
the cloaca.2 The ureteral bud grows off the bend in the mesonephric duct and penetrates the metanephric blastemal ridge,
the kidney progenitor, late in the 5th week (Fig. 26-1). The
ureteral bud subsequently forms the ureter, renal pelvis, calyces, papillary ducts, and collecting tubules. The metanephros
differentiates into the more proximal portions of the nephron.
338
part
Mesonephric
duct
Hindgut
Ureteral
bud
Metanephric
blastoma
Cloaca
Common
excretory
duct
Figure 26-2 A, The ureteral bud expands and inverts into the urogenital sinus by the 8th week of development. B, The ureteral orifice
migrates cephalad and laterally, while the mesonephric duct moves
distally and medially.
URETERAL DUPLICATION
In an autopsy population, ureteral duplication occurs in 1 in
125 patients (0.8%) and constitutes the most frequent ureteral
anomaly.15,16 The right and left kidneys are affected equally.
Bilateral duplication occurs in about 20% to 40% of cases.17,18
There are twice as many girls as boys with duplications.18
Urinary tract infection (UTI) is the most common associated
finding, and the incidence of childhood UTIs is increased
with duplications, as might be expected with the associated
increased incidence of reflux or obstruction. A study of more
than 700 children presenting with UTI found that 8% had
ureteral duplication.18 In one clinical series of patients with
urinary symptoms, there was a much higher incidence of
duplication: 2% to 4%.19
Duplication may be transmitted as an autosomal dominant
trait with incomplete penetrance.20 When an index child with
a duplication is found in a family, the frequency of a sibling
with a duplication increases from 1 in 25 to 1 in 8 or 9.21-23
Other urinary tract anomalies associated with ureteral duplication include renal scarring or hydronephrosis or both.24 In
children who present with UTI and are found to have ureteral duplication, associated ectopic ureteroceles are present
chapter
339
Figure 26-3 A, Complete ureteral duplication formed by two ureteral buds originating from a normal site on the mesonephric duct. The Weigert-
Meyer rule stating that an upper pole orifice is medial and caudal to the lower pole orifice results from the rotation of the ureters during incorporation into the trigone. B, One of the two ureteral buds has a lower than normal origin, resulting in complete duplication with vesicoureteral reflux
into this ureter, which during migration was carried most cranially and laterally. C, One of the two ureteral buds has a higher than normal origin,
resulting in complete duplication with an ectopic upper pole ureter. (A-C, Redrawn from Snyder HM III. Anomalies of the ureter. In: Gillenwater JY,
Howards SS, Grayhack JT, Duckett JW, eds. Adult and Pediatric Urology. 3rd ed. St. Louis: Mosby-Year Book; 1996.)
340
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341
Figure 26-5 Complete ureteral duplication and vesicoureteral reflux. A, Intravenous pyelogram shows completed duplication of the ureters.
B, Voiding cystourethrogram shows bilateral lower pole vesicoureteral reflux. (From Gillenwater JY, Howards SS, Grayhack JT, Duckett JW. Adult
and Pediatric Urology. 3rd ed. St. Louis: Mosby-Year Book; 1996:2205.)
URETEROCELES
Incidence and Diagnosis
Campbell16 reported the incidence of ureteroceles to be 1 in
4000 (0.025%) autopsies of children, whereas Uson and colleagues53 reported a much higher incidence of 1 in 500 (0.2%)
autopsies. Ureteroceles are seen most commonly in whites and
are uncommon in blacks. Ureteroceles occur four to seven times
more frequently in girls than in boys.54 Some series suggest a
slight left-sided predominance, and about 10% are bilateral.55
Of ureteroceles, 60% to 80% are ectopic, whereas intravesical
ureteroceles are less common.3,56,57 About 80% of all ureteroceles are associated with the upper pole ureter of a duplex
kidney.58 Single-system ectopic ureteroceles are rare and occur
most frequently in boys; they may be associated with cardiac
and genital anomalies.59 Rarely, a ureterocele may be associated with a blind-ending ureter.60 Associated urologic anomalies, especially the renal anomalies of fusion and ectopia, are
also seen with ureteroceles. When the ureterocele arises from
the upper pole of a duplex kidney, the upper pole shows evidence of renal dysplasia in about two thirds of cases.61,62
The most frequent presentation of ureteroceles currently is
by prenatal ultrasound, although urinary infection continues
to be a common presentation.63-66 Occasionally, an infant presents with a palpable abdominal mass representing the bladder
or the obstructed renal unit (Fig. 26-6). Prolapse of a ureterocele may lead to bladder outlet obstruction, which constitutes
the most common cause of urethral obstruction and urinary
retention in girls.67-69 The ureteroceles that obstruct the urethra
tend to ball valve into the bladder neck and are tense (Fig.
26-7). Because most ureteroceles are compressible during voiding, obstruction of the urethra is infrequently seen even with
ectopic ureteroceles. Occasionally, a large ureterocele with an
abnormally lax distorted bladder neck may lead to incontinence before or after the ureterocele is surgically treated.70,71
IVP had historically been the most useful study in the
diagnosis of a ureterocele,61-74 but today the diagnosis of a
ureterocele relies predominantly on ultrasonography.66,75-77
Ultrasonography typically shows a well-defined cystic intravesical mass along the posterior bladder wall (Fig. 26-8). The
ultrasound appearance of a ureterocele can be deceiving,
and accurate diagnosis requires analysis by an experienced
radiologist. Because many ureteroceles are compressible with
bladder filling, observation when the bladder is very full may
miss the mucosal irregularity of the bladder base. The dilated
ureter behind the bladder also may be confused with an
ectopic ureter or primary obstructive megaureter. Ultrasound
also can evaluate for renal parenchymal thickness and echogenicity, and the presence of a duplex kidney with upper pole
hydronephrosis.
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part
Figure 26-6 A, Small ureterocele. Lower pole ureteral orifice can be seen to be elevated by the ureterocele. B, Large ureterocele. Catheters are
in the orifice of the ureterocele and ipsilateral lower pole ureteral orifice. (From Gillenwater JY, Howards SS, Grayhack JT, Duckett JW. Adult and
Pediatric Urology. 3rd ed. St. Louis: Mosby-Year Book; 1996:2206.)
Figure 26-8 Ultrasonography shows the echogenic wall of the intravesical ureterocele.
Figure 26-7 Filling defect seen from the ureterocele prolapsing into
the posterior urethra.
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343
Choice of Treatment
Figure 26-9 Intravenous pyelogram of bilateral single-system intravesical ureteroceles shows typical cobra-head deformity of distal
ureter.
A good-quality VCUG constitutes a crucial component in
the evaluation of all ureteroceles. With duplex ureteroceles,
reflux is seen to the ipsilateral lower pole in about 50% of
cases, and contralaterally in approximately 25%, and in
about 10% there is reflux into the ureterocele itself.58,65,78,79
Reflux into a single-system ureterocele is less frequent,
but can occur.78,80,81 This reflux usually occurs into a widemouth sphincteric, ruptured, or blind-ending ureterocele.
The VCUG is also useful to ascertain the degree of detrusor
backing present for the ureterocele. If detrusor support is
poor, and the ureterocele prolapses through the detrusor with
voiding, the ureterocele can mimic a bladder diverticulum
(Fig. 26-10).81-83 Prolapse may occur either into the dilated
ureter associated with the ureterocele or through the hiatus
paraureterally.84 Occasionally, after decompression of a ureterocele, detrusor backing may seem to improve. When tense,
a ureterocele may obstruct the ipsilateral lower pole ureter or
contralateral ureter and the bladder outlet. Occasionally in
boys, an ectopic ureterocele can prolapse toward the urethra
and produce an image that may be confused with posterior
urethral valves.85
Cystoscopic detection of ureteroceles varies and is frequently confusing. When a ureterocele is small, it may not be
apparent until a peristaltic wave or flank compression causes
it to fill. With very large ureteroceles, identification of any
ureteral orifice in the bladder may be impossible. With a large
ureterocele causing bilateral obstruction, it can be difficult to
tell from which system the ureterocele originated. In this situation, a small needle wedged into the end of a fine ureteral
catheter can be used to puncture the ureterocele under direct
vision at cystoscopy, and injection of contrast medium may
permit an intraoperative radiograph to define the anatomy.
An alternative approach is to use a spinal needle passed
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part
Figure 26-10 Cystograms show a large intravesical ureterocele (A), which prolapses through the ureteral hiatus (B and C), with subsequent
reflux into the more proximal ureter (D).
parenchyma may be relatively more successful than in a kidney with scarring. The upper pole system associated with the
ureterocele typically involves only the parenchyma subserved
by the upper pole infundibulum,24 however, which is usually
less than one third of the renal function of the kidney. Upper
pole nephrectomy specimens show histologic changes (fibrosis,
tubular atrophy, chronic inflammation, glomerulosclerosis,
dysplasia) in nearly all specimens, including moderate to severe
histologic lesions in two thirds.62 Preservation of this renal tissue
should not be a paramount part of decision making. A poorly
functioning renal unit drained by a decompressed ureterocele
with no reflux has no routine indication for removal. Chertin
and colleagues91 evaluated poorly functioning or nonfunctioning renal moiety after endoscopic puncture, and reported 6%
had a postoperative UTI, and only 4% subsequently required
nephrectomy or partial nephrectomy for recurrent UTI.
chapter
345
Figure 26-12 Patient with a right upper pole ectopic ureter creating
a pseudoureterocele (arrow).
346
part
be performed as described for ectopic ureteroceles in the following section. This approach is particularly attractive when
there is no VUR because this simplified approach is likely
to permit the avoidance of any bladder-level surgery.71 The
incidence of VUR after endoscopic incision of intravesical ureteroceles is sufficiently low (see earlier discussion), however,
to make the endoscopic approach perhaps even more attractive in treatment of an intravesical ureterocele in a duplex
system.
At partial nephrectomy, the ureter associated with the
decompressed ureterocele is usually left open and drained
if no reflux is present preoperatively. Intraoperatively, attention must be paid to avoid damage to the lower pole ureter.
An intravesical ureterocele as part of a duplex unit may be
associated with adequate function and a ureter small enough
(especially after endoscopic decompression) to permit ureterocele excision and a common sheath reimplant of the two
ureters. Occasionally, the associated ureter is too dilated to
be reimplanted without tailoring. If there is no reflux driving surgery at the bladder level, and if upper pole function
justifies salvage, a renal-level ureteroureterostomy or ureteral
pyelostomy may be employed effectively. The distal upper
pole ureter in these salvageable cases is handled as previously
discussed.
chapter
347
348
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chapter
349
Figure 26-13 A, Ureteral ectopia in the male. Possible sites of ectopic ureter are above the external sphincter. B, Ureteral ectopia in the female.
Ectopic ureter may be located beyond the continence mechanism and produce incontinence. (From Johnston JH. Problems in diagnosis and
management of ectopic ureters and ureteroceles. In: Johnston JH, Scholtmejer RJ, eds. Problems in Pediatric Urology. Amsterdam: Excerpta Medica;
1972:57.)
ECTOPIC URETER
A ureteral bud with an abnormally high origin from the mesonephric duct may result in an ectopic ureter opening at the
bladder neck or more caudally (see embryology section earlier
in this chapter). There are multiple possible sites for an ectopic ureter in boys (always above the external urethral sphincter) and girls (Fig. 26-13). In autopsy series, the incidence of
ectopic ureters is 1 in 1900 (0.05%).16 Ectopic ureters are much
more common in girls, with only about 15% of ectopic ureters
occurring in boys.130 In 80% of all ectopic ureters, the ureter is
attached to the upper pole of a duplicated renal system. The
percentage of ectopic ureters associated with duplication in
girls is even higher than 80%; however, in boys, an ectopic ureter drains a single system more commonly.131,132 About 10% of
ectopic ureters are bilateral.133 When an ectopic ureter is part
of a duplex system, the contralateral system is duplicated in
about 80% of cases, and 21% of these have contralateral ectopy
as well.134
Renal hypoplasia or dysplasia constitutes the most frequently encountered anomaly associated with an ectopic
ureter. Generally, the degree of ureteral ectopy away from
the bladder correlates with the degree of renal abnormality,
although this correlation is more apparent for duplex systems
than for single systems.135 Severe ectopy with an orifice in the
genital system is almost always associated with nonfunctioning renal tissue.130,136 Some series have shown a higher incidence of other associated anomalies, especially imperforate
anus, in single-system ectopy than in duplex ectopy.88
A single ectopic ureter with a normal contralateral system
usually does not result in any deficiency of the bladder neck,
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Figure 26-14 Cystogram shows ectopic ureter entering at the bladder neck. (From Gillenwater JY, Howards SS, Grayhack JT, Duckett JW.
Adult and Pediatric Urology. 3rd ed. St. Louis: Mosby-Year Book;
1996:2222.)
common wall. Ureteral ectopy into the rectum is very rare, but
has been reported.143
About one half of girls with ectopic ureter present with a
classic history of continuous dribbling incontinence despite
what seems to be a normal voiding pattern.130,134,135 Sometimes,
parents may not note the abnormal character of continuous
incontinence in a preschool-aged girl, and commonly the
problem in the female goes unrecognized until adulthood.144
If the associated ureter is very dilated, the child may be continent when supine, and the pattern may be daytime wetting
erroneously suggestive of stress incontinence or overactive
bladder. Occasionally, the presentation consists of a persistent
foul-smelling vaginal discharge. If the ureter ends in a Gartner
duct cyst, the child may present with a mass on the anterior
vaginal wall. When the ectopic orifice is quite high, and there
is significant obstruction or reflux or both, urinary infection is
frequent and is the most common presentation for an ectopic
ureter in a small child. The evaluation of prenatal hydronephrosis is another form of presentation.145 An infant may
present with an abdominal mass resulting from a severely
obstructed ectopic ureter.142 There are well-documented cases
of girls with ectopic ureters entering the vestibule or distal
urethra without incontinence, presumably owing to obstruction of the ureter as it traverses the continence mechanism
with emptying only during voiding.146
The diagnosis of an ectopic ureter in a girl may be very difficult. With ectopy into the external genitalia, the associated
renal unit is likely not to be visualized on IVP.147 Ultrasound
may be especially useful, detecting the dilated ectopic ureter
behind the bladder. If there is little hydroureteronephrosis
of the ectopic upper pole system, diagnosis may depend on
recognizing the absence of an upper pole calyx or an apparent
excessive thickness of the renal tissue on the medial aspect of
the upper pole. Tomography during IVP, computed tomography, or renal scintigraphy may aid in making this diagnosis.148,149 Magnetic resonance imaging (MRI) has been used to
delineate the fluid-filled ureter and its anatomy.150 Bilateral
ectopic ureters occur in about 10% of cases, and diagnosis
frequently requires a high index of suspicion.133
If the ectopic ureter is single and beyond the continence
mechanism, the associated renal tissue frequently is nonfunctional, and the diagnosis may be rendered even more difficult
by the fact that the associated kidney itself may be ectopic
or even crossed and fused.151 Renal function may be inadequate to permit visualization by either IVP or renal scan.152
The finding of a hemitrigone at cystoscopy may lead to the
erroneous diagnosis of renal agenesis. Associated genital and
anal anomalies occur in about one third of cases,153 and may
mask the presentation of single ectopy. Ultrasound used to
detect a dilated ureter behind the bladder may be particularly
useful in this situation.154 Vaginograms carried out by occluding the introitus with a Foley balloon may show reflux into a
vaginal ectopic ureter. The ectopic ureter alternatively may be
visualized at vaginoscopy. There are cases, however, in which
exploratory surgery is required to look just above the bladder
for the ureter. When found, the ureter can be traced upward
to its associated renal unit.
Physical examination with close observation of the area
around the urethral meatus and distal vagina may reveal
a recurring drop of liquid over a very small opening that can
be probed and retrogradely injected to confirm the location
of an ectopic ureter (Fig. 26-15). The presence of an ectopic
ureter may be suggested if the bladder is filled with indigo
carminestained or methylene bluestained saline solution
via a Foley catheter, and observation of the perineum reveals
a continued slow drip of clear urine. Phenazopyridine hydrochloride (Pyridium) seems to be a better color marker excreted
by poorly functioning renal tissue than methylene blue or
indigo carmine,151 and if a cotton swab is left high in the
vagina overnight and stains orange, it suggests the diagnosis
of a vaginally ectopic ureter. Vaginoscopy with attention to the
superior lateral aspect of the vagina may reveal the vaginal
ectopic ureter. Exerting pressure on the anterior vaginal wall
may produce a jet of cloudy fluid or pus from the ectopic orifice, revealing its presence.
The surgical treatment of an ectopic ureter in a girl depends
on the associated ipsilateral renal function. A single-system
ectopic ureter to the genital system usually has poor function,
and a nephroureterectomy is appropriate, either by an open
or by a laparoscopic approach.155 With single-system ectopic
ureter to the bladder neck or urethra, the function may justify
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351
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part
than those seen in boys with bilateral single ectopic ureters.166,167 Because some urine enters the bladder in boys, it
is often of slightly larger capacity than the bladder seen in
girls. Although enough urine may enter the bladder in boys
to permit some voiding to occur, boys may also present with
incontinence.
When bilateral single ectopic ureters are present at the
bladder neck level, children may present with infection and
upper urinary tract dilation from obstruction or reflux or both,
but the bladder neck is generally better formed, and continence is more likely. When one ureter is ectopic to the urethra
and one is ectopic at the bladder neck, there is an intermediate
condition, but incontinence is usually present.137
Diagnosis of bilateral single ectopic ureters is usually
established by a carefully executed IVP and VCUG.170,171 The
associated renal units may show very poor function. The
VCUG shows a small bladder with an open bladder neck. If
the ectopic ureters are in the urethra, reflux is commonly present, and the VCUG usually makes the diagnosis. If the ureters
are further down the ectopic pathway than the urethra, they
usually are not shown by the VCUG. Ultrasound or MRI may
be useful. A retrograde flush vaginogram with a Foley balloon
occluding the introitus may similarly detect refluxing vaginally
ectopic ureters. At cystoscopy, a child with bilateral single
ectopic ureters usually is noted to have a poorly defined,
funnel-shaped bladder neck and a small bladder capacity. In
boys, the ureteral orifices are usually located in the distal bladder neck or urethra, but in girls, they may be more ectopic and
more difficult to locate.
A child who is incontinent with bilateral single ectopic
ureters presents a major challenge to reconstructive surgery. In
the case in which bladder capacity seems to be adequate, reimplantation of the ureters into the bladder and a Young-DeesLeadbetter type of reconstruction of the bladder outlet may
be appropriate.172 If bladder capacity is inadequate, it may be
feasible to turn the entire bladder into a long detrusor tube
to provide continence and to create an adequate reservoir by
augmentation cystoplasty with antirefluxing anastomoses of
the ureters to the bowel segment.173 The difficulty of creating a
continent bladder outlet in this patient population frequently
leads to eventual bladder neck closure and appendicovesicostomy to achieve continence.174
REFERENCES
For complete list of references log onto www.expertconsult.com
PART
IV
bladder
chapter
27
PATHOPHYSIOLOGY OF BLADDER
DYSFUNCTION
C. K. Yeung, G. M. Barker, and G. Lckgren
During the first few years of life, the bladder develops and
matures into a unique organ that is capable of storing urine to
be emptied in socially appropriate situations. During the filling phase, quiescence and relaxation of the detrusor smooth
muscle facilitates the unfolding and stretching of the bladder
wall in a viscoelastic manner, allowing urine to be stored at
low pressure. Involuntary urine leakage is prevented by contraction of the striated external urinary sphincter muscle. During the voiding phase, the detrusor muscle contracts as a unit
to increase the intravesical pressure, and the sphincter muscles relax, decreasing outflow resistance, allowing complete
bladder emptying.1-4 From early infancy, there is a gradual
development to an adult type of voluntary micturition control
that conforms to the social norms; this control depends on an
intact nervous system in addition to at least three other events
occurring concomitantly: (1) an increase in functional storage
capacity, (2) maturation of function of the external urinary
sphincter, and (3) achievement of volitional control over the
bladder-sphincter unit so that the child can voluntarily initiate
or inhibit a micturition reflex.4-7
The dynamics and functional disturbances of the lower
urinary tract in children are very different from those in
adults and are often associated with no identifiable anatomic
abnormalities. Also, continuous changes and evolution in
normal bladder-sphincter function occur as growth and maturation take place.8-11 Various functional derangements of the
bladder-sphincter-perineal complex may occur during this
sophisticated course of early development of normal micturition control mechanisms. Infant boys normally void with
significantly higher detrusor pressures than infant girls and
adults.8 This physiologic detrusor hypercontractility tends to
diminish and normalize after the second year of life. What
should be regarded as normal detrusor pressures in a boy a few
months old can be abnormally high for a girl of similar age or
an older boy. One type of bladder dysfunction often may progress with time and evolve imperceptibly into another, without
a sharp distinction between the different stages, and these
acquired functional disorders may overlap with other types
of bladder functional disturbances, which may have a more
organic but congenital underlying pathophysiologic basis.
Bladder-sphincter dysfunction, often manifested as urinary
incontinence, is a common condition in childhood. In a group
of 1192 otherwise healthy American children, daytime urinary
incontinence was noted in 10%, with a higher prevalence
among girls.12 In another survey of 3556 7-year-old Swedish
schoolchildren, the incidence of daytime incontinence was
6% in girls and 3.8% in boys.13 In addition, the symptom of
354
part
IV: Bladder
Brain stem
1
Sympathetic trunk
Thoracolumbar spinal cord
Sympathetic T10-L2
(hypogastric nerve)
Pelvic N.
afferents
2
Parasympathetic
(pelvic nerve)
Bladder
Pelvic N. efferents
Urethra
Innervation
Activation, coordination, and integration of various parts of the
bladder-sphincter complex involve the central somatic and the
autonomic nervous systems through three sets of peripheral
nerves: sacral parasympathetic (pelvic nerve), thoracolumbar
sympathetic (hypogastric nerves and sympathetic chain), and
sacral somatic (primarily the pudendal nerve) nerves (Fig. 27-1).2,3
Parasympathetic nerve fibers run in the pelvic nerve (from S2
to S4) to supply the pelvic and vesical plexuses before entering
the bladder. Parasympathetic ganglia are found in these plexuses and in the bladder wall. Sympathetic nerves arise from
segments T10 to L2 of the spinal cord and go to the inferior
mesenteric ganglion through the sympathetic trunk. From the
inferior mesenteric ganglion, the nerve fibers pass to the pelvic
plexus and bladder through the hypogastric nerves. There is
also sympathetic innervation originating from T10 to L2 supplying the detrusor and urethral sphincter.32 The somatic nervous
system (pudendal nerve) supplies the periurethral pelvic floor
musculature.3 All three nerves (hypogastric, pelvic, and pudendal) carry motor and sensory neurons.33 The sensory and motor
Voiding Frequency
During the last trimester, the voiding frequency of the fetus is
approximately 30 times every 24 hours.6 In the first few days
of life, voiding is usually very infrequent. Voiding frequency
increases rapidly after the first week, peaks at the age of 2 to
4 weeks (an average of once per hour), and then decreases and
subsequently stabilizes after 6 months to about 10 to 15 times
a day toward the end of the first year of life.6,11,34-37 During
the next 2 to 3 years, the voiding frequency decreases further
to about 8 to 10 voids a day, and the mean voided volume
increases by threefold to fourfold.6,11 This reduction in voiding
frequency observed during the first few years of life seems to
be related mainly to an increase in bladder capacity in parallel to body growth, which is proportionately greater than the
simultaneous increase in urine volume production.4,5,35 By age
12 years, the voiding pattern is very similar to that in an adult
and usually comprises four to six voids a day.
chapter
355
ALL CHILDREN
200
Capacity (mL)
160
120
80
40
0
10
15
Age (months)
20
25
30
Figure 27-2 Progressive increase in bladder capacity with age that can be expressed by the formula: Capacity (mL) = 30 + 2.7 age (mo). (Courtesy of CK Yeung and colleagues, unpublished data.)
356
part
IV: Bladder
FEMALE
150
120
120
MALE
150
90
60
30
0
10
15
20
25
90
60
30
0
30
Age (months)
10
15
20
25
30
Age (months)
ALL CHILDREN
150
120
90
60
30
0
10
15
20
25
30
Age (months)
C
Figure 27-3 A-C, Progressive decrease in maximal detrusor pressure during micturition (Pdet max) with age in infants and young children with
normal lower urinary tracts using natural filling cystometry in boys (A), in girls (B), and in all children (C).
BC
Pdet [cmH2O]
100
0
Pves [cmH2O]
100
0
100
Pabd [cmH2O]
1000
0
EMG1 [uV]
5s
Figure 27-4 Interrupted voiding pattern caused by detrusor-sphincter dyscoordination as revealed by urodynamic study with simultaneous
perineal electromyographic (EMG) monitoring and videocystourethrography. A, Arrows in top figure correspond to urethrograms at bottom.
B, Urinary flow starts. Premature sphincter contraction and urethral closure as evidenced by the urethrogram and increase in sphincter EMG activities lead to a sharp spike of detrusor pressure (isometric increase) associated with a paradoxical abrupt cessation of urinary flow. Urinary flow
resumes in parallel with sphincter relaxation. Repeated sphincter contraction leads to another sharp increase in detrusor pressure and paradoxical
interruption of urinary flow. Pabd, abdominal pressure; Pdet, detrusor pressure; Pves, intravesical pressure.
chapter
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IV: Bladder
Table 27-1 Terms Defined in the International Childrens Continence Society Terminology (2006)*
Bladder diary
Standard chart to be completed by the child or family, used for evaluation of bladder function and including
data regarding at least voided volumes, voiding frequency, fluid intake, nocturia, enuresis, and incontinence
episodes
Detrusor overactivity
Observation during cystometry of involuntary detrusor contractions during the filling phase; this replaces
the term detrusor instability
Detrusor-sphincter
dyssynergia
Cystometric observation of a detrusor voiding contraction concurrent with an involuntary contraction of the
urethra
Detrusor underactivity
Dysfunctional voiding
Habitual contraction of the urethral sphincter during voiding, as observed by uroflow measurements
Enuresis
Intermittent incontinence of urine while sleeping, synonymous with (intermittent) nocturnal incontinence;
the term is used regardless of whether daytime incontinence or other lower urinary tract symptoms are also
present; nocturnal may be added for extra clarity
Enuresis, monosymptomatic
Enuresis, nonmonosymptomatic
Enuresis in a child with (other) lower urinary tract symptoms, such as daytime incontinence, urgency, or
holding maneuvers
Enuresis, primary
Enuresis, secondary
Age-related expected maximum voided volume, as calculated via the formula [30 + (age in years 30)] in
mL, and used as a standard for comparisons
Frequency-volume chart
Chart to be completed by the child or family used for evaluation of bladder function, but not including all
data required of a bladder diary; see above
Incontinence, continuous
Continuous leakage of urine, not in discrete portions, which indicates malformation or iatrogenic damage
Incontinence, intermittent
Incontinence, nocturnal
See enuresis
Overactive bladder
Condition affecting patients experiencing urgency symptoms; it replaces the term bladder instability
Polyuria, nocturnal
Residual urine
Urine left in the bladder after voiding; residual urine >5-20 mL indicates incomplete bladder emptying
Underactive bladder
Condition affecting patients with low voiding frequency and the need to increase intra-abdominal pressure
to void; it replaces the term lazy bladder
Urge incontinence
Incontinence in patients experiencing urgency (i.e., incontinence in children with overactive bladder)
Voided volume
Voided volume at micturition, as documented in a bladder diary; it replaces the term bladder capacity
Largest voided volume, as documented in a bladder diary; it replaces the term functional bladder capacity
Voiding postponement
*This
table is provided as a quick reference for terms used in association with children who are investigated for lower urinary tract malfunction.
Adapted from Nevus T, von Gontard A, Hoebeke P, et al. The standardization of terminology of lower urinary tract function in children and adolescents: report
from the Standardisation Committee of the International Childrens Continence Society. J Urol. 2006;176:314.
Committee of the ICCS has published the new recommendations for a terminology for lower urinary tract function and
malfunction, and the present chapter has tried to follow these
new recommendations (Table 27-1).
Certain general principles for the new terminology62
have been used, and most importantly it has been considered that the terms to be used should be descriptive and
with a focus on the child as a growing, maturing individual.
When possible and reasonable, pediatric terminology should
follow the terminology for adults as established by the
International Continence Society.33 The new terminology
chapter
Pdet
Pves
Pabd
Pabd
Qura
Qura
Pdet
Pves
359
Pdet
Pves
EMG
EMG
Pdet
Pabd
Pves
Pabd
Qura
Qura
EMG
EMG
Leak
Figure 27-5 Various bladder functional patterns. A, Dyssynergic pattern with an increase in sphincter electromyogram (EMG) activities dur-
ing micturition (arrow), leading to an interrupted urinary flow. B, Overactive bladder, characterized by frequent unstable detrusor contractions
(arrows) during the filling phase. C, Normal female micturition pattern; note the pelvic floor relaxation as evidenced by a decrease in abdominal
pressure during micturition. D, Bladder with low (poor) compliance as evidenced by a rapid increase in intravesical pressure during filling, often
associated with urinary leakage (arrows). Pabd, abdominal pressure; Pdet, detrusor pressure; Pves, intravesical pressure; Qura, uroflow.
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IV: Bladder
Urinary Incontinence
Urinary incontinence can be defined as the involuntary loss
of urine, owing to a failure of control of the bladder-sphincter
unit, that is frequent enough to constitute a social or hygienic
problem, and occurs in the absence of underlying anatomic
causes.23 Apart from urge incontinence that is associated with
detrusor overactivity and urge syndrome as described earlier,
other forms of functional urinary incontinence exist as a result
of failure of the bladder storage or sphincter control mechanisms, or both. Stress incontinence represents the involuntary
leakage of urine occurring at times when the intravesical
pressure exceeds the bladder outlet or urethral resistance, in
the absence of measurable detrusor contraction. In contrast
to the situation in adults and particularly in elderly women,
true stress incontinence is rare in children and is generally
not associated with any demonstrable urodynamic abnormalities. It is likely that this condition may represent a mild
form of bladder overactivity, with small unstable detrusor
contractions appearing only on provocation or at times of
increased intra-abdominal pressure. Insufficient bladder outlet or urethral resistance is usually not a main factor. Because
the amount of urine leakage in most patients is usually small,
the incontinence may sometimes be only scarcely discernible.
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361
syndrome, to describe a presumably acquired form of bladdersphincter dysfunction in children characterized by a combination of bladder decompensation with incontinence, poor
emptying, and recurrent UTIs.80-83 Most children also have
significant bowel dysfunctions, including encopresis, constipation, and fecal impaction. In British literature, the condition
is often referred to as occult neuropathic bladder after the article
by Williams and associates.84 The condition has all the clinical
and urodynamic features typical of neuropathic bladder dysfunctions, but no neurologic abnormality can be shown.
It was initially hypothesized by Hinman and Baumann80
that the condition could be ascribed to acquired psychologically abnormal behavior with voluntary incoordination
between the detrusor muscle and the pelvic floorexternal
urethral sphincter complex during voiding. They supported
their theory with a group of 13 boys having significant personality problems evidenced by anxiety, depression, and timidity. All these patients responded to a program of short-term
anticholinergic medication, fecal disimpaction, counseling,
and hypnotic suggestion therapy.80,81,85 This notion has not
received strong support from later studies, however.
Controversies still exist about whether a very subtle or
occult spinal abnormality can occur to account for an isolated bladder neuropathy in a child who does not exhibit
other somatic neurologic deficits and has normal magnetic
resonance imaging of the spinal cord. Urodynamic studies
often revealed marked sphincter overactivity and abrupt contractions of the pelvic floor as the child attempted to control
incontinence from uninhibited bladder contractions. In its
severe form, the vesicosphincter dyssynergia can cause fullblown bladder decompensation with day-and-night wetting,
large postmicturition residues, recurrent UTIs, and significant
damage to the upper tracts.80-86 Imaging studies often reveal
profound changes in the urinary tracts, with about two thirds
of the children developing hydroureteronephrosis, and more
than half having VUR. Nearly every patient has a grossly trabeculated, large-capacity bladder with a large postmicturition
residual urine.
The condition probably represents an extreme end stage
of detrusor-sphincter incoordination or dysfunctional voiding, most probably secondary to a subtle or occult organic
neuropathy, although in some children an element of emotional disturbance may superimpose to interfere with normal
voiding and complicate the issue further. It is conceivable that
the bladder could decompensate, with its detrusor muscle
losing contractility after long-standing functional outflow
obstruction owing to sphincter overactivity, whether on an
organic neuropathic or a behavioral basis, resulting in chronic
distention with a large capacity and poor emptying efficiency.
Treatment is control of infection and restoration of normal
bladder storage and emptying functions.
Because of the similarities to neuropathic bladder dysfunction, the management strategy in these children generally follows very similar principles for the former condition. Standard
urotherapy includes bladder retraining, pharmacologic bladder manipulation to target specific urodynamic abnormalities,
and improvement of bowel function, especially the avoidance
of severe constipation and fecal impaction; all have been
shown to be effective. Biofeedback has also been reported to
achieve good results.87,88 In a multicenter prospective study
in more than 200 children with non-neuropathic bladdersphincter dysfunction reported in 2000 by Van Gool and associates89 on behalf of the European Bladder Dysfunction Study
Group, there were no statistically significant differences,
however, in outcome between bladder rehabilitation with
biofeedback and standard urotherapy. This disparity probably highlights the heterogeneity of the condition and further
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IV: Bladder
chapter
Structural Abnormalities
Structural abnormalities include congenital conditions (e.g.,
bladder exstrophy, epispadias, cloacal anomaly, ureteroceles,
posterior urethral valves and other urethral anomalies, prunebelly syndrome) and acquired conditions (e.g., traumatic stricture or damage to the sphincter or urethra).
NEUROPATHIC BLADDER-SPHINCTER
DYSFUNCTION
Dysfunction of the lower urinary tract resulting from an identifiable neurologic lesion constitutes a significant proportion
of the clinical problems seen in pediatric urology.110 In principle, any lesion that interferes with the afferent or efferent
pathways between the bladder and the higher centers can
result in neuropathic bladder-sphincter dysfunction. In contrast to in adults, however, most neuropathic bladder dysfunctions in infants and children are due to abnormal spinal
column development, or myelodysplasia, and are very rarely
caused by trauma or other disease conditions.22,111 Other associated conditions include spinal dysraphism (including lipomeningocele, diastomyelia, dermoid cyst, or lipoma of the
spinal cord with tethering of the filum terminale) and sacral
agenesis.
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IV: Bladder
Detrusor-Sphincter Dyssynergy
Detrusor-sphincter dyssynergy is a major problem in children with myelomeningoceles and occurs when the external
sphincter fails to relax or increases its activity during a detrusor contraction.122 As described earlier in this chapter, some
degree of detrusor-sphincter incoordination, which is associated with high voiding pressure and interruption of flow but
with no impairment of overall bladder emptying, can be seen
even in healthy infants during the first year of life.8,16,34,43,44 In
children with neuropathic bladder, the detrusor-sphincter dyssynergia manifests in a much more pronounced manner, and
together with pelvic floor overactivity may produce significant functional outflow obstruction, leading to elevated intravesical pressure, upper tract dilation, high-pressure VUR, and
incomplete bladder emptying. This obstruction predisposes to
recurrent UTI, and together the adverse hydrodynamic factors
and infections can cause substantial damage to the upper tract
within a short time.122,123
When bladder outlet resistance is chronically increased
because of sphincter dyssynergia, bladder compliance is likely
to decrease as a result of detrusor overactivity and progressive
collagen deposition, which can occur alone or in combination.124 This situation results in a small, contracted, poorly
compliant bladder with continuously elevated intravesical
pressures during filling and emptying. The decreased compliance not only may lead to increasing incontinence, but also
may produce a considerable degree of functional obstruction
to upper tract drainage and can be of crucial importance in the
predisposition to renal functional impairment. Bladder emptying may be maintained by progressive compensatory detrusor hypertrophy and overactivity until the detrusor muscle
becomes fatigued, and bladder decompensation occurs. The
bladder then loses its contractility, increases substantially in
capacity, and fails to empty. Urinary retention occurs, and the
resulting residual urine predisposes to recurrent infections if
artificial emptying by clean intermittent catheterization is not
implemented. The combination of high intravesical pressures,
chapter
365
CONCLUSION
REFERENCES
Despite extensive clinical and animal research, the exact neurologic mechanisms of the development of micturition control from newborn to infancy and later childhood, and the
CHAPTER
28
EPIDEMIOLOGY
Symptoms typical of functional bladder disturbances, such as
postponement of voiding, urgency, and leakage of urine, have
been shown to be common even in healthy children before age
5 to 6 years, but not on a daily basis.1,2 From this point of view,
age 7 is an appropriate time for the investigation of prevalence
of functional non-neurogenic bladder disturbances. Most epidemiologic studies do not look specifically at the different
diagnoses associated with functional disturbances, such as
366
overactive bladder (OAB), dysfunctional voiding, and postponement of voiding, but investigate only the prevalence of
urinary incontinence. From the studies available, it is difficult
to draw conclusions about the prevalence of urinary incontinence because different studies use different definitions and
criteria. Examples of the latter are variation in frequency of
incontinence episodes and inclusion of daytime incontinence
only or daytime and nighttime incontinence.
The mean prevalence of daytime wetting at age 7 years
for all children is approximately 4.5% (range 3.2% to 6.7%),
according to cross-sectional studies.3,4 When only children
with frequent episodes of urinary incontinencemore than
once a weekare included, the corresponding figure is 2.5%.
For children 15 to 17 years old, the mean for all kinds of daytime wetting is 2% (range 1.2% to 3%); the mean for children
at this age with more than one episode a week is only 0.3%.5,6
The spontaneous and treated cure rate is approximately 6%
per year, including all daytime wetting, and the corresponding figure for children with frequent wetting is 9%.
All functional urinary incontinence is more common in
girls in all age groups. From the prevalences found in different
studies, it can be assumed that incontinence is 1.5 times more
common in girls than in boys at age 7 years. At age 16, the
difference is even more pronounced, with incontinence 5 to
10 times more common in girls.
Risk factors for functional voiding disorders are listed in
Table 28-1. A positive family history has been reported to
increase the risk of daytime incontinence.2,7 Psychopathology
has also been shown to be a risk factor. Lettgren and associates8
have found significant increases in attention problems and delinquent behavior to be associated with a certain type of daytime
wetting in children (voiding postponement) using the Child
Behavior Checklist. Minor neurologic dysfunctions, such as
attention-deficit/hyperactivity disorder, carry an increased risk
of daytime incontinence by a factor of 9.9 Children with mental
developmental delay or retardation are also at increased risk.
EVALUATION
The initial evaluation of children with daytime voiding disorders should include voiding and bowel history taking, physical examination, urinalysis, a bladder diary, and in most cases
urinary flow and residual urine evaluation using ultrasound,
and quantification of urine loss (Table 28-2). These noninvasive measures often provide insights enabling the clinician to
categorize the childs urinary problems in a way that allows
for a preliminary diagnosis and management. In a few incontinent children, these noninvasive assessments yield uncertain
results, or results suggesting deviations from normal function.
In these situations, invasive investigations, such as voiding
cystourethrography (VCUG), invasive urodynamics, renal
scans, urography, and cystourethroscopy, are indicated.
chapter
28: Pragmatic Approach to the Evaluation and Management of Non-neuropathic Daytime Voiding Disorders
Voiding Disorders
Family history
Sociocultural factors
Physical examination
Psychopathology
Urinalysis
Bladder diary
Developmental delay
Sexual abuse
History
For the pediatric age group, the history is obtained jointly from
parents and child. The history should include a general health
history and a specific voiding history. The general history
should include questions of relevance to familial disorders,
neurologic and congenital abnormalities, and relevant surgery
and menstrual and sexual functions (in pubertal and older
children). Information about urinary tract infections (UTIs) is
also important, as are any previous problems related to the
urinary tract, such as vesicoureteral reflux (VUR).
A validated questionnaire is a very useful tool in taking
a voiding history, and in structuring the history taking or at
least providing a checklist (Fig. 28-1). If possible, the child
should be addressed as the patient and questioned directly, to
elucidate what symptoms are most problematic for the child.
Information about onset (primary or secondary) of the
problems should be obtained. Failed prior treatment attempts
should be noted. Voiding frequency and voided volumes must
be determined. To be able to count the number of voids, it is
recommended that the voiding be related to special routines:
Do you void directly after getting up in the morning? Do
you void during school hours? For correct information about
frequency and volume of voiding, however, a bladder diary is
mandatory in addition to the verbal assessment.
Incontinence episodes during the day and night should also
be estimated: How often? How much (a few drops, damp or
wet underwear, need to change, use pads)? When does the
leakage occur? Does it occur together with urgency attacks?
Does it occur with giggling? Is it unrelated to such events? At
what time of the day does it occur? Urgency attacks and holding maneuvers, such as squatting, crossing ones legs, or standing on tiptoes, should be noted. Voiding symptoms, such as
hesitancy, staining, and weak or intermittent stream, should also
be recorded in the voiding history.
History taking should include assessment of bowel function.
A similar proactive process using a questionnaire should be
followed for defecation and fecal soiling. Stool habits, including interval, size, and consistency, should be investigated. Is
there soiling, how often, and in what situations? Have any
medications been used to treat bowel function?
Physical Examination
In addition to a general pediatric examination, the physical
examination should include the assessment of perineal sensation, the perineal reflexes from the sacral segments S1-S4
(standing on toes, bulbocavernosus), and anal sphincter tone
and control. Special attention should be paid to inspection
of the genital region and of the urethral meatus. Asymmetry of buttocks, legs, or feet, and other signs of occult spinal
dysraphism in the lumbosacral area (subcutaneous lipoma,
367
Urinalysis
Urinalysis with a dipstick is essential to exclude infection, glucosuria, and proteinuria. Although urinalysis can be helpful in
signaling infection, UTI can reliably be excluded only with a
urine culture.
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part
IV: Bladder
VOIDING HISTORY
Name
Date of birth
Date
Holding
Awareness of need
Daily
Once a day
No
Hold pattern
Daily
Once a day
No
Need to be reminded
Daily
Once a day
No
Urgency
Daily
Once a day
No
Holding maneuvers
Daily
Once a day
No
Void at school
Daily
Once a day
No
Daily
Once a night
No
Starting difficulties
Daily
Once a day
No
Straining
Daily
Once a day
No
Daily
Once a day
No
Position
Sitting
Yes
No
Urinary stream
Ample
Thin
Pain
Daily
Emptying
Varies
No
Once a day
When
Start
During
After
Where
Bladder
Urethra/
meatus
Flank/
back
How
Smarting
Pain
Spasm
No
Cy
Py
ABU
Urinary tract
infection
Bowel function
Bowel movements
Daily or
every other day
Consistency according
to Bristol scale
3 times a week
Laxatives
Fecal incontinence
Daily
Once/week
Soiling
Once a day
No
Encopresis
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28: Pragmatic Approach to the Evaluation and Management of Non-neuropathic Daytime Voiding Disorders
Incontinence (daytime)
Incontinence?
Yes
No
Type
Primary
Secondary
When
At urge
At giggle
At stress
Unknown reason
Drop
Small spot
Large spot
All
Once a day
1 once a week
How
How often
Once a month
Earlier treatments?
Yes
No
What
Regimen
Detrusor relaxant
Other
Treatment efficacy
Improved
Good
Bad
Heredity
Parents/siblings
No
Incontinence (night/enuresis)
Incontinence?
Yes
No
Type
Primary
Secondary
How
Small spot
Everything
How often
Once a night
Once a week
Once a month
Arousal
When voiding
Afterwards
Yes
No
What
Alarm
Desmopressin
Regimen
Detrusor relaxant
Good
Improved
Treatment efficacy
Bad
Number of dry nights
(no/2 weeks)
Heredity
Parents/siblings
No
Voiding diary
Number of voidings (mean)
no/day
mL
Shortest interval
no/day
mL
mL/day
mL
mL
Residual-flow measurement
Flow curve
Bell/tower
Staccato
Plateau
Interrupted
Voided volume
mL
Flow time
sec
MaxQ
mL/sec
Residual urine
mL
Suggested treatment
Regimen
CIC
Enuresis alarm
Desmopressin
Detrusor relaxant
TENS
Biofeedback
Other treatment
369
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part
IV: Bladder
Bowel movements
Diagnosis and successful management of most pediatric patients with daytime voiding problems do not require
invasive diagnostic studies. Whether invasive diagnostic procedures are necessary is decided by the results of the
noninvasive procedures. Invasive procedures should be used
only if the outcome would influence management. Symptoms
indicating a need for further diagnostic procedures are voiding frequency of three or fewer voids per day, straining, weak
urinary stream, previous febrile UTI, continuous dribbling
incontinence, or previously identified VUR. Findings that
suggest a need for invasive diagnostic techniques are signs
of occult spinal dysraphism at physical examination, a plateau-shaped flow curve typical for structural bladder outlet
obstruction, intermittent flow suggesting detrusor-sphincter
dyscoordination, a clinically significant postvoid residual at
repeated occasions, and continence test indicating continuous dribbling. Invasive diagnostic techniques are indicated
when noninvasive procedures raise suspicion of neurogenic
detrusor-sphincter dysfunction, obstruction (posterior urethral valves), genitourinary abnormalities (e.g., epispadias,
ectopic ureter in girls), advanced non-neurogenic detrusorsphincter dysfunction (dilating VUR or febrile UTI or both), or
significant postvoid residuals.
Urinary Flow
Voiding should be analyzed in detail in all children with daytime incontinence. The investigation is mainly used as a diagnostic instrument, but also can be used in treatment (e.g., as
flow biofeedback). Registration of the urinary flow rate during voiding is becoming a standard office procedure. In these
cases, measurement of urinary flow is done as a noninvasive
procedure with filling of the bladder by diuresis (spontaneous or forced by instructions of standardized excessive drinking). Flow patterns and rates should be repeated if abnormal
because sometimes several recordings are needed to obtain
consistency.
A bell-shaped flow curve is present in 99% of healthy children.11 If the voided volume is less than 50% of the expected
capacity, the flow curve can be bell-shaped even if there is an
obstruction because a small volume creates a low maximal
flow, but with a bell-shaped curve. The voided volume must
be more than 50% of expected capacity for a urinary flow
examination to be reliable. Another suggested rule is that the
square of the maximal flow should exceed the voided volume.12 Otherwise, the volume may be too low, or there may
be an obstruction.
Urinary flow may be described in terms of rate and pattern,
and may be continuous, intermittent (fractionated), or staccato. An intermittent flow pattern shows interruption of the
flow curve, whereas in staccato voiding the flow does not stop
completely, but fluctuates because of incomplete relaxation
of the sphincter. The parameters of interest in a urinary flow
investigation are pattern of the curve, voided volume, maximal flow rate, and voiding time (Table 28-5). For illustrations
of the different flow curves, see Chapter 9.
Voiding Cystourethrography
VCUG is indicated in children with recurrent UTIs to detect
reflux and in children with an abnormal flow pattern to detect
bladder outlet abnormalities (e.g., valves, strictures). In children with non-neurogenic detrusor-sphincter dysfunction and
in children with the same dysfunction but of neurogenic origin, the proximal urethra may show a spinning top configuration during filling or voiding. With detrusor and pelvic floor
muscles contracting at the same time, the detrusor contraction
dilates the proximal urethra down to the level of the forcefully
closed external sphincter.15
Urodynamics
The identification or exclusion of postvoid residual is an integral part of the study of micturition. Residual urine is usually
assessed with ultrasound after uroflow measurement. Healthy
children after toilet training age empty their bladders completely
with each voiding. The inevitable delay of a few minutes after
finishing voiding until an ultrasound calculation can be made
would result in the bladder refilling with up to 5 mL, which is
the upper value of residual accepted as completely normal. In
case of a longer time delay, this can be compensated for by subtracting 1 to 2 mL from the measured residual for every minute
beyond 5. A range of 5 to 20 mL may be associated with insufficient emptying, but can also be occasional, and in these cases
the investigation must be repeated. More than 20 mL of residual
on repetitive occasions indicates abnormal emptying.
It is sufficient to use a bladder scanner when investigating older children, in whom higher residual volumes can be
expected. In infants and young children, however, in whom
chapter
Time
Voiding Time
Drinks
Volume/mL Dry/Wet (mL)
Date
Bowels
Voiding Time
Volume/mL
Dry/Wet
Drinks
(mL) Bowels
Time
Date
Time
Night
Night
Night
05 a.m.
05 a.m.
05 a.m.
06 a.m.
06 a.m.
06 a.m.
07 a.m.
07 a.m.
07 a.m.
08 a.m.
08 a.m.
08 a.m.
09 a.m.
09 a.m.
09 a.m.
10 a.m.
10 a.m.
10 a.m.
11 a.m.
11 a.m.
11 a.m.
12 p.m.
12 p.m.
12 p.m.
01 p.m.
01 p.m.
01 p.m.
02 p.m.
02 p.m.
02 p.m.
03 p.m.
03 p.m.
03 p.m.
04 p.m.
04 p.m.
04 p.m.
05 p.m.
05 p.m.
05 p.m.
06 p.m.
06 p.m.
06 p.m.
07 p.m.
07 p.m.
07 p.m.
08 p.m.
08 p.m.
08 p.m.
09 p.m.
09 p.m.
09 p.m.
10 p.m.
10 p.m.
10 p.m.
11 p.m.
11 p.m.
11 p.m.
Voiding Time
Volume/mL
Dry/Wet
Drinks
(mL)
Bowels
28: Pragmatic Approach to the Evaluation and Management of Non-neuropathic Daytime Voiding Disorders
Date
371
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IV: Bladder
12-HOUR CONTINENCE TEST
Date:
1. Empty the bladder in the morning and measure the volume.
2. Take pad no 1. Then use them in order, 212.
3. Change the pad every hour and put it in its plastic bag; seal carefully.
4. Record intakes, roughly.
5. Once during the afternoon you should drink extra (about 300 mL).
6. Try to do what you want to do and do not avoid situations when you usually leak.
7. Mail the package or deliver it yourself to the hospital within 2 days.
Time
Pad
No.
Weight
Void. Vol.
(mL)
Food
Drinks
Activities of Importance
for Leakage
1
2
3
4
5
6
7
8
9
10
11
12
Extra drink
Urine vol.
mL
mL
Time
Time
Total leakage
Largest leakage
No. of leakages
Total voided volume
Largest voided volume
No. of micturitions
Drink provocation
Total fluid intake
only. Symptoms that might be an indication for such a problem, possibly of non-neurogenic or neurogenic origin, are
straining at voiding, fewer than three voids a day, fractionated
flow curve, or high postvoid residual. In children with recurrent UTI and daytime voiding symptoms, the recommended
VCUG sometimes shows increased bladder wall thickness
and trabeculation, which is also an indication for urodynamic
studies.
The most important indication is probably in patients in
whom conventional treatment of daytime voiding disorders
is unsuccessful. Even if the investigation only confirms the
diagnosis from the noninvasive studies, it is often reassuring
for the patient and the parents. The cystometric curve also can
be used to help the child understand better what happens in
the bladder, as a biofeedback lesson.
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28: Pragmatic Approach to the Evaluation and Management of Non-neuropathic Daytime Voiding Disorders
373
Fractionated or intermittent
Obstructed
Bowel Regimen
Overt constipation should be dealt with before embarking on
treatment of incontinence or detrusor-sphincter dysfunction. If
history indicates fecal retention, or if there is soiling, treatment
should be instituted for achievement of normal bowel habits
before starting treatment of urinary incontinence. The regimen
should include the following:
Explanation of soiling
Toileting program
Diet and fluid intake
Laxatives
In 95% of cases, soiling is attributable to fecal retention,
which should be explained to the patient and the parents. This
often is a relief to the child because this connection has not
earlier been believed.17 Establishing a normal, regular pattern
of bowel evacuation is a key to eventual success for children
with soiling. Charts should be used.
A well-balanced diet with reasonable fiber intake is likely
to be helpful. Excessive consumption of milk should be prohibited, and the overall fluid intake should be increased.
There is a general consensus that children with constipation and overflow soiling require laxative treatment, with
the aim of evacuating retained stool and maintaining regular
bowel activity. Over the last few years, osmotic laxative treatment with macrogols (polyethylene glycol variations, with
Standard Urotherapy
Standard urotherapy is a first step in most cases of non-neurogenic
daytime voiding disorders. It includes the following:
Education regarding the function of the bladder and
sphincter mechanism (information and demystification)
Instructions on proper voiding position
Instructions on a voiding regimen promoting regular
voiding habits
Lifestyle advice (e.g., fluid intake, constipation)
Bladder diaries
Support and encouragement
Treatment of UTI, and antibiotic prophylaxis in children
with recurrent infections
The first step is a dialogue between the child and the
therapist about normal bladder function and about the
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IV: Bladder
Additional Therapies
Biofeedback
Biofeedback is often used in conjunction with a comprehensive
rehabilitation program. It is a technique in which physiologic
activity is conveyed to the patient as visual or acoustic signals,
providing the patient with information about physiologic
processes. Biofeedback may be used for the management of
filling (detrusor overactivity) and voiding (dysfunctional voiding owing to pelvic floor muscle overactivity) phase abnormalities. In relation to the filling phase, it can help the child to
recognize involuntary detrusor contractions, and in relation to
the voiding phase, it can help the child to identify how to relax
the pelvic floor muscles.
Biofeedback may be performed using a cystometrogram
for children with involuntary detrusor contractions. In this situation, the child is taught how to recognize early and inhibit
involuntary detrusor contractions, by watching the pressure
curve during cystometry. When an involuntary contraction
occurs, the child is encouraged to try consciously to suppress
the contraction. This form of biofeedback is invasive and
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28: Pragmatic Approach to the Evaluation and Management of Non-neuropathic Daytime Voiding Disorders
Neuromodulation
Neuromodulation has been used in adults for various lower
urinary tract symptoms. The invasive nature of the procedure
(stimulation via anal or genital probe or via urethral catheter)
makes it less attractive for children. Some studies report favorable effects in children, however. In OAB, stimulation of inhibitory pathways via an anal probe has been used,24 and in the
underactive bladder, the detrusor has been activated through
intravesical stimulation.25
One technique that is easy to apply is transcutaneous
electrical nerve stimulation with surface electrodes, aiming to
stimulate the inhibitory nerves to the bladder via cutaneous
stimulation over the sacral root (S3). Promising results have
been shown in a few studies,26 but no controlled studies are
available. The technique has mainly been used in children in
whom other treatment modalities have failed.
Pharmacotherapy
Anticholinergic Drugs
Antimuscarinic therapy remains one of the more common
forms of therapy for OAB. It is based on the concept that
parasympathetic blockade of muscarinic receptors inhibits activity in the bladder detrusor and is beneficial in the
treatment of overactivity. Such agents have also been shown
to increase bladder capacity, increase bladder compliance
375
Botulinum Toxin
Botulinum toxin type A is currently used in children mainly
with neurogenic detrusor overactivity, but has also been used
for non-neurogenic OAB.32 The initial results seem promising.
In the study by Hoebeke and coworkers,32 100 IU were injected
in the detrusor. The results lasted at least 12 months in most of
the patients. Injection into the external sphincter is also possible in cases with pelvic floor overactivity. Results from a study
with botulinum toxin type A in non-neurogenic conditions in
children have been published more recently, with good but
transient results.33 The use of botulinum toxin type A in the
non-neurogenic bladder regarding OAB and dysfunctional
voiding has to be studied further before recommendations
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part
IV: Bladder
Antibiotics
All children with symptomatic UTI require appropriate antibiotic therapy. If a child has an underlying voiding disorder
associated with recurrent UTIs, prophylactic antibiotic therapy
is recommended during the training period. Trimethoprimsulfamethoxazole, nitrofurantoin, and trimethoprim alone
have proven to be successful for antibiotic prophylaxis.
SPECIFIC CONDITIONS
The classification of the non-neurogenic daytime voiding disorders in Table 28-7 is according to the International Childrens
Continence Society Standardisation Committee document34
and is in line with what is suggested in Chapter 27; for more
information about the different conditions, see that chapter.
With the noninvasive diagnostic tools discussed earlier, most
of these conditions can be diagnosed to such an extent that
treatment can be started without invasive diagnostic studies.
In the case of no or poor response to the treatment, invasive
diagnostic investigations might be warranted.
Overactive Bladder
The term overactive bladder is used to describe the symptom
complex of urgency, with or without incontinence and frequent voiding (more than seven times a day), with overactive
Table 28-7 Classification of Non-neuropathic
Table 28-8 Symptoms and Findings in Overactive Bladder, Dysfunctional Voiding, and Voiding Postponement
Symptoms
Overactive Bladder/Urge
Syndrome
Dysfunctional Voiding
Voiding Postponement
Frequency
>7/day
Varying
<5/day
Urgency
Yes
Yes
Incontinence
Varying, decrease
Urge incontinence
Uroflowmetry
May be tower-shaped
Staccato/interrupted
Normal or staccato
Postvoid residual
Usually <20 mL
Varying
Presenting symptoms
Recurrent UTI/incontinence
Incontinence, holding
aneuvers
m
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28: Pragmatic Approach to the Evaluation and Management of Non-neuropathic Daytime Voiding Disorders
Voiding Postponement
In voiding postponement, children postpone imminent micturition until overwhelmed by urgency, which makes them rush
to the toilet, but often they are too late, and urge incontinence
occurs. It has been suggested that the strong sphincter activity in voiding postponement is a behavioral maladjustment,
and not a primary bladder/sphincter dysfunction.8 Traditionally, this syndrome was thought to be an acquired disorder
attributable to detrusor overactivity and caused by voluntary
overactivity of the urethral sphincter until the bladder became
filled.
A typical history includes urgency and incontinence with
holding maneuvers, postponement of voiding, and quite a
few micturitions per day (see Table 28-8). In the most benign
cases, uroflow is often normal, and emptying is complete. In
others, postvoid residual might be increased. No invasive
investigations are recommended in the initial phase.
Treatment should start with standard urotherapy with
the institution of a timed voiding schedule every 3 hours.
Children are encouraged to go to the toilet even if they do not
feel any need. This treatment is usually the only one needed
for improvement.
Dysfunctional Voiding
Dysfunctional voiding refers to overactivity in the external
sphincter or the pelvic floor during voiding, often with incomplete emptying as a result. The overactivity can be seen either
as a staccato flow pattern caused by periodic bursts of pelvic
Treat constipation
Treat constipation
Anticholinergic drugs
Flow-EMG biofeedback
377
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part
IV: Bladder
Underactive Detrusor
The previous term for the rarely seen condition of underactive
detrusor was lazy bladder. It is considered to be the result of
dysfunctional voiding, but there are no data that support this.
A child can qualify for the diagnosis only after examination
with invasive urodynamics, to prove that detrusor activity is
more or less absent during voiding, detrusor activity is driven
by straining, and bladder capacity is high. The symptoms are
low voiding frequency, straining and intermittent flow at voiding, recurrent UTI, incontinence, and often constipation.
Treatment of these children is aimed at improving bladder
emptying, and clean intermittent self-catheterization is the
procedure of choice. Intravesical electrostimulation has been
described, but it is not yet recommended as a routine procedure for children.20
Giggle Incontinence
In some children, giggling can trigger partial or complete
bladder emptying well into their teenage years and sometimes
into adulthood.40 Typically, the patient does not experience
any other lower urinary tract symptoms, such as incontinence
during the day or night. The etiology is unknown, but it has
been suggested that laughter triggers the micturition reflex via
central mechanisms in such a way that the central inhibition
is blocked.
No simple treatment is available. One way to describe the
problem is as OAB triggered by giggling. Standard therapy
can be useful together with pelvic floor muscle exercises to
strengthen awareness of the muscles, to provide an emergency brake. Central nervous system stimulatory drugs, such
as methylphenidate, have been reported to have good effects.
Treatment with central nervous systemstimulating drugs
should be done very selectively, however, because of the
addictive nature of these drugs.41
Elimination Syndrome
The term elimination syndrome is used to designate nonneurogenic voiding disturbances seen together with bowel
dysfunction (i.e., when there is a dysfunction of emptying of
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28: Pragmatic Approach to the Evaluation and Management of Non-neuropathic Daytime Voiding Disorders
Urethral Obstruction
In a boy with daytime voiding problems in whom uroflow
metry shows an obstructive flow curve in repeated assessments, VCUG should be performed to rule out an anatomic
obstruction in the urethra, such as posterior urethral valve,
strictures, and syringocele.
Urinary Retention
Urinary retention in sometimes seen in children, often
younger than 4 or 5 years old, who void infrequently, usually
in combination with voiding postponement and constipation.
Important structural differential diagnoses may explain the
retention, however, indicating prostatic rhabdomyosarcoma
379
Sexual Abuse
Sexual abuse is defined as imposed sexual activity. Some have
suggested that 25% of girls and 10% of boys have been sexually abused before age 16.42 Often there is a sudden change in
behavior. Regression can be seen in preschool children with
development of enuresis; they start to suck their thumbs,
use baby talk, and are afraid of sleeping alone. In school-age
children, signs such as sleep difficulties, phobias, and acting out sexually are seen. The most common symptoms are
psychosomatic complaints, such as voiding problems, headache, and stomachache. History taking is important in these
cases.
Clinicians who evaluate voiding disorders must always
bear the possibility of sexual abuse in mind as an underlying cause of secondary voiding dysfunction, particularly in
older children. A question about sexual abuse can be included in a structured voiding history. Asking does not mean
suspecting. Because the media is very attentive to stories
about sexual abuse, parents can understand why you are
asking. In the physical examination situation, there can be
a question about other physical examinations of the child or
touching of the genitalia. One can expect a prompt answer,
but the question may also provoke thoughts. If sexual abuse
is suspected, there are standards regarding how to handle
the situation.
Epispadias in Girls
Continuous leakage of urine in a girl may be attributable to
isolated epispadias anomaly. This diagnosis can often be made
with a thorough examination of the region of the urethral
meatus.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
29
NOCTURNAL ENURESIS
Tryggve Nevus and Arne Stenberg
DEFINITIONS
According to the new International Childrens Continence
Society guidelines for lower urinary tract terminology,1 which
are consistently adhered to in this chapter, enuresis is synonymous to nocturnal incontinence and means involuntary voiding while asleep in a child 5 years old or older. Bed-wetting
is called enuresis (or nocturnal enuresis for clarity) regardless
of whether the voids are complete and urologically normal or
not, and regardless of whether or not the child also has daytime incontinence. The only kind of bed-wetting that is not
included in the term is the continuous incontinence affecting
children with urogenital malformations or iatrogenic sphincter damage.
Secondary enuresis denotes bed-wetting in a child who
has previously been dry for at least 6 months, whereas primary enuresis denotes that no such intervening period of dryness has occurred. Enuresis without any other concomitant
lower urinary tract symptoms, such as daytime incontinence,
urgency, or interrupted stream, is called monosymptomatic
enuresis. According to earlier terminology, monosymptomatic
enuresis denoted only enuresis without daytime incontinence.
In accordance with the International Childrens Continence
Society and International Continence Society guidelines, we
use the term voided volumes instead of bladder capacity when
discussing bladder volumes.
EPIDEMIOLOGY
Enuresis is a common condition. If a wetting frequency of at
least one wet night per month is taken into account, the
prevalence is probably greater than 10% among 6-year-olds,2
around 5% among 10-year-olds,3,4 and 0.5% to 1% among teenagers and young adults.5 The natural history of enuresis is difficult to assess, but a spontaneous cure rate of 15% per year is
often quoted.6
Enuresis without daytime incontinence is 1.5 to 2 times
more common in boys than girls.2,3,7 In children with combined daytime and nighttime wetting and in adults, no such
380
GENETICS
Enuresis has long been known to be strongly influenced by
hereditary factors, as shown by twin studies8 and numerous
epidemiologic surveys.3,9-13 The recurrence risk for a child to
be affected by enuresis is 40% if one parent and 70% if both
parents had been enuretic.14 Several different enuresis genes
have been found.15 In a more recent study on a large group of
children with different kinds of enuresis (i.e., monosymptomatic nocturnal enuresis, combined enuresis and incontinence,
primary enuresis, and secondary enuresis), it was found, however, that there was no clear correspondence between phenotype (subtype of enuresis) and genotype.16
PATHOGENESIS
Nocturnal Polyuria
The discovery that many enuretic children have an exaggerated nocturnal urine production has justly been considered the
starting point of modern enuresis research. It was shown that
this group of children lacked the physiologic nocturnal peak
of the antidiuretic neurohypophyseal hormone vasopressin
secretion, and consequently had a nocturnal urine production exceeding the amount that their bladders could hold.17,18
This finding has since been repeated19-21 and contradicted.22-25
A contributing explanation for the conflicting results could
be the fact that vasopressin is released in a pulsatile fashion,26
and accurate assessment of circadian profiles would call for
measurements every 15 minutes or so. It has also been shown
that the polyuria of some enuretic children is not caused by
vasopressin deficiency.21,27
Another problem with the polyuria hypothesis is the finding that nocturnal polyuria is not a phenomenon exclusive to
bed wetters. It has been shown that approximately 10% of dry
children produce more urine during the night than during the
day.28 The fact that nocturia is a common phenomenon among
dry children3,7 indicates that nocturnal polyuria may be common as well.
Even with these objections taken in consideration, it is
generally agreed that nocturnal polyuria is common among
enuretic children, and that vasopressin deficiency may be
causing this polyuria at least in some of them. All bed-wetting
children do not have polyuria, however. The polyuria hypothesis does not explain why the children do not wake up to
void.
Detrusor Overactivity
Because of the great overlap between the groups of bedwetting and daytime incontinent children,2,3,5,7,10 and the
prominent role of detrusor overactivity in the pathogenesis of
the latter condition, detrusor overactivity has been implicated
as a pathogenic factor in nocturnal enuresis as well. Sleep
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381
382
part
IV: Bladder
The alarm may help
Nocturnal
polyuria
Detrusor
overactivity
Daytime
incontinence
Nocturia
Enuresis
Enuresis
Diuresisdependent
enuresis
Desmopressin
helps
Urgency
Enuresis
Sound,
undisturbed
sleep
High arousal threshold
Detrusordependent
enuresis
Desmopressin
ineffective
INITIAL EVALUATION
The primary evaluation of an enuretic child is simple and
straightforward, but it is time-consuming because assessment and diagnosis are based on history data. Also, treatment
success depends to significant degree on establishing a good
patient-physician relationship. The initial evaluation requires
at least half an hour.
The history is heavily focused on micturition habits. How
often is the bed wet? Has it always been this way? Do you
wet your underwear during the day as well, or has that been
the problem earlier? It is paramount to differentiate children
with secondary enuresis from children who have never been
reliably dry at night because the few bed wetters with kidney
disease or diabetes as an underlying cause usually belong to
the former group. For the same reason, questions should be
asked about the childs general health and the childs drinking behavior. Children with excessive thirst and a need to get
up and drink at night may have decreased renal concentration capacity. Urgency symptoms and signs of urinary tract
infection (e.g., dysuria) should be sought, and also symptoms
suggesting constipation, such as encopresis, infrequent bowel
movements, or the passage of hard stools.
Parents should be asked about enuresis in other family
members, and about the arousability of the child at night.
Although almost all bed wetters are perceived as deep
s leepers by their parents, children who are difficult to communicate with even when they have been forcefully awakened
at night may not be ideal candidates for the alarm treatment
(see later). It is also important to find out whether the child
regards the enuresis as a serious problem, and if it affects his
or her life greatly. A penetrating psychiatric evaluation is not
needed if the child does not exhibit overt signs of psychiatric
disease or serious social maladjustment.
The physical examination should include inspection of
the genitals and a standard neurologic examination. A rectal
examination should be performed if constipation is suspected
because the presence of stool in the rectum (without the child
sensing a need to go to the toilet) is strongly indicative of fecal
impaction.76
Blood samples or other invasive investigations are not
needed at this stage (and seldom later) if the case history and
physical examination does not indicate underlying kidney
disease or urologic abnormality. Ultrasound or other radiologic
evaluations are not informative. Even the need for urinalyses
can be questioned if the child has never been reliably dry
because it would be strange for bed-wetting to be the sole
manifestation of diabetes mellitus or urinary tract infection for
several years. In secondary enuresis, however, urinalyses are
needed, and when there is concomitant daytime incontinence
or dysuria as well.
INITIAL TREATMENT
When organic disease is not suspected, daytime incontinence
is not an issue, and the child has nocturnal enuresis that he or
she considers a significant problem (usually by approximately
age 6 years), it should be treated. Although success has been
claimed for numerous drugs and nonpharmacologic therapies,
only a few of them have stood the test of controlled trials. Only
the enuresis alarm and desmopressin can presently be recommended as first-line therapies. Initial treatment usually is with
one of these, and our recommendation is to leave this choice to
the child and family.
General Advice
Regardless of whether the alarm or desmopressin is the first
choice, the family needs to be informed about simple measures
that can be undertaken to facilitate the process of becoming
chapter
Psychological Aspects
Although most parents nowadays do not reproach or punish
their bed-wetting children, many children nevertheless think
that bed-wetting is their own fault. One of the duties of
health care professionals is to tell the child that this is not the
case. We usually tell the child that you wet your bed because
your bladder is not as smart as you are, or the reason that
you pee in your bed is that your kidneys make too much pee
during the night. Another common problem is that the child
thinks that he or she is (almost) the only bed-wetting person in
the world. This misconception is strengthened by the fact that
most bed-wetting children keep their problem top secret even
from their closest friends. This dark secret can make the child
terribly lonely. Some children even report that because of that
eternal hidden knowledge, they can never feel really happy.
Consequently, the physician should inform the child that
enuresis is a very common disorder, and that it can be successfully treated. A good piece of advice to these children is that
they tell their best friends about their problem; this usually
in contrast to the childs beliefdoes not result in teasing and
bullying, and it lessens the childs sense of loneliness.
Enuresis Alarm
The principle behind the enuresis alarm is deceivingly simple:
By waking the child from sleep at the moment of enuresis, he or
she gradually learns to recognize the imminent bladder voiding, and either suppresses the detrusor contraction or wakes
up and goes to the toilet. Although it has been questioned
whether we can really be taught anything while we sleep,
the fact remains that the alarm workssuccess rate is around
60% to 70%,78,79 and can be even higher in well-motivated
and well-informed families. Although 5% to 30% of children
may relapse after treatment,78,80 it can still be considered the
only truly curative method.
The apparatus consists of a urine detectorplaced either
in the childs underclothes or beneath the sheetsthat is connected to an alarm that emits a strong wake-up signal when
the detector is activated. The advantages of the alarm treatment are that it has a definite curative potential, and that it is
completely harmless. It does require a high degree of compliance and motivation, however, from the parents and the child
to be effective. Children with infrequent wetting episodes are
not suitable candidates. Children whose parents show signs of
intolerance toward the childs bed-wetting also are unsuitable
candidates.
383
Desmopressin
Desmopressin is a synthetic analogue of vasopressin, devoid
of pressor effects but with intact antidiuretic action.81 Since the
late 1970s, many studies have shown that the drug is useful
against enuresis.48,78,82-91 Reported success rates have ranged
from 40% to 80%, but relapse after treatment cessation is the
rule.85,88 The mechanism of action is probably that the time of
bladder (over-) filling is delayed until the morning, although
this explanation has been questioned.92 Treatment with desmopressin can be considered safe, and side effects are exceedingly rare,93 but if the drug is combined with excessive fluid
intake, there is a significant risk of hyponatremia with convulsions or unconsciousness.94
The advantages of desmopressin, apart from the lack of
toxicity, are that it is easy to administer, and effects appear
without delay. The major drawbacks are the low curative
potential and the cost. The usual dose is 0.2 to 0.4 mg orally,
or 120 to 240 g with the quick-melting oral lyophilisate tablets, or 20 to 40 g intranasally at bedtime. When prescribing
desmopressin, the physician must tell the family that large
amounts of liquid should not be consumed on nights when
the drug is taken. One practical approach is to allow one glass
to drink at dinner and half a glass at bedtime.
Because the response or nonresponse to this drug is evident without delay, there is no reason to treat for more than
2 weeks if the child experiences no beneficial effects of the
drug. For treatment responders, the decision to take medication continuously or just on important nights should be
left to the families. If the child chooses the former strategy, a
1-week interruption is recommended every 3 months to see
if the problem has disappeared and treatment is no longer
necessary.
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IV: Bladder
micturition, fluid intake over 2 to 3 days, and documentation of wetting accidents, and bowel movements for at least
1 week. This diary provides indispensable information
regarding bladder and bowel function. Uroflowmetry measurements are performed to detect signs of outlet obstruction or
detrusor underactivity, and residual urine is assessed with
a simple ultrasound examination. Morning urine osmolality should be tested in children who exhibit excessive fluid
intake, but is not otherwise necessary. If osmolality is repeatedly found to be low (<500 mOsm/kg), an inpatient thirst
provocation test may be indicated to assess renal concentration capacity.
Cystometry, cystoscopy, and radiologic evaluation of the
kidneys and urinary tract are unnecessary, provided that the
above-mentioned examinations do not reveal signs of neurogenic bladder disturbances, renal damage, or bladder outlet
obstruction. Blood tests do not give much useful information
if there are no indications of kidney disease.
In many cases, nonresponse to the enuresis alarm may simply be due to the family not having been properly instructed.
The parents may not have been informed that their child
may be unable to wake up by himself or herself at the start
of treatment, or the treatment may have been interrupted.
A new treatment session after proper information may solve
the problem. If a long time has elapsed since the last alarm
treatment, a new try might have greater success because the
child may now be more easily awakened at night, or the family may be more motivated. We recommend a new alarm treatment session every second year or so.
Constipation should always be kept in mind in children
with therapy-resistant enuresis, especially if they also have
encopresis. Some constipated children defecate every day and
have no definite bowel complaints. The diagnosis of constipation is not difficult to ascertain, however, if bowel movements are included in the bladder diary, and a manual rectal
examination is performed. Treatment of these children should
be aimed at the bowel first: (1) enemas; (2) laxatives; and
(3) institution of regular, daily bowel habits.
Anticholinergics
Foremost among parasympatholytic substances used in urologic practice is oxybutynin, a drug with anticholinergic and
smooth muscle relaxant properties99 that has proven to be effective in the treatment of daytime incontinence caused by detrusor overactivity.100 Some investigators have treated enuresis
with oxybutynin and have reported some success.101-103
Tricyclic Antidepressants
Since the early 1960s, imipramine has been successfully used
in the treatment of enuresis.114 Numerous studies, several
of them placebo-controlled, have shown that about 50% of
enuretic children are helped.78,115-118 The antienuretic potential
of imipramine is likely to reside in central noradrenergic facilitation, not in the anticholinergic side effects.119 Side effects of
imipramine treatment (e.g., nausea, anticholinergic side effects)
are usually minor,120 but the substance is potentially cardiotoxic, and even lethal reactions have been reported when the
drug has been overdosed or given to individuals with unstable
chapter
385
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
30
BLADDER EXSTROPHY
Incidence and Inheritance
Data from the International Clearinghouse of Birth Defects
Monitoring Systems1 and the Healthcare Cost and Utilization
Project Nationwide Inpatient Sample2 estimate the incidence of
bladder exstrophy to be 3.3 in 100,000 and 2.15 in 100,000 live
births, respectively. Population-based studies have shown the
incidence to be almost identical between males and females.2
Insight into the genetics of exstrophy has been gleaned
from family studies, facilitated by the fact that exstrophy
patients are now more likely to produce offspring than in
the past. The risk of recurrence of bladder exstrophy in a
given family has been estimated to be approximately 1 in
100.3 A report of seven cases of familial bladder exstrophy
and epispadias found inheritance patterns between siblings,
third-degree cousins and uncle/nephew pairs, which suggest
a complex inheritance phenomenon involving multiple genes
and possibly an environmental component.4
Whereas nongenetic risk factors appear to play a role in the
appearance of these defects, definitive information relating to
biologic and environmental contributors is lacking. The incidence of bladder exstrophy or epispadias appears to be higher
with decreased maternal age, higher parity,1 and Caucasian
race.2 Conception through the use of in vitro fertilization has
also been implicated in higher incidences of exstrophy.5 With
respect to endogenous teratogens, a Brazilian report found
that misoprostol exposure increases the incidence of exstrophy
as well as other congenital anomalies.6 Finally, a geographic
variation within the United States showing higher incidences
in the South and Midwest and lower incidences in the West2
indicates again that environmental factors may be significant.
386
Embryology
Bladder exstrophy (60% of patients within the complex),
epispadias (30%), and cloacal exstrophy or minor variants
(10%) result from the failure of the cloacal membrane to be
reinforced by the ingrowth of mesoderm. Normally, ingrowth
of mesenchymal tissue between the ectodermal and endodermal layers of the cloacal membrane forms the lower abdominal musculature and pelvic bones.7 According to the theory
by Marshall and Muecke,8 an abnormal development of the
cloacal membrane prohibits this medial migration, resulting in
an unstable embryonic state subject to premature rupture. The
timing of this perforation determines whether it will result in
cloacal exstrophy, bladder exstrophy, or epispadias.9
Examples of classic bladder exstrophy in a male and a
female infant are shown in Figures 30-1 and 30-2, respectively.
Morphogenetic models of exstrophy development have
been predominantly based on observations from affected
fetuses and from what is known about normal embryologic
development. Manner and Kluth10 reported a chick embryo
model of cloacal exstrophy, found serendipitously during
experiments involving fetal exposure to the teratogen, suramin.
They noted that 4 of their 50 experimental animals displayed
malformations similar to cloacal exstrophy and subsequently
collected embryos displaying cloacal malformations, including
abnormal ventral perforation.
Anatomic Considerations
Pelvic Bony Defects
The pelvis in exstrophy patients demonstrates widening of the
pubic symphysis and eversion of the innominate bones. Comparing computed tomographic (CT) data between normal children and those with exstrophy, there is a mean external rotation
of the posterior aspect of the pelvis of 12 degrees on each side,
retroversion of the acetabulum, a mean 18 degrees of external
rotation of the anterior pelvis, along with 30% shortening of
the pubic rami (Fig. 30-3).11 Other studies12 have revealed that
the posterior pelvic deformity is caused, at least in part, by the
sacroiliac joints being externally rotated 9.9 degrees more than
normal, with an inferior rotation of the pelvis on the order of
14.7 degrees in the superoinferior plane. In cloacal exstrophy,
the pelvic deformities are more extreme and more asymmetric
and occasionally involve hip dislocation.11
Outward rotation and lateral displacement of the innominate bones accounts for the increased distance between the
hips, the waddling gait, and outward rotation of the lower
limbs in these children, features that cause minimal disability
as they grow older.
The inherent potential for growth and development appears
to be normal; histologic bone analysis of 28- to 30-week fetuses with classic and cloacal exstrophy, compared with normal
fetuses of the same age, showed no difference in microscopic
growth patterns or endochondral ossification.13
chapter
387
18
Anterior
segment
12
Posterior
segment
Intertriradiate
distance
Figure 30-1 Male with classic bladder exstrophy. Notice the excellent
size of the bladder template and the reasonably good size of the phallus.
Divergence of the pelvic floor muscles results in a widening and lengthening of the hiatus through which the urethra,
vagina, and rectum pass. The exstrophic pelvic floor has a twofold increase in its transverse width and a 1.3-fold increase in
its length. Therefore, in an uncorrected pelvis, organ prolapse
is seen as a common complication.
We suspect that repositioning the levator group and
decreasing the size of the hiatus contributes to continence16
and prevention of prolapse. During primary closure, meticulous mobilization and placement of the bladder and posterior
urethra deep in the pelvis is essential.
388
part
IV: Bladder
Normal
Exstrophy
Sa
cr
Sa
um
cr
um
Obt. int.
Coccyx
Post.
lev. ani
Ant. lev. ani
Pelvic floor
arched
Anus
Obt. int.
Ant. lev. ani
(shortened)
Normal
Sacrum
Obt. int.
Anus
Lev. ani
Exstrophy
Sacrum
Obt. int.
Lev. ani
Anus
Figure 30-4 A, Displacement of the levator ani (lev. ani) to a more posterior position in patients with exstrophy, such that 68% of the muscle lies
posterior to the anus, compared with the normal 52%. Consequently, only 32% of the anterior segment of the levator ani lies anterior to the anus,
compared with 48% in controls. Ant., anterior; Obt. int., obturator internus; Post., posterior. B, There is greater outward rotation of the obturator
internus (15.1 degrees) in exstrophy patients versus controls. Also note that the area encompassed by the puborectalis is twice as large as that of
controls and more flattened. (From Stec AA, Pannu HK, Tadros YE, et al. Pelvic floor anatomy in classic bladder exstrophy using 3-dimensional
computerized tomography: initial insights. J Urol. 2001;166:1444.)
chapter
389
EXSTROPHY
NORMAL
ISD
Pubic bone
Obturator
foramen
Superior
ramus
r
rio
fe s
In mu
ra
Cdiam
ICD
ISD
aCC
aCC
PCL
Cdiam
ACL
PCL
Shorter
by 30%
ICD
ACL
TCL = ACL + PCL
Figure 30-5 Male genital defect in patients with bladder exstrophy. The penile and pelvic measurements in normal men and in patients with
exstrophy. aCC, corporal cavernosa subtended angle; ACL, anterior corporal length; Cdiam, corpus cavernosum diameter; ICD, intracorporal
distance; ISD, intersymphyseal distance; PCL, posterior corporal length; TCL, total corporal length. (From Silver RI, Yang A, Ben-Chaim J, et al.
Penile length in adulthood after exstrophy reconstruction. J Urol. 1997;157:999.)
Urinary Defects
At birth, the bladder mucosa may appear normal; however,
hamartomatous polyps may be present on the bladder surface,
representing squamous metaplasia and, commonly, cystitis
glandularis.22 Such findings warrant future surveillance with
bladder cytology and cystoscopy. If the bladder mucosa is not
frequently irrigated with saline solution and protected from
surface trauma by the interposition of some form of protective
membrane before closure, cystic or metaplastic changes in the
mucosal surface may occur.22
Many basic science studies have been published that
further delineate the exact nature of the exstrophied bladder
in the newborn. Work by Shapiro and associates23 in 1985
showed that the density and binding affinity of muscarinic
cholinergic receptors was similar in exstrophied and normal
bladders. Mathews and colleagues24 used electron microscopy to evaluate the histology of bladder tissue in newborns
before closure, in patients undergoing reclosure after failure,
in patients undergoing bladder neck reconstruction, and also
at the time of augmentation cystoplasty. They found that
future continence correlated with a normal or near-normal
ultrastructure with regard to smooth muscle arrangement,
preservation of mitochondria, presence of caveolae, and nerve
profiles.
Several studies have investigated both the neural innervation of the newborn exstrophied bladder and its muscle and
collagen content. Mathews and colleagues25 looked at myelinated nerve density in the newborn with bladder exstrophy
compared with newborn controls and found a statistically significant decrease in the former. The reduction in nerve fibers
appeared to be due to a lack of small fibers with preservation
of larger nerve fibers, which likely represents a maturational
delay in overall development. Lee and coworkers,26 looking
390
part
IV: Bladder
Patient Selection
Successful treatment of exstrophy by functional closure
demands that the potential for success in each child be carefully considered at birth. The size and functional capacity of
the detrusor muscle are important considerations in the eventual success of functional closure. The apparent bladder size
must not be confused with potential bladder capacity. The
bladder may appear small yet demonstrate acceptable capacity, either by bulging when the baby cries or by indenting easily when touched by a sterile gloved finger in the operating
room, with the child under anesthesia. Sometimes a good bit
of previously unappreciated bladder is discovered behind the
fascia during examination under surgery. Once removed from
surface irritation and repeated trauma, the small bladder can
enlarge.
Early Management
Cardiopulmonary and general physical assessment can be
carried out immediately after delivery. Ultrasound studies
can provide evidence of normal renal appearance before the
patient undergoes closure of the exstrophy defect.
In less than ideal circumstances, a thorough neonatal
assessment may have to be deferred until transfer of the baby
to a major childrens medical center. During transportation,
the bladder should be protected by a plastic membrane.
chapter
391
Osteotomies
Posterior
periosteum
and cortex
remain intact
Surgical Procedure
Since the early 1980s, modifications in the management of functional bladder closure have contributed to a dramatic increase
in the success of the procedure. The most significant changes
have been (1) early bladder, posterior urethra, and abdominal
wall closure, usually with pelvic osteotomy; (2) early epispadias repair; (3) reconstruction of a competent bladder neck and
reimplantation of the ureters; and, most importantly, (4) defining strict criteria for the selection of patients suitable for this
approach.
Osteotomy
Pelvic osteotomies performed at the time of closure confer
advantages, including (1) easy reapproximation of the symphysis with diminished tension on the abdominal wall closure
and elimination of the need for fascial flaps, (2) placement
of the urethra deep within the pelvic ring, and (3) ability to
bring the large pelvic floor muscles toward the midline, where
they can support the bladder neck and aid in eventual urinary
control. In a review of a large number of patients with failed
exstrophy procedures referred to our institution, most of those
referred with partial or complete dehiscence of the bladder, as
well as those with major bladder prolapse, had not undergone
prior osteotomy.43
Our recommendation is to perform bilateral transverse
innominate and vertical iliac osteotomies when the bladder
closure is performed after 72 hours of age. In addition, if the
pelvis is not malleable or if the pubic bones are greater than
4 cm apart at the time of initial examination under anesthesia,
osteotomy should be performed, even if closure occurs before
72 hours of age.
If examination under anesthesia reveals the pubic bones to
be malleable and able to be brought together easily, the patient
can undergo closure without osteotomy. However, if there is any
doubt regarding this decision, osteotomy should be performed.
Improved approximation lessens the tension on the midline
abdominal closure and decreases the rate of bladder dehiscence
and prolapse.37 In addition, pubic closure allows approximation
of the levator ani and puborectalis sling, inclusion of the bladder
neck and posterior urethra deep within the pelvic ring, and an
improved continence rate. In addition to ease of approximation,
anterior innominate osteotomy combined with vertical iliac
osteotomy was developed for three reasons: (1) the procedure
can be performed with the child in the supine position, as in
the urologic repair; (2) it allows placement of an external fixator
device and intrafragmentary pins under direct vision; and (3) the
cosmetic appearance is superior to that of other approaches.
With the patient in a supine position, transverse and posterior osteotomies are performed (Fig. 30-7).44 Radiographs are
obtained to confirm pin placement, soft tissues are closed, and
the urologic repair is performed.
Postoperative pelvic immobilization has a significant
impact on the success of the operation.45 After repair with
osteotomy, we use 4 to 6 weeks of modified Bucks traction
(Fig. 30-8) and keep the external fixator on for approximately
6 weeks until a radiograph shows adequate calculus at the
site of osteotomy. Newborns undergoing repair without
osteotomy may be immobilized with modified Bryants traction (Fig. 30-9) for 4 weeks. Given the high rate of failure and
complications, spica cast and mummy wrapping techniques
are not recommended.
After good callus formation is seen on radiographs, the
fixating device and pins are removed. Although both classic
and cloacal exstrophy patients gained approximation from
392
part
IV: Bladder
and
Management
Figure 30-9 Modified Bryants traction in a newborn who underwent closure without pelvic osteotomy. This traction is maintained for
4 full weeks.
after
Primary Closure
The procedure just described converts a patient with exstrophy into one with proximal shaft epispadias and incontinence.
Before removal of the suprapubic tube 4 weeks postoperatively,
the bladder outlet is calibrated by urethral catheter or sound to
ensure free drainage. An ultrasound examination is obtained
to ascertain the status of the renal pelves and ureter, and
appropriate urinary antibiotics are administered to treat any
bladder contamination that might be present after removal of
the suprapubic tube. Residual urine is estimated by clamping
the suprapubic tube, and specimens for culture are obtained
before the patient leaves the hospital and at subsequent intervals to detect infection. If initial ultrasonography shows good
drainage, upper tract imaging by ultrasonography is repeated
3 months after discharge and at intervals of 6 months to 1 year
during the next 2 to 3 years to detect any upper tract changes
caused by reflux, infection, or silent obstruction.
Prophylactic antibiotic therapy should be continuous,
because all patients with bladder exstrophy, once closed,
have vesicoureteral reflux. If a useful continence interval has
resulted from initial closure, a further operation for incontinence may not be required; however, this situation is quite
unusual. In our experience, this has occurred in 3 patients, all
of whom were female.
At yearly intervals, gravity cystograms with the patient
under anesthesia detect bilateral reflux in almost 100% of
patients and provide an estimate of bladder capacity. In some
patients with very small bladders, 4 to 5 years may be necessary to achieve adequate capacity. However, if the bladder
has not achieved a capacity of at least 30 mL by 1 to 2 years,
concern must be voiced to parents about the overall ability of
the bladder to undergo a continence procedure.
Should bladder outlet resistance be such that urine is
retained within the bladder and high-grade reflux and ureteral dilation develop with infected urine, it may be necessary
to dilate the urethra or to begin a program of clean intermittent catheterization. Sometimes, posterior urethral obstruction
is severe enough to require a transurethral incision of the
stricture to maintain adequate drainage; if this is not effective, surgical revision of the bladder outlet by advancing skin
flaps into the orifice or even patching the stricture may be
chapter
393
Incision follows
bladder template
and incorporates
umbilicus
Incision to
midshaft
of penis
Lateral aspect
of bladder
dissected
Urachal
remnant
used for
retraction
Figure 30-10, Schematic for initial closure of the bladder and poste-
rior urethra. The bladder plate is dissected off the anterior abdominal
wall. A, Initial incision around the bladder plate in the male. B, Incision
follows the bladder template and includes the umbilicus. C, Dissection
of the lateral aspect of the bladder from the abdominal wall.
394
part
IV: Bladder
Malecot
catheter
Ureteral
stents
Ant. rectus
sheath
Symphysis
pubis
Crura is dissected
and visualized
completely
Urogenital
diaphragm
incised
Divided
suspensory
ligament
Figure 30-10, contd D, Dissection of the crura from the symphysis pubis. E, Division of the urogenital diaphragm fibers. Note stents and
suprapubic tube in place in the bladder.
Epispadias Repair
Based on evidence that bladder capacity increases after epispadias repair, the modern staged repair of exstrophy now
prescribes that this be done before bladder neck reconstruction.51 In a group of patients with a small bladder capacity
after initial closure, there was a mean increase in capacity to 55
mL only 22 months after epispadias repair. We now perform
the repair at 6 months of age in all patients. The objective is to
have all patients achieve an appropriate bladder capacity by
the time they are physically and mentally ready to undergo
bladder neck reconstruction. Because a majority of boys with
exstrophy have a somewhat small penis with a paucity of
penile skin, all patients undergo testosterone stimulation therapy (intramuscular testosterone enanthate, 2mg/kg at 5 weeks
and 2 weeks preoperatively) before urethroplasty and penile
reconstruction.52
Many surgical techniques have been described for reconstruction of the penis and urethra in patients with classic bladder exstrophy. The most current methods are the
chapter
395
Rectus fascia
is reapproximated
Symphysis
sutured using
20 nylon
Bladder wall
is closed
Sound used
to calibrate
urethral
opening
Figure 30-10, contd F, Initial layer of the bladder closure. The urethral meatus is calibrated to 14F (4.62 mm) in diameter. Stents are brought
out of the bladder. G, Pubic approximation is performed with no. 2 nylon mattress suture (inset). Abdominal wall closure is completed. The suprapubic tube and stents are brought out through the umbilicus. (Adapted from Gearhart JP, Mathews R. Exstrophy-epispadias complex. In: Wein AJ
et al., eds. Campbell-Walsh Urology. 9th ed. Philadelphia: WB Saunders; 2007, chapter 119.)
Chordee
and
Urethral Reconstruction
skin contraction and upward tethering of the penis. The ventral foreskin can be split in the midline (reverse-Byars concept)
and brought to the dorsum as lateral preputial flaps for coverage of the penile shaft. Khoury and colleagues60 overcame
this obstacle by creating a ventral preputial transverse island
flap, rotated dorsally to cover the dorsal penile shaft, and an
advancement flap from penoscrotal skin to cover the ventral
surface.
Female Genitalia
Reconstruction of the mons and external genitalia is done at
the time of initial exstrophy closure. Although this adds a bit
of time to the operation, once the pubic bones are brought into
apposition with osteotomy it is quite easy to reconstruct the
genitalia.43 A recent report from Toronto described a simple
monsplasty technique that demonstrated good cosmetic
results with no complications.61
Postoperative Problems
Postoperative pain and bladder spasms after extensive external genitalia reconstructive surgery require a combined effort
by the pediatric anesthesia pain service and the surgical service. Control of bladder spasms is paramount, because they
are associated with more urinary extravasation and fistula
396
part
IV: Bladder
Urethral strip
incision carried
to ventral
surface
Incision
glanular
urethra
IPGAM
closure
Penile skin is
dissected off
the corpora
chapter
397
Incisions
extended
onto glans
Stent
Urethral plate
NVB
Stent positioned
in urethra
Neourethra
Stent
Neourethra
is created
D
Figure 30-11, contd C, The corpora are dissected off the urethral plate, and parallel incisions are made into the glans to create glans wings.
Note the lateral position of the neurovascular bundles (NVB, inset). D, The urethra is tubularized with the use of a continuous running suture.
398
part
IV: Bladder
Midline suturing
rolls corporal
bodies medially
Neourethra
now ventral
NVB
moves
dorsally
Glans sutured
in 2 layers
Subcuticular closure
Neourethra
Anchoring
suture
foreskin to
corpora
. . . and
sewn to
coronal
margin
Ventral
foreskin
is split . . .
F
Figure 30-11, contd E, The corpora are approximated above the urethra to provide an anatomically ventral location of the urethra (inset). The
glans is reconstructed in two layers. F, A suture is placed at the base of the penis to locate the foreskin on the shaft of the penis and to provide an
area of distinction between the penis and scrotum. Foreskin is sewn to the coronal sulcus. (Adapted from Gearhart JP, Mathews R. Exstrophyepispadias complex. In: Wein AJ et al., eds. Campbell-Walsh Urology. 9th ed. Philadelphia: WB Saunders; 2007, chapter 119.)
c hildren who were completely dry after bladder neck reconstruction. Most of these children were 4 to 5 years old and
were ready emotionally, maturationally, and intellectually to
participate in a postoperative voiding program.
The modified Young-Dees-Leadbetter bladder neck reconstruction63 and antireflux procedures as performed at our
institution are illustrated in Figure 30-12. A very radical dissection of the bladder, bladder neck, and posterior urethra is
required, not only within the pelvis but also from the posterior
aspect of the pubic bar, to provide enough mobility for the
bladder neck reconstruction. This maneuver allows adequate
narrowing and tightening of the bladder neck repair and
s ubsequent anterior suspension of the newly created posterior urethra and bladder neck. If visualization of the posterior
urethra is problematic, the intrasymphyseal bar can be cut,
widening the field of exposure. If the intrasymphyseal bar is
cut, mobility of the child should be restricted postoperatively
to allow for proper healing.
Postoperative Care
Ureteral stents are placed in the reimplanted ureters and
brought out through the wall of the bladder, and the bladder is drained by a suprapubic tube that is left indwelling
chapter
399
Incision from
umbilicus to
base of penis
Peritoneum
Bladder incision
extends to post.
urethra
Ureteral stent
sutured to
mucosa
Pubic
symphysis
Triangular mucosal
strips denuded
leaving central
urethral plate
Ureter is
tunneled and
reimplanted
cephalad
Incisions used
to lengthen
denuded muscle
Tubularization
of mucosal strip
400
part
IV: Bladder
Muscle wrapped
around neourethra
Interrupted
sutures to
close bladder
wall
Suspension sutures
tied over rectus fascia
chapter
401
Malecot
catheter
inserted
Ureteral
orifices
Prostatic
utricle
Urogenital
diaphragm
incised
Ureteral
stents
Dissecting
corpora
cavernosa
Dissecting
corpus
spongiosum
C
Figure 30-13 Combined bladder closure and epispadias repair. A, The initial incision extends around bladder and includes the urethral
plate. B, Stents are placed in the ureters, and a suprapubic tube is placed. Urogenital fibers are divided. C, The corpus spongiosum is dissected,
leaving a ventral vascularized pedicle. The corpora are dissected proximally toward the bladder.
402
part
IV: Bladder
1st layer
bladder
closure
Malecot
catheter and
ureteral stents
Mattress suture
used to
approximate
pubis
Neourethra
created
Figure 30-13, contd D, Dissection of the urethral plate and corpora is completed. Bladder closure is completed. E, The urethral plate is tubularized with the use of a continuous running suture. F, Pubic bones are approximated.
chapter
Corpora
approximated
over neourethra
403
Glans
closed
1st row of
sutures
within glans
2nd row
of sutures
in glans
Completed
repair
c ompleted, and the corpora are closed over the urethral closure (see CantwellRansley repair). Glans closure is then completed. H, Completed penile and
abdominal wall skin closure. The urethral stent is omitted in children having initial closure but is left in place in those undergoing reclosure. (Adapted
from Gearhart JP, Mathews R. Exstrophy-epispadias complex. In: Wein AJ
et al., eds. Campbell-Walsh Urology. 9th ed. Philadelphia: WB Saunders; 2007,
chapter 119.)
404
part
IV: Bladder
Epispadias RepairResults
Anxiety about inadequate, unattractive genitalia still poses the
greatest concern to male patients.69 Modern penile reconstructive techniques should create a straight, functional penis with
a glandular meatus and an easily catheterizable neourethral
channel, if needed, as well as an acceptable cosmetic result.
Many adolescents are dissatisfied by their decreased length;
however, no modern technique to our knowledge produces a
true increase in penile length, even with complete disassembly
or free grafts.
Evolution of penile reconstruction at our institution has
continued. In 1994, we modified the Cantwell-Ransley repair
by detaching the mucosal plate from the corpora except for
the distal 0.5 to 1 cm of the plate (see Fig. 30-11C).
Outcomes from our institution have been reported for
93 patients (79 with classic exstrophy, 14 with epispadias) who
underwent primary (77 patients) or secondary (16 patients)
repair.54 At a mean follow-up of 68 months, 87 patients (93%)
had a horizontal- or downward-angled penis, whereas 6 (7%)
required further straightening operations. The rate of fistula
formation was 23% immediately and 19% at 3 months postoperatively. Seven patients developed stricture, and 5 required
minor procedures for dorsal skin closure. All of the 77 children
who have had cystoscopy demonstrated easily negotiated
neourethral channels. Ten of 12 patients older than 16 years
have engaged in intercourse and reported satisfaction with
cosmesis and function. Kajbafzadeh and colleagues70 reported
their experience with 95 patients and found a stricture rate of
only 5% and a fistula rate of 4%. Their revision rate of 16%
included minor skin procedures with or without repair of
fistula or stricture.
In 1996, Mitchell and Bagley56 introduced the penile disassembly technique and reported on 10 patients who underwent
the procedure. All of their patients had good cosmetic results.
Although two patients developed fistulas (one patient had
two), these were repeat surgeries for prior failure. A multicenter report71 on the use of this repair in 17 boys included
3 instances of fistula, 2 of which healed spontaneously, and
1 complete wound dehiscence. Hammoudas series72 of 42
patients included no fistulas or strictures, but he did report 5
cases in which significant ischemic changes of the glans were
noted. In addition to revisions required for fistula, the penile
chapter
Combined ClosureResults
At the Johns Hopkins Hospital, the combination of bladder closure with epispadias repair has been used predominantly in boys who have already had a failed initial closure or
patients in whom closure has been delayed for 5 to 6 months.77
Results from 33 reclosures and 5 delayed closures have been
presented, although the data from the delayed closures is still
early, with 3 of the patients awaiting adequate bladder growth.
Of the 33 reclosures, 19 (57%) have progressed to bladder neck
reconstruction and 12 of these 19 demonstrated at least social
continence without the need for intermittent catheterization.
Fourteen patients did not undergo bladder neck reconstruction
because 3 were dry after bladder closure and epispadias repair,
3 underwent diversion for failure to develop adequate bladder capacity, and 8 are still awaiting bladder growth. Ureteral
reimplantation was performed in 22 (66%) of the 33 patients for
persistent hydronephrosis, vesicoureteral reflux, recurrent urinary tract infections, or some combination of these conditions.
Nineteen patients required further endoscopic procedures or
surgery of the bladder neck, penis, or urethra, including 10 for
urethrocutaneous fistula and 4 for stricture. Overall, the data
suggest that a combination procedure as a means for reclosure
yields a continence rate of 50% at best, with significant need
for subsequent procedures.
The modern concept of combined bladder closure and epispadias repair in the neonate, or complete primary repair,
was introduced by Mitchell38,78 in the 1990s, and several
groups have now reported on their experience. A comparison of staged reconstruction versus complete primary repair
was performed by the group at Boston Childrens Hospital79
to investigate the impact of surgical technique on bladder
development. The 23 patients who underwent complete primary repair demonstrated similar bladder capacities to those
undergoing staged repair, but the bladders appeared to have
a more normal compliance. Bladder instability was commonly
seen after staged repair (46% in this series) but was nonexistent in the group undergoing complete repair. However, 70%
still required an outlet procedure for dryness. Recent data
from Gearhart and associates80 described 14 patients who had
undergone successful complete primary closure of exstrophy
in infancy and were then referred for incontinence. Several
had dry intervals for 1 to 2 hours but continued to leak
urine and, therefore, required bladder neck repair.
Complications and failures after complete primary repair
are similar to those seen with modern versions of staged repair,
with some caveats.81 Hydronephrosis with vesicoureteral
reflux has been reported in 63%82 to 74%83 of patients after
complete primary repair. Management has usually consisted
of performing a subsequent antireflux procedure. Therefore,
these authors and others84 now recommend performing
ureteral reimplantation at the time of the initial closure.
Most of the unique complications are associated with the
use of the complete penile disassembly technique during
complete primary closure. Hypospadias occurred in 77% of
the children at Boston Childrens Hospital83 and in 59% of
those in an Egyptian series.82 A multi-institutional study by
Alpert and associates raised the concern for development
of bladder neck fistulas, which occurred in 41% of their
22 patients.85 All of the fistulas occurred in males, and most
required surgical repair.
Husmann and Gearhart86 reported several cases of ischemic
penile injuries in patients who were referred after undergoing the penile disassembly technique as part of the complete
405
Other Techniques
Not all children with bladder exstrophy are candidates for
bladder closure, because of a small bladder plate or significant
hydronephrosis. Additional reasons for seeking other methods
of treatment include failed initial closure with a small remaining bladder and failure of continence surgery. Excluding those
patients for whom initial treatment fails, this discussion deals
with options available if closure is not chosen or for other reasons has not been suitable.
Ureterosigmoidostomy
Whichever urinary diversion is chosen, the upper tracts and
renal function are initially normal. This allows reimplantation of normal-sized ureters in a reliable, nonrefluxing manner
into the colon or other suitable reservoir. Ureterosigmoidostomy has been associated with multiple metabolic problems,87
pyelonephritis, and rectal incontinence secondary to pelvic
floor anomalies.88 The Mainz group employs a rectosigmoid
pouch technique that has demonstrated acceptable continence rates and renal preservation in follow-up of greater than
10 years.41,89 They found that metabolic acidosis requiring
alkali supplementation was common but rarely led to significant clinical complications. However, this form of diversion
should not be offered until one is certain that anal continence
is normal and the family is aware of the potential for serious
complications, including pyelonephritis, hyperkalemic acidosis, rectal incontinence, ureteral obstruction, and delayed
development of malignancy.90-92 Surveillance for malignancy
in these patients should be initiated 10 years after performance
of the ureterosigmoidostomy.
406
part
IV: Bladder
chapter
EPISPADIAS
Epispadias is the least severe form of the exstrophy-epispadias
complex but still represents a major clinical problem and management challenge. It consists of a dorsally located ectopic
meatus that results from nonclosure of the urethral plate, often
extended to the level of the bladder neck. This is a rare entity,
with an estimated incidence of 1 in 117,000 males and 1 in
484,000 females.37
Embryologically, epispadias occurs when there is defective migration of the primordium of the genital tubercles as it
moves toward the midline superior to the cloacal membrane
to form the genital tubercle at approximately the 5th week
of gestation. The result is a defect in the dorsal wall of the
urethra. Instead of the normal urethra, the nontubularized
urethral plate overlies the dorsum of the corpora cavernosa.
Urinary incontinence is the result in the more severe forms
when the bladder neck is involved.
There is a characteristic widening of the pubic symphysis secondary to outward rotation of the innominate bones.
However, the diastasis is minimal and rarely requires osteotomy for pelvic reconstruction.
407
Male Epispadias
In males, the dorsal meatus may be found on the glans, penile
shaft, or penopubic region, and all types are associated with
varying degrees of dorsal chordee. Urinary continence is
directly related to the severity of the deformity. The most common form of male epispadias is the penopubic subtype (Fig.
30-14), followed by the intermediate form with the meatus
on the penile shaft; the rarest type is the glandular variant.
Kramer and Kelalis122 reviewed their experience with 82 male
patients and found 49 penopubic cases, 21 penile variants, and
12 patients with the glandular form.
The penopubic or complete epispadias defect involves
the entire urethral plate, beginning at the bladder neck, and
includes a cleft striated sphincter. Lack of a congenital continence mechanism results in a thin-walled bladder with poor
capacity. A small gap is seen between the two pubic bones, but
the symphysis is dense and fibrous, and the pelvic ring is completely closed. Vesicoureteral reflux occurs in 30% to 85% of
the patients in some series,122-124 which is significantly lower
than the 100% incidence seen in classic exstrophy patients.
Inguinal hernias occur at a relatively high rate, 33% in the
series from Johns Hopkins,125 but again this is much lower
than in the classic exstrophy population.
Intermediate forms of epispadias involve an intact bladder
neck, so incontinence is not usually a problem. Corporal malrotation and dorsal chordee are present and must be addressed at
the time of reconstructive surgery. The glandular presentation
is somewhat more subtle in that the foreskin may be intact. In
these patients, the penis is commonly shorter than normal, and
chordee may be obvious only during erections. Therefore, the
surgeon should investigate via production of an artificial erection at the time of repair and address the situation accordingly.
Surgical Management
Reconstructive surgery aims to create a functional and cosmetically acceptable phallus and to achieve urinary continence
with renal preservation. Surgical management is virtually
identical to that for closed bladder exstrophy.
The modified Cantwell-Ransley procedure and the complete
disassembly technique (both described earlier in this chapter)
are two methods used to reconstruct complete epispadias.
There is little disagreement that epispadias repair and bladder neck reconstruction may be combined in selected patients
when bladder capacity is good. Bladder capacity increases as a
direct result of the higher outlet resistance after urethroplasty.
Ben-Chaim and associates125 found an average increase of
408
part
IV: Bladder
42 mL in bladder capacity within 18 months after urethroplasty. Those who support the complete penile disassembly technique argue that many of their patients are continent without
the need for further bladder neck reconstruction, and in those
with a patulous bladder neck, reconstruction can be performed
at the time of urethroplasty, obviating a second procedure.126
Genital reconstruction involves the release of chordee
and division of the suspensory ligaments, dissection of the
corpora from their attachments to the inferior pubic ramus,
lengthening of the urethral groove, and lengthening of the
corpora, if needed, by incision and anastomosis or grafting,
or more commonly by medial rotation of the ventral corpora
in a more downward direction. The use of a cavernostomy is
uncommon, because there is little or no intrinsic deformity of
the corpora; medial rotation is almost always sufficient, and
mobilization of the neurovascular bundles can be avoided.
In the modified Cantwell-Ransley procedure (see Fig. 30-12),
the urethra is completely reconstructed from the urethral
plate, which is mobilized on its pedicle, retubularized, and
repositioned ventrally. A main point of difference from the
Mitchell technique is that the distal 1 cm of the urethral plate
is not dissected free from the glans penis. Once the corpora
have been rotated medially and glanuloplasty and meatoplasty have been performed, Z-plasty is done at the dorsal base
of the penis, to provide adequate skin and to prevent dorsal
retractile scarring. Complete penile disassembly38 depends
on the blood supply of the epispadiac penis, which consists
of paired dorsal arteries and neurovascular bundles to each
hemiglans, deep cavernosal arteries to the corporal bodies,
and supply via the spongiosa to the proximal urethral plate.
In this case, the three components of the penis, including the
two corporal bodies and their respective hemiglans, and the
urethral wedge consisting of the urethral plate and underlying
spongiosum, are dissected completely free from each other.
The hemicorporal bodies can then be rotated medially to correct the chordee, and cavernostomy is never performed.
Female Epispadias
As in the male, there are three types of epispadias in the female,
based on the severity and location of the defect. Because of the
rarity of this malformation and the variance of presentation,
these patients are frequently not diagnosed at birth and pre
sent at a later age complaining of constant wetness.129 In the
most severe and common form of epispadias (Fig. 30-15), the
defect extends along the entire length of the urethra and bladder neck, which cleaves the sphincteric mechanism, rendering the child incontinent. The genitalia are remarkable for the
bifid clitoris and a depressed mons that is covered by smooth,
glabrous skin. The labia minora are usually poorly developed
and terminate anteriorly at the corresponding half of the bifid
clitoris, where there may be a rudiment of a preputial fold. As
in the male, the pubic symphysis may have a very small gap
(compared to that seen in classic exstrophy) which is traversed
by a narrow fibrous band.130
Previous comments regarding vesicoureteral reflux in
male epispadias also apply to females. As in males, ureteral
reimplantation is performed at the time of bladder neck reconstruction. We recommend doing this for all patients, because
the increased bladder neck resistance may contribute to de
novo reflux in patients in whom it is initially absent.
Surgical Management
Repair of the epispadias defect in females strives to achieve
urinary continence, preserve the upper urinary tract, and
create functional and cosmetically acceptable external genitalia. Procedures that merely increase urethral resistance without
correcting incontinence or addressing congenital malformation, such as transvaginal plication of the urethra and bladder
neck, muscle transplantations, urethra twisting, cauterization
chapter
Urethral
mucosa
409
Hemiclitoris
Labia
minora
Bladder
neck
Vagina
Neourethra
sutured
Redundant
tissue is
removed
B
Figure 30-16 A, Typical appearance of female epispadias with initial incisions outlined. B, Excision of the glabrous skin of the mons. Tapering
of the urethra with a dorsal resection of a wedge of tissue. Reconstruction of the urethra over a catheter with a running suture.
of the urethra, bladder flap, and Marshall-Marchetti vesicourethral suspension, have yielded disappointing results.131-134
As with males, increasing outlet resistance results in an
increase in bladder capacity, so we perform the reconstruction as a staged procedure. Typically, urethral and genital
reconstruction is performed at 1 year of age, followed by
bladder neck reconstruction when the patient is 4 to 5 years
old. This timetable allows adequate bladder development and
allows the child to mature enough to participate in a voiding
program. Reconstruction of the urethra and external genitalia
is performed at the same time (Fig. 30-16). A 10F (3.3-mm)
catheter is placed at the end of the procedure. If bladder neck
Surgical Results
Urinary continence rates of better than 80% have been reported
in several series, with very infrequent need for intermittent
catheterization, augmentation, or urinary diversion for failed
reconstructions.130,135,136 All of the patients in the reported
series achieved bladder capacities greater than 80 mL. At our
institution,135 the mean capacity after genitourethral reconstruction and at the time of bladder neck reconstruction was
410
part
IV: Bladder
1st layer
of closure
Medial aspect
of labia minora
and hemiclitoris
denuded
Approximation of
hemiclitoris and
labia minora
2nd layer
of closure
E
Figure 30-16, contd C, Denuding of the medial aspect of the labia minora and clitoris. D, Initial layer of the mons closure. E, Approximation
of the labia minora over the urethral reconstruction and second layer of mons closure.
121 mL. We also found that the time interval to achieve continence was 18 months after combined genitourethral and bladder neck reconstruction, compared with 23 months if these
procedures were performed in a staged fashion. Kramer and
Kelalis136 found that several of their patients became continent within a short period, whereas other patients took several years to obtain complete continence. They attributed this
result to a delay in pelvic muscular development. Although
there appears to be an advantage, in terms of interval to dryness, in combining the genitourethral and bladder neck reconstructions, we believe that the increased bladder capacity
obtained with the preliminary urethroplasty outweighs this
benefit.
CLOACAL EXSTROPHY
Cloacal exstrophy, commonly referred to as the omphalocele,
exstrophy of the bladder, imperforate anus, and spinal abnormalities (OEIS) complex137 in nonurologic literature, represents one of the most severe congenital anomalies compatible
with intrauterine viability. It is exceedingly rare, occurring in
approximately 1 of every 200,000 to 400,000 live births.138 Surgical reports102,139 have indicated a male-to-female ratio of 2:1,
but a Spanish population-based study140 including 1.6 million
live births and 10,000 stillbirths found a female preponderance, with a ratio of 0.5:1. The inheritance pattern of cloacal
exstrophy is unknown.
chapter
411
Subcuticular
skin closure
Figure 30-17 Cloacal exstrophy in a newborn male. A large omphalocele with prolapse of the ileum through the ileocecal area between
exstrophied hemibladders and a small part of the right hemiphallus
are visible.
the mons closure. (Adapted from Gearhart JP, Mathews R. Exstrophy-epispadias complex. In: Wein AJ et al., eds. Campbell-Walsh Urology. 9th ed.
Philadelphia: WB Saunders; 2007, chapter 119.)
septum descends caudally between weeks 6 and 8. If perforation of the anterior cloacal membrane occurs before complete
descent of the urorectal septum, the common cloaca will be
affected, and cloacal exstrophy will be the result. The anomaly must represent not an arrest in development but, more
likely, some form of primary polytopic developmental field
defect.140
According to Muecke,142 an abnormally extensive cloacal
membrane produces a wedge effect, serving as a mechanical
barrier to mesodermal migration, which results in impaired
development of the abdominal wall, failure of fusion of the
paired genital tubercles, and diastasis pubis. Exstrophy of the
cloaca results when the wedge effect occurs before the complete caudal migration of the urorectal septum at 6 weeks.143
Ultrasound prenatal imaging data, however, have cast
some serious doubt regarding the current thought that inciting events occur between the 6th and 8th week of gestation.
Langer144 and Bruch145 and their colleagues reported prenatal
diagnoses of cloacal exstrophy in fetuses with intact cloacal
membranes at 18 to 24 weeks. In 1996, Vermeij-Keers and associates146 postulated that the embryologic maldevelopment of
cloacal exstrophy is caused by poorly orchestrated cellular
proliferation and apoptosis, with resultant poor mesodermal
malformation from the umbilical ectodermal placode. Rather
than debate about the exact timing of the disintegration of
the cloacal membrane (8 versus 22 weeks), they describe the
urorectal septum, abdominal wall, and cloacal membrane as
related, with a similar origin (ectodermal placodes), and an
imbalance between cellular proliferation and cell death.
Anatomically, there is exstrophy of the foreshortened hindgut or cecum, which displays its bulging mucosa between the
two exstrophied hemibladders (Fig. 30-17). The orifice of the
terminal ileum, rudimentary tailgut, and a single appendix are
apparent on the surface of the everted cecum. The tailgut is
blind ending and is of varying length. The ileum may be prolapsed. The pubic symphysis is widely separated, the hips are
externally rotated and abducted, and the phallus is separated
into a right and a left half with an adjacent labium or scrotal
half. Sponseller and associates described the anatomy of the
bony pelvis in the patient with cloacal exstrophy.11 Using
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IV: Bladder
Prenatal Diagnosis
Since the use of ultrasonography for prenatal diagnosis of
cloacal exstrophy was initially described in the early 1980s,
further refinements have occurred.139,149 Chitrit and coworkers149 reported in 1993 the diagnosis of monozygotic twins
with cloacal exstrophy detected during antenatal ultrasound
Surgical Management
Immediate management is directed to the medical stabilization
of the infant. Evaluation and appropriate management of associated malformations should be undertaken. In infants with
few other associated malformations who are medically stable,
both bladder and omphalocele closure should be considered.
Bladder and bowel should be moistened with saline solution
and covered with a protective plastic dressing. Evaluation
of the genitalia and gender assignment should be made by a
gender assignment team, including a pediatric urologist, pediatric general surgeon, general pediatrician, pediatric endocrinologist, and psychiatrist familiar with ambiguous genitalia.
Consultation from the social work service, pediatric orthopedic surgical staff, and other relevant professionals should
also be obtained. In a large medical center with experience in
dealing with these patients, these multiple consultations can
be accomplished in a short period. In those patients with acute
medical issues, delayed closure after gastrointestinal diversion
is appropriate.153
Gender Assignment
Gender assignment decisions are limited to the genetic male
patient with cloacal exstrophy. Male gender assignment is certainly appropriate for boys with adequate bilateral or unilateral phallic structures. One of the most controversial issues in
pediatric urology concerns the genetic male patient who does
not have adequate phallic structures. A survey by Diamond
and associates154 questioned 185 pediatric urologists about
their management preferences for these patients. The two
thirds majority who favored male assignment voiced concerns
about testosterone imprinting on the brain during fetal and
early infantile development. They also interpreted the available data to indicate that patients raised male had better outcomes. A desire to avoid gonadectomy in very young patients
and optimism about future fertility with assisted reproductive technology were important factors as well. The minority
position of assigning female gender was supported by older
chapter
Surgical Reconstruction
Complete surgical reconstruction may be considered in an
infant who is medically stable. This includes closure of the
omphalocele, closure of the bladder and urethra, bony pelvis
closure, and repair of the external genitalia. Cloacal exstrophy
patients should undergo carefully planned and individualized
reconstruction procedures.158,159 In infants with spinal dysraphism and myelocystocele, neurosurgical consultation should
be obtained, and closure should be undertaken as soon as the
infant is medically stable. After closure of the myelocystocele, long-term follow-up is mandatory to evaluate for subtle
changes in neurologic examination findings that could herald
cord tethering.
Once the infant has recovered from closure of the myelocystocele, reconstruction should focus on the management of
the gastrointestinal tract. Omphalocele closures are combined
with gastrointestinal diversion or reconstruction. Formerly, initial attempts focused on ileostomy with resection of the hindgut remnant. With the recognition of the metabolic changes
in patients with ileostomy, the hindgut remnant was used to
provide an additional length of bowel for fluid absorption.153
Enlargement of the hindgut remnant and increased water
absorption have been noted in children who have had the
segment incorporated into construction of a fecal colostomy.
The hindgut segment may be anastomosed in an isoperistaltic
or retroperistaltic fashion to decrease motility and generate
formed stool. Children who have adequate colon, less severe
spinal abnormalities, good sphincter functionality, and the
413
Role of Osteotomy
Osteotomy is indicated in all children with cloacal exstrophy
at the time of bladder closure because of the wide pubic diastasis that is invariably present. Osteotomy allows the pelvic ring,
bladder, and abdominal wall to be closed without undue tension on the closure. Reduction in the incidence of dehiscence
and postoperative ventral hernias has been noted in patients
treated with osteotomy. In a large series reported by Ben-Chaim
and associates,160 significant complications occurred in 89% of
patients who underwent closure of cloacal exstrophy without
osteotomy, whereas these occurred in only 17% of patients who
underwent osteotomy at the time of initial closure. Patients
in the two groups were similar in terms of the size of the
omphalocele, the presence of myelomeningocele, and the time
of primary closure. However, osteotomy had no effect on the
eventual continence of cloacal exstrophy patients.
Currently, combined anterior innominate and vertical
iliac osteotomies are routinely used at our institution.160 This
approach does not require the patient to be repositioned on
the operating table before bladder and abdominal wall closure
procedures are commenced. The use of a posterior approach
and any complications from this procedure related to the
spinal and lower back closure are obviated. In a 1999 series
of five patients with extreme pubic diastasis (>10 cm), Silver
and coworkers161 described an initial pelvic osteotomy and
gradual closure of the pelvic fixator for 1 to 2 weeks, followed
by abdominal wall and bladder closure. Closure was successful in all patients without technical problems or surgical complications. This technique of staged pelvic closure also proved
reliable in a large series162 for secondary repair of cloacal
exstrophy when one-stage pelvic closure was unfeasible.
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Gastrointestinal Function
The growth and development of children with cloacal exstrophy strongly depends on a properly functioning gastrointestinal system.167 Recently, a greater emphasis has been placed
on preserving as much bowel as possible, in an effort to
reduce metabolic dysfunction and to provide the best possible
options for bowel management. Soffer and colleagues170 recommended that initial management of the newborn should
include omphalocele repair, bladder closure, and colostomy
using all available colon, including the hindgut remnant. They
discouraged the use of the hindgut for any genitourinary
reconstruction at that time. After a year or more of observation, the decision to perform a pull-through procedure or
definitive colostomy can be made based on availability of
colon, neurologic status, and ability to produce formed stools.
Avoidance of stomas and external appliances should be a priority if at all possible. This is a matter of convenience but also
a means to avoid life-threatening complications that are seen,
for example, in patients undergoing terminal ileostomy.171 It
should be noted that normal fecal continence is not the rule in
these patients, even in those undergoing pull-through procedures. Therefore, a frank discussion with parents describing
the ultimate need for dietary guidelines, motility agents, and
enemas should be part of early management. All reconstructive strategies should be developed in consultation with the
pediatric surgeons responsible for management of the gastrointestinal system, and involvement of a pediatric gastroenterologist who is interested in the complex care of these patients
is mandatory.
Summary
The management of cloacal exstrophy has evolved from
merely providing survival to providing improved quality of life for these children. Reconstruction using complete
chapter
415
Dedication
The authors would like to dedicate this chapter to the memory
of Robert Jeffs, MD, FCRS, FAAP, the first Pediatric Urology
Professor at the Johns Hopkins Hospital.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
31
BLADDER DIVERTICULA
Presentation
Although in some children bladder diverticula have no functional consequences, in others they produce bladder outlet
obstruction, vesicoureteral reflux (VUR), or ureteral obstruction or predispose to urinary tract infections. Bladder diverticula may enlarge to the extent that they compress the bladder
neck or proximal urethra (Fig. 31-3).18,19 A vicious cycle may
develop in which increased outlet resistance promotes further
filling of the diverticulum, resulting in increasing enlargement
of the diverticulum and, consequently, increasing obstruction.18,20 The bladder diverticula may become so large that
they herniate through the femoral or inguinal canal.21 Alternatively, bladder diverticula, especially those near the ureteral
orifice, may incorporate the ureteral tunnel, resulting in VUR
(Fig. 31-4).22 However, it remains unclear whether paraureteral
diverticula cause reflux or are merely associated with it.
In the literature, the incidence of VUR in association with
paraureteral diverticula ranges from 5% to 100%, whereas the
incidence of primary reflux associated with paraureteral diverticula ranges from 8% to 13%.3,7,23 In the past, the presence of
reflux with a paraureteral diverticulum dictated excision of
the diverticulum and ureteral reimplantation. Subsequently,
it was observed that reflux in association with a paraureteral
diverticulum may regress spontaneously. Amar22 noted that,
in girls, especially those with small diverticula, the associated reflux resolves spontaneously as the bladder matures; in
boys, the diverticula tended to be larger, and the associated
reflux was less likely to disappear. More recently, Afshar and
colleauges24 retrospectively evaluated the resolution of VUR
in children with and without congenital paraureteral diverticula. They observed that Kaplan-Meier analysis and the log
rank test did not demonstrate any difference in resolution rate
between the two groups; multivariate analysis demonstrated
grade as the only variable affecting the outcome. Currently,
it is generally accepted that the extent to which bladder
diverticula cause VUR depends on the dynamic interaction
between the ureteral orifice and the diverticulum. The ureteral orifice that becomes incorporated into the diverticulum
on filling is likely to reflux, owing to the displacement of
the ureteral orifice from the trigone and the shortening of its
submucosal tunnel.
Bladder diverticula may also cause ureteral obstruction.25-27
In a large study of children with bladder diverticula, Barrett
and associates7 noted that approximately 5% of the patients
had radiologic evidence of ureteral obstruction. In association
with ureteral obstruction, bladder diverticula may result in
ipsilateral renal dysplasia and may also obstruct the contralateral ureteral orifice. It is likely that the obstruction is caused
by direct ureteral compression by the diverticulum; inflammation or infection leading to peridiverticular and ureteral
fibrosis; or intrinsic hypomuscularity of the distal ureters and
ureterovesical junction resulting in a functional obstruction of
the ureterovesical junction.27
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31: Bladder Diverticula, Urachal Anomalies, and Other Uncommon Anomalies of the Bladder
417
Figure 31-2 Voiding cystourethrogram demonstrates multiple bladder diverticula in a patient with cutis laxa.
c hemotherapy, or both (depending on the type, grade, and
stage of the tumor) is often required.
Radiographic Evaluation
B
C
Figure 31-1 A, Common location for congenital bladder diverticulum. The ureters may insert near (B) or into (C) the diverticulum.
Management
The management of bladder diverticula depends on the symptoms, such as infection, obstruction, or reflux. In their absence,
intervention is often not necessary. However, surgical intervention may be required if there is recurrent infection, bladder
outlet obstruction, persistent VUR, or functionally significant
ureteral obstruction.
In the presence of bladder outlet obstruction, diverticulectomy is often necessary to relieve the obstruction of the
bladder neck or proximal urethra, using open surgical, endoscopic,37 or laparoscopic methods.38
For patients who have persistent reflux, diverticulectomy
with ureteral reimplantation is recommended. Traditionally,
this is performed intravesically, with careful attention to
reinforcing the hiatus to prevent postoperative diverticula
formation. However, extravesical detrusorrhaphy for the
refluxing ureters associated with paraureteral diverticula can
be performed with minimal postoperative morbidity and as
effectively as the intravesical method.39
In the presence of ureteral obstruction, management
depends on upper tract function of the affected renal unit,
requiring either diverticulectomy with reimplantation or
nephrectomy.
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IV: Bladder
Figure 31-3 Voiding cystourethrogram demonstrates progressive filling of the bladder diverticulum (D) during voiding (A and B) with resultant
obstruction of the outlet of the bladder (B) by the large diverticulum (C).
Figure 31-4 Voiding cystourethrogram demonstrates vesicoureteral reflux in a ureter that inserted into a diverticulum (arrow) (A), which allows
contrast material to reflux into the upper collecting system (B).
in diameter. It is surrounded by the umbilicovesical fascial
sheath, which extends laterally to each umbilical artery and
inferiorly over the bladder dome to the hypogastric arteries posteriorly and the pelvic diaphragm anteriorly, forming
a self-contained space that is capable of limiting the spread
of infection or neoplasm. The urachus is composed of three
histologic layers: an inner cuboidal or transition layer, a submucosal tissue layer, and an outer smooth muscle layer. The
central lumen is irregular and beaded and is filled with desquamated epithelial debris.40 In the sheep experimental model,
premature closure of the urachus results in hydronephrosis,41
suggesting that, during fetal life, the urachus provides a lowresistance outlet for drainage of the bladder while the urinary
sphincter matures.
Embryologically, the majority of the urachus is derived
from the bladder, and the proximal portion is formed from
the allantoic duct.42 As the bladder descends into the pelvis,
it retains its attachment to the umbilicus by the urachus. As
the urachus develops, it loses its attachment to the umbilicus.
Based on the differential growth rates of the urachus, anterior abdominal wall, and bladder descent, four anatomic
chapter
31: Bladder Diverticula, Urachal Anomalies, and Other Uncommon Anomalies of the Bladder
419
Figure 31-5 Voiding cystourethrogram demonstrates filling of the diverticulum (D) during bladder (B) filling (A) and during voiding (B). The
bladder diverticulum may fill during voiding and, because of its lack of musculature, cannot empty.
Umbilicus
Umbilicus
Umbilical
artery
Umbilical
artery
Urachus
Umbilical
artery
Bladder
Umbilical
artery
Urachus
Urachal Sinus
Umbilicus
Urachus
Umbilical
artery
Bladder
Umbilicus
Umbilical
artery
Plexus of Luschka
Umbilical
artery
Bladder
Umbilical
artery
Bladder
Urachus
B, type II; C, type III; D, type IV. See text for descriptions.
Urachal Cyst
rocess of the urachus. They rarely manifest in childhood
p
and may not be symptomatic until adulthood. In symptomatic patients, these anomalies are seen equally in males and
females. Common presenting symptoms include periumbilical discharge (42%), an umbilical mass (33%), abdominal or
420
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IV: Bladder
Bladder
Bladder
Urethra
Urethra
Figure 31-8 Contrast material fills in the bladder (B) and in the
Bladder
Bladder
Urethra
Urethra
chapter
31: Bladder Diverticula, Urachal Anomalies, and Other Uncommon Anomalies of the Bladder
421
Figure 31-10 Voiding cystourethrogram demonstrates a catheter in the patent urachus (A), with subsequent filling of the bladder with contrast
material through the patent urachus (B) and voiding through the urethra (C).
Patent Urachus
A patent urachusa communication between the umbilicus
and the bladderresults from the failure of a type I urachal termination variant to obliterate by desquamation of its epithelial
mucosa. In autopsy series, the incidence of a patent urachus
is 1 in 761.49 A patent urachus may be seen in patients with
prune-belly syndrome but is uncommon in those with PUV.52
Patent urachus may manifest as an incidental finding on newborn ultrasonography; as a wet umbilicus with surrounding
granulation tissue; as intermittent or continuous urinary drainage that is accentuated in the prone position or with crying,
straining, or voiding; or as a periumbilical swelling or mass
secondary to an associated umbilical hernia or engorgement
of the urachal vasculature.48 The diagnosis of a patent urachus
in patients with these symptoms should be differentiated from
that of omphalitis, granulation of a healing umbilical stump,
patent vitelline or omphalomesenteric duct, infected umbilical
vessel, and external urachal sinus. Analysis of periumbilical
fluid for creatinine or urea is useful in differentiating a patent
urachus from these other conditions, and a fistulogram with
radiopaque material is often diagnostic.45 A voiding cystourethrogram should be obtained to identify the fistula tract (Fig.
31-10) and, more importantly, to rule out the concomitant presence of bladder outlet obstruction or VUR.
In the management of a patent urachus, observation may
be indicated for young infants without symptoms, because the
involution of the urachus is not complete at birth, and spontaneous closure can occur during the first months of life.53 In
patients who have a patent urachus in association with bladder outlet obstruction, treatment of only the bladder outlet
Vesicourachal Diverticulum
Vesicourachal diverticulum develops when the communication between the bladder and the urachus fails to obliterate in
a type II or III urachal termination variant, resulting in a fusiform outpouching at the apex of the bladder (Fig. 31-11). The
422
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IV: Bladder
diverticulum is often nonobstructive, drains well, and therefore does not predispose to stagnation of urine or infection.48
It may be found in association with prune-belly syndrome
and other bladder outlet obstructive disorders. However,
vesicourachal diverticulum can also occur in the absence of
functional or anatomic obstruction.
The diverticulum does not usually require treatment. On
the rare occasions when it is large, empties poorly because of
a narrowed neck, or contracts paradoxically, excision of the
vesicourachal diverticulum may be required.
Management
Although most of these urachal anomalies are treated surgically, some patients with these anomalies are observed. Urachal carcinoma may develop within these anomalies, but it is
rare in children (0.01%55) and accounts for fewer than 0.34%
of all bladder cancers.56,57 The most common histologic type
is adenocarcinoma, but other types have been reported,
including transitional cell carcinoma,57 neuroblastoma,55
rhabdomyosarcoma,58 teratoma,59 yolk sac carcinoma,60 and
inflammatory myofibroblastic tumors.61 Patients with urachal
carcinoma most often present with hematuria and a palpable
mass. The most common finding on radiologic evaluation is a
filling defect within the bladder, with stippled calcifications.
Patients with adenocarcinoma of the urachus have improved
overall and disease-specific mortality risks compared to those
with adenocarcinoma of the bladder.62 However, the prognosis of patients with urachal adenocarcinoma often remains
poor because of late presentation with local invasion. Close
radiologic evaluation is therefore warranted in children with
urachal anomalies.
Bladder Agenesis
Bladder agenesis is a rare anomaly in viable newborns65,66;
most with this anomaly do not survive. Fewer than 20 live
births of infants with bladder agenesis have been reported in
the literature, with the majority being girls.67-69 Although most
of these patients are diagnosed during infancy, some patients
with bladder agenesis are not diagnosed until a later age.67 In
the absence of the bladder and trigone, the ureteral orifices follow the terminations of the mesonephric ducts and enter into
the urethra, the vestibule, or Gartner duct in the female or the
prostatic urethra in the male; or they may enter the rectum
or the patent urachus.69-72 The ureters may remain separate or
form a common channel. They are often hydronephrotic with
or without associated renal dysplasia. Bladder agenesis is
most often associated with neurologic, orthopedic,73 or other
urogenital anomalies such as solitary kidney, renal agenesis,
renal dysplasia, or an absence of the prostate, vagina, seminal
(arrow).
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31: Bladder Diverticula, Urachal Anomalies, and Other Uncommon Anomalies of the Bladder
423
Bladder Duplication
Bladder duplication anomalies can be classified as complete or
incomplete. In complete duplication, two bladder halves are
present, each with a full-thickness muscular wall and mucosa
(Fig. 31-14).85,86 Each bladder half is on one side of the midline,
has an ipsilateral ureter, and drains into its complementary
urethra. Fewer than 50 cases of complete bladder duplication
have been reported in the literature. This duplication anomaly
is more common in males. In 90% of cases, there is an associated
complete duplication of the penis in the male or of the vagina
terial filling two separate bladders (B) through two urethras (arrows).
There is reflux into the right collecting system. Each bladder has a
separate renal unit emptying into it.
424
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IV: Bladder
Figure 31-15 Ultrasound study (A) suggests the presence of bladder septation (arrow), which was later confirmed on intravenous pyelog
raphy (B).
ACKNOWLEDGMENT
We thank Dr. Robert Lebowitz for his invaluable assistance
with the photographs in this chapter.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
32
PRUNE-BELLY SYNDROME
Anthony A. Caldamone and John R. Woodard
EMBRYOLOGY
There have been several theories as to the embryogenesis of
PBS. However, there is no experimental model that can be
used to test these theories, so the exact mechanism remains
elusive. The four principal theories are (1) early in utero posterior urethral obstruction resulting in severe dilation of the urinary tract and possible fetal ascites and oligohydramnios7,10-12;
(2) a primary defect in the lateral plate mesoderm, which is
the precursor of the ureters, bladder, prostate, urethra, and
gubernaculum13,14; (3) an intrinsic defect of the urinary tract
leading to ureteral dilation and fetal ascites15-19; and (4) a yolk
sac defect.20,21 None of these theories has universal acceptance,
and there is some overlap among them.
GENETICS
A genetic basis to PBS is suggested by the high male-to-female
ratio, occasional occurrence in male siblings and cousins, and
the increased occurrence in twins. Yet most cases are sporadic
and have a normal karyotype. One in 23 children with PBS is the
product of a twin pregnancy.13 However, the majority of reported
twins have been discordant for PBS, evidence against a genetic
etiology. It has been suggested that the etiology in twins may
be an uneven distribution of mesenchymal tissue at a critical
time of primitive streak development during the third week of
Cardiac Anomalies
Cardiac anomalies, such as patent ductus arteriosus, atrial
septal defect, ventricular septal defect, and tetralogy of Fallot,
occur in 10% of children with PBS.43 Cardiac abnormalities at
birth may take precedence over urologic issues.
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IV: Bladder
Pulmonary
Lobar atelectasis
Pulmonary hypoplasia
Pneumothorax
Pneumomediastinum
Gastrointestinal
Intestinal malrotation
Intestinal atresias or stenosis
Omphalocele
Gastroschisis
Hirschsprungs disease
Imperforate anus
Hepatobiliary anomalies
Orthopedic
Miscellaneous
Splenic torsion
Adrenal cystic dysplasia
Modified from Woodard JR, Smith EA. Prune-belly syndrome. In: Walsh
PC, Retik AB, Vaughan ED Jr, Wein AJ, eds. Campbells Urology. 7th ed.
Philadelphia: WB Saunders; 1998:1991
Pulmonary Abnormalities
Pulmonary difficulties can be observed at any age in patients
with PBS. Pulmonary hypoplasia can result from severe oligohydramnios due to renal dysplasia or severe bladder outlet
obstruction and may result in death of the newborn. In addition,
pneumothorax and pneumomediastinum can be seen with or
without pulmonary hypoplasia.44 Significant pulmonary difficulties have been reported in 55% of PBS survivors.33 The lack of
ability to generate significant intra-abdominal pressure may contribute to pneumonia and lobar atelectasis.45,46 Acute respiratory
illnesses or an anesthetic procedure can easily lead to respiratory insufficiency in the PBS patient, who may have underlying chronic bronchitis from repeated respiratory illnesses. Many
patients demonstrate significant restrictive lung disease secondary to musculoskeletal abnormalities such as scoliosis, rib cage
abnormalities, and compromised abdominal musculature.22
Gastrointestinal Abnormalities
In at least 30% of cases, gastrointestinal anomalies are
observed. Most result from incomplete rotation of the midgut, which produces a wide mesentery, resulting in increased
bowel mobility with intestinal malrotation, volvulus, atresias,
and stenosis.47,48 Splenic torsion has also been reported due
to abnormal mesenteric fixation.49,50 Omphalocele, gastroschisis, and anorectal abnormalities (Fig. 32-3) have also been
reported.51-55 With a limited ability to generate intra-abdominal
pressure, constipation becomes a lifelong problem and leads
to acquired megacolon.41
Orthopedic Abnormalities
Orthopedic abnormalities, ranging in incidence from 30% to
45%, are second in frequency to those of the genitourinary tract
and abdominal wall. Many of these abnormalities result from
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427
Genitourinary Anomalies
Kidneys
The spectrum of renal abnormalities extends from normal
renal parenchyma to dysplasia. The more severely dysplastic
kidneys are generally associated with bladder outlet obstruction in which there has not been decompression through a patent urachus.59 Dysplasia is present in 50% of cases; however, it
may vary in degree and laterality.20,60 Renal dysplasia in PBS
of the Potter type II and IV varieties are seen. The Potter type
II variety with few nephrons and parenchymal disorganization is more indicative of a renal mesenchymal defect, whereas
the Potter type IV with cortical and tubular cysts is associated
with outlet obstruction.61
The renal collecting system is characteristically dilated, often
to a severe degree (Fig. 32-3). The degree of dilation, however,
does not correlate with the degree of renal dysplasia. Calyceal
morphology may be well preserved even in the face of massively
dilated ureters and renal pelves.62 Ureteropelvic junction obstruction can occur on a primary or secondary basis; however, nonobstructive hydronephrosis is the rule.63 It is renal infection, rather
than obstruction, that poses the greatest risk to renal function.
Ureters
The ureters are typically dilated, tortuous, and redundant
(see Fig. 32-3). The proximal (upper) portions of the ureters
are usually less abnormal than the distal segments, although
Bladder
The bladder usually appears massively enlarged, with a pseudodiverticulum at the urachus (see Fig. 32-4). The urachus is
patent at birth in 25% to 30% of children21,61,68 Histologically, the
bladder has an increased ratio of collagen to muscle fibers in the
absence of obstruction.69 The wall is smooth, unlike that seen
in obstructed bladders. The pelvic distribution of ganglion cells
has been shown to be normal.42,70 Smooth muscle hypertrophy
is seen in the obstructed prune bladder.71 As noted by Williams
and Burkholder, Stephens had demonstrated that the trigone is
splayed, with the ureteral orifices displaced laterally and superiorly, possibly contributing to the high incidence of reflux.6
On voiding, the bladder neck opens widely into a dilated
prostatic urethra (Fig. 32-5). Urodynamic assessment usually
shows normal compliance; however, there is a delayed first
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Anterior Urethra
The anterior urethra of the PBS child is usually normal, but
several anomalies have been reported, with the most common being urethral atresia and megalourethra.76,77 Unless it
is associated with a patent urachus, urethral atresia can be
lethal (Fig. 32-6). It has been postulated that urethral atresia or
microurethra occurs because the urethra is unused rather than
malformed. Spontaneous bladder rupture with fistula formation has also been reported.78
PBS is associated with two variations of megalourethra.79,80
The fusiform type is a deficiency of the corpus cavernosa as
well as the spongiosum, whereas the scaphoid variety is a
deficiency of the spongiosum only, with preservation of the
glans and corpora cavernosa (Fig. 32-7). With the scaphoid
variety, the ventral urethra dilates with voiding; with the
fusiform variety, the entire phallus dilates with voiding. The
fusiform variety is thought to result from a mesenchymal
deficiency of the urethral folds, whereas the scaphoid variety
results from a mesenchymal deficiency of the urethral supportive tissues.81 Megalourethra is more commonly seen in
PBS than in any other syndrome.82 Transient in utero obstruction of the junction between the glanular and penile urethra
has been proposed to cause megalourethra.
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Testes
The most typical finding is bilateral intra-abdominal testes lying
over the iliac vessels. Although mechanical forces such as a distended bladder and intra-abdominal pressure have been implicated in maldescent of the testes,83,84 the fact that some patients
with the typical urinary tract and abdominal musculature
anomalies (termed pseudo-prune patients) may have descended
testes raises some doubt as to a purely mechanical etiology.
Pak and colleagues85 compared the histology of the testis
in PBS patients with that of nonprune-belly intra-abdominal
testis as well as age-matched controls. They found no difference in germ cell counts, spermatogonia, or Leydig cells
between PBS and non-PBS patients with intra-abdominal testes.
However, germ cell counts in PBS patients younger than 1
year of age were similar to those of age-matched controls,
implying that the environmental state of the abdomen is a
major factor in their later spermatogenic potential.22,42 This
mirrors the finding by Nunn and Stephens of normal germinal
epithelium in fetal and newborn PBS testes.42 Alternatively,
Orvis and associates86 noted a decreased number of spermatogonia and Leydig cell hyperplasia in fetal PBS testes, implying
an intrinsic testicular abnormality. Azoospermia was found in
adult PBS patients, and no patient with PBS has been reported
to have fathered a child.87 More recently, Ross and associates88
documented paternity in three adults with classic PBS, which
was achieved by sperm retrieval techniques and intracytoplasmic sperm injection (ICSI). The infertility is thought to be
caused by a combination of testicular histologic abnormalities,
structural defects of the ducts, and prostatic abnormalities.89
Three cases of testis tumor have been reported.90-93 Massad
and coworkers93 described histologic testicular patterns similar
to intratubular germ cell neoplasia in three infants. Although
the risk of malignancy may be relatively low considering the
lack of germinal epithelium,94 it is clear that placement of the
testis in the scrotum and long-term follow-up are necessary
to potentially reduce the risk of testicular malignancy and
enhance detection.
PRESENTATION
Prenatal Diagnosis and Management
Fetal hydronephrosis can be diagnosed accurately in the second trimester and is present in approximately 1% of all pregnancies. However, the cause of the hydronephrosis cannot be
B
Figure 32-9 A, Prenatal ultrasound scan demonstrates distended
bladder with dilated proximal urethra. B, Echogenic renal parenchyma bilaterally with moderate hydronephrosis. (Courtesy of
L. Ruiz.)
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IV: Bladder
Category Classification
Oligohydramnios, pulmonary
hypoplasia, or pneumothorax;
may have urethral obstruction or
patent urachus
II
III
From Woodard JR. Prune belly syndrome. In: Kelalis PP, King LR, Belman
AB, eds. Clinical Pediatric Urology. Philadelphia: WB Saunders; 1985:805-824.
Neonatal Presentation
The appearance of the abdominal wall immediately suggests
the diagnosis of PBS (see Fig. 32-1), whether or not the diagnosis was suspected prenatally. It should be remembered that
other associated abnormalities, such as cardiac or pulmonary,
often should take precedence over the urinary tract, because in
the absence of true bladder outlet obstruction, as seen with urethral atresia, the hydroureteronephrosis is not life-threatening.
Spectrum of Disease
With the number of variable anomalies present in PBS, it is
understandable that there is a wide spectrum of clinical presentations. Three major categories of presentation in the neonatal period were described by Woodard 116 (Table 32-2).
In category I are neonates who have experienced marked
oligohydramnios as a result of renal dysplasia or severe bladder outlet obstruction or both, with resultant pulmonary hypoplasia and skeletal abnormalities. Most infants with urethral
atresia are in this category. The exceptions are those patients
with urethral atresia and a patent urachus.60 Patients in this
category who are not stillborn commonly succumb within
a few days of life to pulmonary hypoplasia or later to renal
failure. Approximately 20% of newborns with PBS die in the
perinatal period.63,66,117 It would be unusual for any urologic
intervention in this category of patients to alter the course of
events. Simple catheter drainage is all that is justifiable.
Category II demonstrates the full spectrum of the disorder,
with moderate or unilateral renal insufficiency and moderate
to severe hydroureteronephrosis. Pulmonary hypoplasia is
Incomplete Syndrome
Male patients who may not have all the features of the triad
syndrome but share other features are said to have incomplete
syndrome. Most typically, they lack the typical abdominal wall
features but have the common uropathy and cryptorchidism.
Because many of these patients go on to renal failure, they
require close observation, monitoring, and selective intervention. Bellah and associates121 reported a relatively high
tendency to progressive renal failure in their population of
pseudo-prune patients. This finding may be partially attributed to a delay in diagnosis in the absence of the obvious
abdominal musculature deficiency and a resultant tendency to
present with recurring urinary tract infections.
Adult Presentation
Patients with incomplete forms of PBS, and specifically those
who lack the abdominal wall features, may present as late
as adulthood with symptoms of renal failure and hypertension.122,123 Although there have been isolated reports of adults
with no history of urinary tract infections, most others who
present in adulthood eventually develop urinary infections
because of the chronic urinary stasis associated with the
syndrome.124
Female Syndrome
Five percent of PBS patients are female; most of them have the
abdominal wall deficiency and the abnormal urinary tract.9
Rabinowitz and Schillinger8 reported female patients with the
typical abdominal wall deficit and a normal urinary tract. In
the series by Reinberg and colleagues, bladder outlet obstruction was commonly seen, along with a 40% occurrence of anorectal anomalies; like male with PBS, 40% did not survive the
newborn period.9
MANAGEMENT
Postnatal Evaluation and Management
The initial evaluation of the newborn with PBS requires a team
consisting of a neonatologist, a nephrologist, and a urologist.
As dictated by the findings, other specialists, particularly
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the testes reach the scrotum after neonatal transabdominal mobilization of the spermatic cords. (From Wein AJ, Kavoussi LR, Novick AC,
et al., eds. Campbell-Walsh Urology. 9th ed. Philadelphia: WB Saunders; 2007, Chapter 118, Fig. 11.)
persist regarding category II patients until accurate application of a medical or surgical approach is possible based on
distinct clinical features. Dnes and coworkers136 emphasized
the individualization of care in their 17-year experience with
32 patients.
Surgical Management
Surgical management of children with PBS can be divided into
three categories: urinary tract reconstruction, abdominal wall
reconstruction, and orchidopexy. Urinary tract reconstruction
is generally reserved for those children with progressive or
severe hydronephrosis, recurrent upper tract infections, true
obstructive uropathy, and progressive renal failure. Temporary urinary diversion also has a role in the very young or the
very ill child.
usually provides adequate upper tract drainage and decompression, in rare instances more proximal diversion is indicated because of ureteropelvic or ureterovesical junction
obstruction. Here, a cutaneous pyeloplasty is advocated
rather than proximal ureterostomy, because the former procedure provides the best upper tract drainage and avoids the
sacrifice of a normal proximal ureter that might be useful in
later reconstruction.
Urinary diversion may be necessary as a temporary measure
in children with acute renal failure, urinary sepsis, or bladder
outlet obstruction from urethral atresia with limited patency
of the urachus.137 If temporary urinary diversion is indicated,
a cutaneous vesicostomy is the procedure of choice. This is best
done by the Blocksom technique as described by Duckett.138,139
If there is a large urachal diverticula, it can be excised at that
time. It is advisable to create a larger than normal stoma in the
PBS patient, because stenosis is common, most likely because
of the decreased intra-abdominal pressure.140
Ureteral Reconstruction
Ureteral remodeling remains controversial. It is best undertaken in those children who have demonstrated repeated,
nonsuppressible upper urinary tract infections and those with
progressive upper tract deterioration. The goal of remodeling is to reduce urinary stasis. The key to success relies on
meticulous surgical technique and preservation of the upper
few centimeters of proximal ureter for reconstruction. Ureteral reimplantation into the abnormal bladder can be difficult
because the creation of a submucosal tunnel is challenging.141
Woodards group has demonstrated excellent success in this
population with procedures performed in the neonatal period
or in the older child.63,142 However, they no longer recommend
chapter
Internal Urethrotomy
In the absence of urethral atresia, true anatomic obstruction of
the urethra is rare in PBS. However, the normal resistance of
the urinary sphincter has been implicated in unbalanced urethrovesical function contributing to large postvoid residuals.
Snyder 72 and Cukier143 and their colleagues proposed lowering the urethral resistance by internal urethrotomy to improve
bladder emptying. In patients studied by urodynamic flow
rate profilometry, improved flow rates with reduced residual
urine and improvement in the radiographic appearance of the
upper tracts were demonstrated.129 Although sustained longterm success has not been demonstrated, internal urethrotomy
should be considered in PBS children with high postvoid
433
Figure 32-12 Surgical technique for Monfort abdominoplasty and concomitant reconstruction of prune-belly uropathy. A, Redundancy is de-
lineated by tenting up the abdominal wall. B, Skin incisions are outlined with a separate circumscribing incision to isolate the umbilicus. C, Skin
(epidermis and dermis only) is excised with electrocautery. D, Abdominal wall central plate is incised at the lateral border of the rectus muscle on
either side, from the superior epigastric to the inferior epigastric vessels, creating a central musculofascial plate. E, Adequate exposure is provided
for concomitant transperitoneal genitourinary procedures. F, Only the more normal proximal ureter is preserved for vesicoureteral reimplantation, and the urachal diverticulum is excised.
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Figure 32-12, contd G, Transtrigonal ureteral reimplantation is performed with or without ureteral tapering as necessary. The bladder is
closed in two layers, and ureteral stents (not shown) and a cystostomy tube are employed. H, Abdominoplasty is completed by scoring the parietal peritoneum overlying the lateral abdominal wall musculature with electrocautery. I, The edges of the central plate are sutured to the lateral
abdominal wall musculature along the scored line. J, Lateral flaps are brought together in the midline, with closed suction drains placed between
the lateral flaps and the central plate. Skin is brought together in the midline, enveloping the previously isolated umbilicus. (From Woodard JR,
Perez LM. Prune-belly syndrome. In: Marshall FF, ed. Operative Urology. Philadelphia: WB Saunders; 1996.)
colleagues, however, this technique is not uniformly successful, and a more formal urethroplasty may be required, with
skin flaps or grafts or both.78
Megalourethra in PBS may be either fusiform or scaphoid.82 This is best approached with a circumferential subcoronal incision and penile degloving (Fig. 32-10). The redundant
urethra can be excised and the urethra reconstructed over a
catheter of appropriate size. Alternatively, some of the urethra
can be used to reinforce the urethroplasty, because in either
form of megalourethra the spongiosum is deficient.
Reduction Cystoplasty
In many PBS patients, poor bladder contractibility leads to
incomplete and infrequent emptying, resulting from the compli
cating urinary stasis and vesicoureteral reflux issues. This
has led to the concept of reducing the size of the bladder and
remodeling it into a more spherical shape to better direct the
contractible forces.71 A variety of approaches have been proposed, from simple excision of the urachal diverticulum to the
excision of redundant mucosa with the creation of overlapping
flaps to improve contractibility.141,147 Over time, however, high
bladder capacity and residual volumes seem to recur.148,149
Therefore, it would seem that reduction cystoplasty is justified
only to remove the larger urachal diverticulum or as part of a
more extensive internal reconstruction. Intermittent catheterization through the urethra or through an appendicovesicostomy
Orchidopexy
The timing of orchidopexy is dictated by our current understanding of the need for early treatment of the undescended
testis in non-PBS patients as well as the individual PBS
patients needs for either temporary or reconstructive surgery.
Although the fertility potential of the PBS patient is known to
be compromised, germ cells are present in the testes of infants
with PBS, and the prognosis for normal hormonal function
at puberty is excellent. These factors, along with the potential risk of testicular carcinoma,93,94 justify early orchidopexy.
Because the testes are uniformly located in the abdomen, most
commonly on a broad mesorchium overlying the iliac vessels,22 standard inguinal approaches are not usually successful
in achieving a satisfactory scrotal position. Four alternative
approaches may be considered.
Woodard and Parrott,63,150 as well as others,39,66 observed
that, if an orchidopexy is done in the neonatal period and up to
6 months of age by a transabdominal approach, adequate spermatic vessel mobilization can usually be achieved for scrotal
placement (Fig. 32-11). Transabdominal bilateral orchidopexy
at about 6 months of age is currently considered the approach
of choice. This approach is often used in conjunction with
other abdominal surgeries, such as vesicostomy, urinary
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435
LONG-TERM OUTLOOK
The nadir creatinine concentration during infancy has proved
to be a useful predictor of long-term renal function. If the
nadir value is less than 0.7 mg/dL, renal function tends to be
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IV: Bladder
stable during childhood unless there is further renal compromise from pyelonephritis.33,126,127 The importance of urinary
tract monitoring by periodic cultures and prompt treatment of
urinary tract infections cannot be overemphasized. Unfortunately, the risk of infection is constant in the setting of urinary
tract dilation and stasis.
As many as 30% of patients, typically those with impaired
renal function at initial evaluation, develop chronic renal
failure during childhood or adolescence.33 Renal transplantation is necessary for these patients to ensure normal growth
and development, and success with transplantation in PBS
patients can be expected to equal that in other age-matched
groups.135
Normal growth can be expected in most of the patients
with normal renal function, although growth retardation in
the absence of renal compromise was observed in one third
of the patients in one series.33 A normal pattern of secondary
REFERENCES
For complete list of references log onto www.expertconsult.com
P A R T
33
number of cases and included adult patients who had previously been instrumented. The most common type of obstruction according to the Young classification is type I valves, which
lie as fins of mucosal tissue that radiate from the urethral crest
of the distal verumontanum and sweep across the urethral
lumen to fuse anteriorly.1 Young type III valves are obstructing
diaphragms that lie in a transverse plane to the urethral lumen
and originate distal to the verumontanum, near the bulbomembranous junction. The openings in the type III diaphragm valve
vary in size and location. Type II valves, rarely mentioned in the
literature, are mucosal folds that radiate from the proximal
aspect of the verumontanum and extend cephalad to the bladder neck.1 Among the original 21 valve cases described by Young
and colleagues in 19191 and Young and McKay in 1929,2 there
were only 2 type II valves. Later, type II valves were described
in patients with voiding abnormalities, but their association
with abnormal urethral or bladder function is not documented.
Both Pieretti3 and Hendren4 found patients with simultaneous
type II and type I or III valves, perhaps suggesting that the type
II lesion results from a more distal obstruction.
The Young classification of valves has been challenged by
several urologists, who have argued that prior instrumentation,
inadequate direct endoscopic visualization, and distortion of
the anatomy at postmortem examination tended to make the
Young classification incorrect. Indeed, only 8 of Young and
associates 21 patients were examined endoscopically. Few
can argue that modern videoendoscopic techniques allow a
more rigorous assessment of urethral anatomy. Postmortem
and endoscopic data suggest a diaphragmatic configuration
in all valves that is iatrogenically altered by urethral instrumentation.5-7 Robertson and Hayes6 unroofed the anterior
urethral wall in 17 formalin-fixed postmortem specimens and
found an obstructing diaphragm with a posterior opening,
rather than two valve leaflets, in all cases. In a prospective
endoscopic study, Dewan5 evaluated infants with suspected
urethral obstruction prior to any other urethral instrumentation. On cystourethroscopy, he found that the obstructing
lesions were urethral membranes with a posterior opening.
On passage of the cystoscope, the membrane split into two
leaflets, as had previously been described by Parkkulainen.7
Using endoscopic videorecording, Dewan5 performed a retrospective study of obstructive urethral anatomy. By comparing
Young and associates descriptions with his modern observations, Dewan5 concluded that lesions described as either type
I or type III valves were actually membranes extending from
437
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part
instability. The researchers found minor valve leaflets on cystoscopy and reported improvement in symptoms after valve
ablation.11 The contribution of bladder retraining alone in
this population has not yet been addressed, leaving intact the
argument that these minor urethral lesions exist with functional rather than anatomic obstruction.
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A Bugbee electrode passed through the working channel of a 5F cystourethroscope is a useful technique in very
small infants whose urethras cannot accommodate the larger
instruments. Potassium-titanyl-phosphate (KTP) laser valve
ablation has been reported to be safe in newborn infants, with
no urethral stricture formation at 3 years follow-up; incontinence was not addressed in this study.38 Because the KTP laser
penetrates up to 2 mm and has some forward scatter, its use in
the newborn urethra is not without risk.
On preliminary urethrocystoscopy, it is important to define
the infant urethral anatomy for safe, effective treatment of the
obstruction. Distortion of the normal urethral anatomy may
occur secondary to obstruction and can cause confusion in distinguishing the obstructive lesion from the normal contours of
the posterior urethra.
The concept of the external sphincter as a short band of
circumferential striated muscle distal to the verumontanum is
widely held. However, postmortem dissections in term infants
demonstrate the urethral sphincter extending the entire length
of the prepenile urethra.39 The muscle is horseshoe-shaped at
the bladder neck and extends down over the lateral surfaces of
the prostatic urethra. The proximal extent of the sphincter can
be quite prominent, causing confusion even to the experienced
surgeon. Although uninterrupted from the bladder to the perineal membrane, the distal end of the sphincter as it surrounds
the membranous urethra is twice as thick as the proximal end.
The configuration of the sphincter changes after the newborn
period, with further modifications at puberty and adulthood
secondary to the muscles association with the prostate, bulbourethral glands, and ejaculatory ducts. The verumontanum
is the critical landmark to identify before valve incision.
An endoscopic evaluation of congenital urethral lesions in
44 boys indicated that all obstructing lesions of the posterior
urethra were attached to the caudal end of the verumontanum,
extending obliquely from the back of the posterior urethra and
ending distally on the anterior urethral wall.5 The prominent
distal aspect of the external urinary sphincter appears very
separate from the distal end of the verumontanum and should
not be confused with a valve lesion. Such a finding is common
in boys with functional bladder outlet obstruction only. Once
the structures are clearly identified, the valve tissue can safely
be incised at the 5-, 7-, and 12-oclock positions. An indwelling
catheter is typically left in place at the end of the procedure for
immediate postoperative fluid management.
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443
Figure 33-4 Newborn ultrasonogram in a male infant with severe renal and bladder abnormalities associated with posterior urethral valves.
A, Left multicystic dysplastic kidney with massive right hydroureter in midline. B, Right dysplastic kidney.
Case Report
An infant boy was born at term with minimal maternal
prenatal care and no prenatal ultrasonography. Bilateral
pneumothoraces led to abdominal imaging and renal ultrasonography demonstrating bilateral cystic, dysplastic kidneys (Fig.33-4). The VCUG demonstrated massive right
VUR, several large bladder diverticula, and a small bladder
(Fig. 33-5). The gross dilation of the prostatic urethra was
so severe that it was initially mistaken for the bladder. The
serumcreatinine level fell from 4.1 to 3.9 mg/dL after catheter
drainage.
Cystourethroscopy confirmed large fleshy valves, which
were incised. The bladder was unusually small, and the right
ureteral orifice was obscured within a large diverticulum. At
6 weeks of life, a furosemide (Lasix) renogram was obtained
that demonstrated no function in the left kidney and poor
drainage from the right refluxing kidney. Ultrasonography
continued to demonstrate poor right renal parenchyma,
right hydroureteronephrosis, and a left cystic kidney without
visualization of the left ureter. In the first 4 months of life,
the infant developed recurrent episodes of urosepsis despite
prophylactic antibiotic therapy. A right end-cutaneous ureterostomy was performed, at which time a narrowed ureteral
segment proximal to the right paraureteral diverticulum was
severe urethral obstruction (same infant as in Fig. 33-4). Note the small
bladder (b) with multiple diverticula (d) and high-grade right vesicoureteral reflux into the grossly dilated right ureter. p, prostatic urethra;
u, right refluxing, obstructed ureter.
444
part
Reflux grade
(R)
Pre-op
(L)
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
(R)
Post-op
(L)
6
7
8
9 10 11
Patients
Figure 33-6 Spontaneous resolution of vesicoureteral reflux 1 year
after valve ablation alone. Results from 19 refluxing units in 11 patients are depicted. Persistence of reflux is associated with a nonfunctioning renal unit in 2 patients and upper tract duplication in 1 patient.
Post-op, 1 year postoperative; Pre-op, before valve ablation; L, left;
R, right.
Organ
Pathology
Clinical Results
Kidneys
Dysplasia,
c oncentrating defect
Ureters
Dilated, poor
peristalsis
Bladder
Poor compliance,
relatively small
volume, reduced
sensation to high
pressure
Urethra
Voiding dysfunction
chapter
445
Figure 33-7 A, Voiding cystourethrogram (VCUG) of a newborn infant with posterior urethral valves. Note bladder wall trabeculation and
diverticula. B, VCUG of the same patient 1 year after newborn valve ablation demonstrates a healed bladder with a smooth wall and normal
capacity.
A large study with 10-year follow-up after renal transplantation demonstrated no difference in graft survival and
creatinine levels when comparing children with PUV and
children with nonobstructive causes of renal failure.52 These
data may reflect the improvement in urologic management
of valve bladder. The conclusion that the valve bladder will
not negatively affect renal allografts is not supported by a
long-term follow-up evaluation addressing bladder function
and outcomes of renal transplantation. Salomon and coworkers53 reviewed the voiding history of 44 valve patients who
were monitored for a mean of 9 years after renal transplantation. They found an elevation of serum creatinine after 5 years
of follow-up in boys with symptoms of bladder dysfunction
including incontinence, urinary urgency, frequency, and difficulty emptying. Because of the relentless effects of the bladder on the upper tracts, the preservation of bladder function
must be of primary consideration in all patients with PUV as
management decisions are made.
REFERENCES
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CHAPTER
34
PATHOLOGIC CONDITIONS
Timing of the Urethral Anomalies
1. Urethral duplication: 10 to 14 weeks of gestation
2. Anterior urethral valvesurethral diverticulum: various
prenatal
3. Syringocele: various prenatal
4. Urethral prolapse: various postnatal
5. Urethral stricture: various postnatal
6. Urethrorrhagia idiopathica posterior: puberty
7. Cowper duct and cysts: 10 to 14 weeks of gestation to
postnatal
Classification
The anatomic diversity and lack of a uniform embryologic theory have led to many classifications of urethral duplication. As
a consequence, there is a confusion in the literature concerning
complete versus incomplete duplication and accessory urethra
versus urethral duplication.
According to Ortolano and Nasrallah,6 a urethral duplication
must originate from the bladder, bladder neck, or prostatic
urethra. An accessory urethra originates distally off the prostatic urethra or is a blind-ending passage rising from a separate
external opening.
Middleton and Melzer7 considered a complete urethral
duplication to originate proximally from the external urethral
sphincter, whereas an incomplete urethral duplication originates
distally from that sphincter. They also recognized two channels
ending in one external orifice as an internal urethral duplication. In Table 34-1, a more clinical classification elaborated
by Williams and Kenawi is outlined.10 This classification
is simple and was reported frequently in the literature.11,12
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447
Bladder neck
Venous plexus
External (striated)
sphincter
Mucosa
External meatus
Venous plexus
Mucosa
External (striated)
sphincter
448
part
Primary
urethral
groove
Urethral
fold
Urethral
plate
D
Urethra
(penis)
Embryology
The embryologic explanation of urethral duplication remains
unknown. However, various theories have been proposed.
One theory considers that the defect arises in the 7th week
of embryologic development, when the urorectal septum,
which consists of a superior mesodermal fold (fold of Tourneux) and two lateral mesodermal folds (folds of Rathke),
divides the cloaca into a posterior rectum and an anterior
primitive urogenital sinus.18 Another theory states that if the
urorectal septum does not cease to grow, it can split not only
the cloaca but also the onset of the urethra.7 A third theory
hypothesizes that the ingrowth of the mesonephric wolffian
duct leads to division of the primitive urogenital sinus into
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449
Ectodermal
intrusion
Clinical Findings
Urethral plate
(endodermal)
Urethral fold
Ectodermal
intrusion
Urethral plate
(endodermal)
Fossa navicularis
Associated Findings
Patients with a urethral duplication and an epispadiac meatus
frequently have a wider symphysis pubis, as is found in
patients with isolated epispadias or exstrophy (see Fig. 34-7D).
As mentioned previously, the infraumbilical wall, the genital
tubercle, and the symphysis pubis are formed by the ingrowth
of lateral mesoderm between the ectodermal and the endodermal layers of the cloacal membrane.10 If the cloacal membrane
ruptures too early or is too long and splits the genital tubercle,
the mesodermal structures are not capable of closing the midline defect.18 In the case of isolated epispadias, the cavity on
the dorsum of the penis (former genital tubercle) is linked with
the definitive urogenital sinus. If, however, the urethral plate
canalizes all along the penis, urethral duplication with an epispadiac opening could arise. The abnormally wide symphysis
pubis in these patients strongly suggests that this type of urethral duplication originates according to the same embryologic
mechanism as the epispadias-exstrophy complex.10,13
A type IIA2 urethral duplication with a Y-shaped urethra
might be caused by a failure in the alignment of the folds of
Tourneux and Rathke, so that a congenital urethroperineal fistula is formed.13 However, the urethroperineal or urethroanal
urethra is the more functional one, and the orthotopic urethra
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part
Seminal
vesicles
Prostate
Corporal
body
Prostatic urethra
(region 1)
External striated
sphincter
Penile
urethra
(region 4)
Bulbomembranous
urethra (region 2)
Bulbospongious
urethra (region 3)
Spongious
tissue
urethra: prostatic urethra, bulbomembranous urethra, bulbospongious urethra, and the pars pendulans or penile urethra.
Sagittal Duplications
Epispadiac (dorsal penile accessory meatus)
Complete: two channels leave the bladder separately
Incomplete: one channel from the bladder divides distally
Abortive: blind penile sinus
Hypospadiac (both urethras beneath corpora cavernosa)
Complete: two channels leave the bladder separately
Incomplete: urethra divides below the bladder
Abortive: both orifices in hypospadiac position, with the blind
sinus lying dorsal to the urethra
Spindle urethra (the urethra splits into two and then reunites)
Treatment
If a collateral urethral duplication or a true Y-shaped urethral duplication (type IIA2) is found, a complete workup
with investigation of the spine, kidneys, and lower genitourinary and gastrointestinal tracts should be performed.
Diagnosis
If clinical suspicion of urethral duplication exists, besides
the physical examination, a complete visualization of both
channels should be sought. An antegrade VCUR should be
chapter
Type IA
451
Type IB
Type IIA1
Type IIA2
Type IIA2
Y duplication
Type IIB
Figure 34-5 The classification of urethral duplication developed by Effmann and associates.13 A, Type IA: distal blind duplication. B, Type IB:
proximal blind duplication. C, Type IIA1: two noncommunicating urethras. D, Type IIA2: urethra bifurcates distal of the bladder. E, Type IIA2
with Y-shaped duplication. F, Type IIB: urethra bifurcates and re-fuses. (Courtesy of Jochen Darras, M.D.)
urethroplasty anastomosing the ventral urethra with the dorsal urethra might be a good alternative.6,7
If the patient appears to have a hypoplastic urethroperineal
canal with orthotopic normal functional urethra, the urethroperineal canal can be removed through a perineal incision.
For some urethral duplications in which the two channels are running beside each other, some authors suggest a
transurethral incision of the interurethral septum.11,12 This
technique is useful for patients with a spindle urethra and collateral urethral duplication, but it appears to be less successful
for those with other urethral duplications.6,7
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part
Figure 34-6 This 9-year-old boy has an asymptomatic and blindending second epispadiac urethra.
William Cowper (1699).21 In girls, the homologous glands are
known as Bartholin glands. As depicted in Figure 34-9, the
ducts are located within the spongiosus tissue and have small
openings into the bulbar urethra. The glands normally secrete
a fluid that acts as a lubricant for semen during ejaculation.
Colodny and Lebowitz22 were the first to describe reflux of
contrast medium into the small ducts during urethrography.
In 1983 Maizels and coworkers23 described a classification of
dilations of the gland based on clinical characteristics of eight
boys. They also introduced the term syringocele (from syrongos,
meaning tube, and cele, meaning swelling).
Rarely, a dilated Cowper gland or duct may be seen as a
typical syringocele endoscopically within the urethra, because
the membrane can be ruptured or perforated very easily.
A syringocele (Fig. 34-10) can cause a urethral obstruction in
the neonate (Fig. 34-11). More often, abnormalities of the
Cowper ducts are asymptomatic and diagnosed only occasionally (2% to 3%).21 Sometimes, nonspecific symptoms such as
dribbling, urgency, urethral obstruction, or hematuria occur.
Reflux into dilated ducts can occur secondary to an anterior obstruction.
The diagnosis of a syringocele or other abnormalities of the
Cowper gland or duct is made by antegrade (see Fig. 34-10) or
retrograde urethrography and urethroscopy. However, in the
situation of late diagnosis, complications such as bleeding or
infection may occur. Therefore, in the absence of an abnormal
antegrade VCUG or retrograde urethrography and persistent
problems such as bleeding or infection, a syringocele or other
abnormality of the Cowper gland can be seen by ultrasound of
the urethra or by magnetic resonance imaging (Fig. 34-12).
In most cases, spontaneous perforation or rupture
requires no further treatment. However, if endoscopic persistence is seen, transurethral incision will solve the problem. Only very few patients require open surgical correction
with marsupialization. On rare occasions, secondary dilation due to urethral strictures requires additional or specific
treatment.
Urethral Prolapse
Urethral prolapse can occur in young girls. It consists of a
mostly painless protrusion of the urethral mucosa. Because it
has the clinical characteristic of swelling of the mucosa in the
urogenital area (Fig. 34-13A), it is often falsely diagnosed as a
vaginal tumor. There is a predominance of incidence in black
girls, and the exact cause of the problem is unknown. The most
evident hypothesis for urethral prolapse is poor attachment
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453
Figure 34-7 A 16-year-old boy presented with recurrent urinary infections and a second epispadiac meatus. However, his first urinary infection
was discovered during his stay in the maternity ward as a neonate. He had a total circumcision at 12 years of age because of phimosis, and at that
time a second opening on the glans was observed dorsally (A). B, Voiding excretory urography showed a complete duplication of the urethra.
C, During urethrocystoscopy, after insertion of a guidewire through the supplementary opening, an additional internal urethral orifice was seen
on the level of the bladder neck, ventrolateral left to the orthotopic urethral opening. D, On anteroposterior plain radiographic film, the symphysis
appears at least 7 mm wider than is normal for his age.
between the smooth muscle layers of the urethra in association
with episodic increases in intra-abdominal pressure.
Urethral prolapse can manifest similarly to a urethral
polyp, a prolapsed extravesical ureterocele, a periurethral
abscess, or a vaginal problem.
The diagnosis is mainly clinical and is completed with
endoscopic evaluation.
Conservative treatment should be attempted with Sitz
bathing and oral antibiotics. However, in most cases, surgical
excision of the prolapse and mucosal adaptation is needed.
Placement of a transurethral catheter facilitates the surgical correction and adaptation of the mucosal edges (see Fig. 34-13B).
There are rarely any complications or recurrence.
Urethral Polyps
Urethral polyps in girls are extremely rare and may be diagnosed as small, red, painful masses at the urethra. They are probably prolapsing urothelium that have evolved into polyps and
t herefore can be considered as partial urethral prolapse. The excision, identical to that described for urethral prolapse, is curative.
Urethral Stricture
Strictures can occur in the male or female urethra. They can be
congenital or secondary to trauma, infection, or surgery (Table
34-3). In the male, strictures can occur in the posterior urethra
(membranous and prostatic tract) and in the anterior urethra
(fossa navicularis, penile and bulbar tract).
Seventy-five percent of congenital urethral strictures are
located in the pars bulbosa of the male urethra. The explanation can be found in the embryologic development. This is the
place where the proximal urethra, derived from endodermal
origin, merges with the urogenital membrane. Another explanation for these strictures could be that the urogenital membrane does not retract completely.
Traumatic straddle injuries most frequently lead to bulbar
strictures, whereas pelvic injuries and associated ruptures of
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part
Figure 34-8 Voiding cystourethrogram of an 18-year-old male patient complaining for the first time of anal urinary leakage during
micturition. A normal orthotopic urethra and a hypoplastic secondary urethroanal urethra, arising from the prostatic urethra, are seen.
The urethroanal urethra was surgically removed and ligated up to the
level of the prostate.
Symphysis
Urethra
Cowper duct
Spongiosus
tissue
Cowper gland
chapter
455
Cowper
Cowper
gland
duct
Syringocele
Symphysis
Urethra
Syringocele
Spongiosus
tissue
456
part
Figure 34-12 A, Image obtained during voiding cystourethrography clearly demonstrates a syringocele. B, In the same patient, a retrograde
urethrogram demonstrates a normal urethra. C, Image obtained by ultrasonographic scanning of the urethra demonstrates an inhomogeneous
content of the syringocele and suggests either bleeding or pus. D, Magnetic resonance imaging scan of the same patient demonstrates the syringocele and its relation to the urethra, spongiosus tissue, and cavernosal bodies.
chapter
457
Figure 34-13 A, A 3-year-old girl presented with an asymptomatic urethral prolapse. B, A catheter was placed to facilitate the surgical removal
and adaptation of the mucosal edges.
Strictures
Etiology
Location
Congenital
Bulbar
Bulbar
Infectious
Anterior up to bulbar
Megalourethra
A congenital megalourethra is an enlargement of the pendulous urethra without evidence of distal obstruction. It should
be differentiated from acquired megalourethra, which is most
frequently caused by a complication of the transverse preputial island flap urethroplasty in boys with hypospadias or the
epispadias-exstrophy complex. Dorairajan34 described two
forms of congenital megalourethra based on the shape and
extent of associated defects of erectile tissue (Fig. 34-15):
1. Fusiform type: the ectatic urethra has a focal absence of
corpus cavernosum and corpus spongiosum.
2. Scaphoid type: the ectatic urethra has a focal absence of
corpus spongiosum but is dorsally splinted by intact corpus cavernosum.
The degree of dilation varies. There is no uniform expla
nation, although speculations are made involving temporary
obstruction of the distal fetal urethra or a mesenchymal defect.
The latter could explain the fact that a megalourethra is associated with other severe (mesenchymal) anomalies such as the
prune-belly syndrome, cloacal anomalies, imperforated anus,
458
part
Corporal body
Spongiosus
tissue
Corporal body
Spongiosus
tissue
Figure 34-15 Schematic drawing of the two types of congenital megalourethra. A, Fusiform type shows a defective corpora cavernosa.
B, Scaphoid type has an intact, although thinner, corpora cavernosa.
refluxing megaureters, and the VACTERL (vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula and esophageal atresia, renal agenesis and dysplasia,
and limb defects) syndrome (Fig. 34-16).35 The diagnosis is
mainly clinical, but VCUG or retrograde urethrography can
exclude other urethral anomalies.
The treatment consists of resection of the redundant
urethral mucosa. This is possible if normal dorsal corpus
Figure 34-16 Male newborn with the VACTERL (vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula and esophageal atresia, renal agenesis and dysplasia, and limb
defects) syndrome and a urethral duplication. In addition, the dorsal urethra has the aspect of a megalourethra. Note also the bladder
diverticulum.
REFERENCES
For complete list of references log onto www.expertconsult.com
P A R T
VI
Genitalia
S E C T ION
Ambiguous genitalia
CHAPTER
35
PHYSIOPATHOLOGY
The first step in prenatal sexual development starts with the
chromosomal complement. Most males possess a 46,XY chromosome complement, and most females 46,XX. Up to the
8th week of gestation, human reproductive organs show no
sign of sex differentiation and consist of unipotential wolffian and mllerian ducts and bipotential sinusal and external
genital primordia (Fig. 35-3). Wolffian ducts are the excretory
canals of the primitive kidney, the mesonephros, and they are
incorporated into the genital system when renal function is
taken over by the metanephros, or definitive kidney. Mllerian ducts arise from a cleft lined by coelomic epithelium that
originates between the gonadal ridge and the mesonephros
and grow caudally. The undifferentiated external genitalia are
represented by the genital membranes, which close the ventral
part of the cloaca and are surrounded ventrally by the genital tubercle and laterally by the genital folds or labioscrotal
swellings (see Fig. 35-3). After the corpora cavernosa and glans
have differentiated, the genital tubercle elongates to form the
phallus, whose ventral surface is depressed by a deep furrow,
the urethral groove. The first step of somatic male differentiation is mllerian duct regression, which begins at 8 weeks (see
Fig. 35-1). The time during which the presence or absence of
the fetal testis affects mllerian anatomy is a critical period.
In the human, the mllerian ducts have almost completely
disappeared by 10 weeks of gestation.
The second aspect of internal male differentiation is the
integration of wolffian ducts into the genital system and their
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460
part
VI: Genitalia
Leydig cell
activity
Sertoli cell
activity
Testosterone
Testis descent
Male external
genital differentiation
External
genital growth
Germ cell
migration
11
12
13
14
15
40
Gestation (weeks)
Figure 35-1 Schematic embryology of male sex development. The curve depicts the relative concentration of fetal serum testosterone.
4
TESTOSTERONE
3.0
10.4
7
5.2
3.5
ng/mL
nmol/L
8.7
2.0
1.0
Cord
Prepubertal
boy
1.8
0
100
200
300
Days
Figure 35-2 Postnatal testosterone peak in normal 46,XY males.
10
chapter
461
Genital tubercle
Urethral fold
Labioscrotal swelling
Bladder
Mllerian duct
Rectum
Mllerian tubercle
Urogenital sinus
Anal pit
Tail
9 weeks
Glans
Genital tubercle
Urogenital slit
Urethral fold
Vaginal cord
Labioscrotal swelling
Perineum
12 weeks
Clitoris
Urethral meatus
Uterus
Pubic bone
Prostatic bud
Labia minora
Vaginal orifice
Urethra
Labia majora
Scrotum
Phallic
urethra
Birth
Raphe
Vagina
FEMALE
MALE
FEMALE
MALE
Figure 35-3 Differentiation of the urogenital sinus (left) and external genitalia (right).
462
part
VI: Genitalia
TESTIS
Leydig cell
Sertoli cell
Testosterone
AMH/MIS
AMH/MIS
receptor
Epididymis
Vas deferens
Uterus
Seminal vesicle
DHT
Urogenital sinus and
external genitalia
Androgen
receptor
Gonadal dysgenesis is characterized by abnormal testicular determination. However, 46,XY gonadal dysgenesis syndrome is clinically and genetically heterogeneous. It can be
sporadic or familial. Phenotypic differences can be observed
depending on the extent of testicular development, and a
continuum of phenotypes ranging from female phenotype
to ambiguous external genitalia has been described. Variable
expressivity has been reported within families as well.7 Several
situations of 46,XY sex reversal have resulted from mutations
in genes controlling the primordial gonad and the bipotential
reproductive ducts (see Fig. 35-5).
chapter
463
GENITAL RIDGE
Lhx9
SF1
WT1
Lim1
Emx2
Bipotential
gonad
Ovary
Testis
Spermatogonia
WT1
DAX1
SF1
SOX9
GATA4
DHH DMRT1
AMH
Sertoli
cells
WNT4
DAX1
DAX1
SOX3
Ovogonia
SRF
Supporting cell
progenitors
FOXL2
Granulosa
cells
SF1
Aromatase
WNT4
DMRT1
FGF2
DAX1
SF1
Testosterone
DAX1
WNT4
Leydig
cells
Steroidogenic cell
progenitors
Thecal
cells
Estrogens
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VI: Genitalia
Development
Androgen-secreting tumor
Fetal gonadal androgen production
True hermaphroditism
Transplacental passage of androgens
Drugs administered during pregnancy (progesterone, danazol)
Maternal androgen-secreting tumor (luteoma of pregnancy,
adrenal tumor)
Aromatase deficiency, cytochrome P450 oxidoreductase
deficiency (PORD)
Undervirilization of 46,XY Males
Defective development or maintenance of the testis: testicular
dysgenesis
Pure (complete) 46,XY dysgenesis
Mixed (partial) gonadal dysgenesis 45,X/46,XY
Dysgenetic pseudohermaphroditism
Testicular regression syndromes (agonadism, vanishing testis)
46,XX males
Decreased fetal androgen biosynthesis
Leydig cell hypoplasia
Inborn errors of testosterone biosynthesis (StAR, 3-HSD,
17-hydroxylase/17,20 lyase, 17-HSD, Smith-Lemli-Opitz
syndrome)
5-reductase deficiency
Decreased fetal AMH production or action
Persistent mllerian duct syndrome
Defect in androgen action
Androgen receptor and postreceptor defects (PAIS, CAIS)
Urogenital malformations, dysmorphic syndromes
AMH, anti-mllerian hormone; CAIS, complete androgen insensitivity
syndrome; HSD, hydroxysteroid dehydrogenase; PAIS, partial androgen
insensitivity syndrome; StAR, steroidogenic acute regulatory protein.
chapter
465
Protein
WT1 (11p13)
Transcription factor
SF1 (9q33)
Nuclear receptor
SOX9 (17q24.1)
SRY (Yp11.3)
DHH (12q13.1)
Signaling molecule
ATRX (Xq13.3)
Helicase
DMRT1 (9p24.3)
Transcription factor
WNT4 (1p35)
Signaling molecule
LHCGR (2p21)
G-protein receptor
DHCR7 (11q12-13)
Enzyme
Smith-Lemli-Opitz syndrome
STAR (8p11.2)
CYP11B1 (8q21)
11-hydroxylase
HSD17B3 (9q22)
17-hydroxysteroid dehydrogenase
CYP17A1 (10q24.3)
17-hydroxylase/17,20-lyase
CYP21A2 (6q21.3)
21-hydroxylase
HSD3B2 (1p13.1)
POR (7q11.2)
Enzyme
AMHR2 (12q13)
AMH (19p13.3)
Secreted protein
SRD5A2 (2p23)
5-reductase type 2
AR (Xq11-12)
AMH, anti-mllerian hormone; AMHR2, AMH type II receptor; CAH, congenital adrenal hyperplasia; DHEA, dehydroxyepiandrosterone; POR, cytochrome
P450 oxidoreductase; WAGR, Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation syndrome.
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VI: Genitalia
Normal
II
III
IV
Normal
P450scc
P450c21
3HSD
Pregnenolone
Progesterone
3
2
5
P450c17
Cortisol
4
P450c17
17-Ketoreductase
Androstenedione
2
Aldosterone
8
P450c11
11 Desoxycortisol
3HSD
DHA
P450c21
P450c11
18 OH-Corticosterone
17 OH-Progesterone
P450c17
P450c11
Corticosterone
P450c17
3HSD
17 OH-Pregnenolone
P450c11
DOC
P450 arom
Testosterone
Estradiol
10
46,XX Males
The condition of 46,XX males is characterized by testicular
development in subjects who have two X chromosomes but
lack a normal Y chromosome. About 200 cases have been
chapter
467
External genitalia
Asymmetric
Symmetric
Karyotype
Karyotype
46,XY
46,XY/45,X
46,XY
Gonadal
dysgenesis
Hermaphroditism
Gonadal
dysgenesis
Gonad
palpable
or visualized
Yes
No
(Consider laparoscopy biopsy)
Testosterone
Testosterone
Low
AMH/uterus visualized?
AMH/uterus visualized?
AMH/uterus visualized?
Normal/No
Environmental androgen
insensitivity syndrome
5 -reductase deficiency
Low/Yes
Normal/No
Low/Yes
Undetectable/No
LH receptor mutation
Impaired gonadotropic
action
Testosterone
biosynthesis defect
Gonadal
dysgenesis
Hermaphroditism
Gonadal
dysgenesis
Hermaphroditism
Low/Yes
Testicular
regression
syndrome
Gonadal
dysgenesis
Hermaphroditism
Other symptoms?
No
Yes
Bone
abnormality
Renal disease
(proteinuria)
Adrenal
insufficiency
Duplication: SOX9
Mutation: WT1
Mutation: SF1
Duplication: WNT4
Figure 35-8 Algorithm for etiologic diagnosis in undervirilized male infants. AMH, anti-mllerian hormone; LH, luteinizing hormone.
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part
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chapter
469
Smith-Lemli-Opitz syndrome is an autosomal recessive syndrome characterized by striking craniofacial features, microcephaly, profound mental retardation, severe failure to thrive,
growth retardation, syndactyly, and genital malformations.88
The phenotype is often female in 46,XY affected infants. The
sex of rearing depends on the phenotype and surgical repair
should be made accordingly.89
Smith-Lemli-Opitz syndrome is caused by mutations of the
human 7-dehydrocholesterol reductase gene (DHCR7), which
is located on chromosome 11q13. So far, about 20 different
mutations have been described.90 Although it would appear
that deficiency of cholesterol, an adrenal hormone precursor,
might lead to insufficient synthesis of adrenal and gonadal
steroid hormones, the physiopathology of the syndrome is
not yet fully elucidated.91 Diagnosis is based on the finding of
low serum cholesterol and high serum 7-dehydrocholesterol
levels. Prenatal diagnosis can be made based on high levels of
7-dehydrocholesterol in amniotic fluid.92-94 Today, diagnosis is
confirmed by molecular studies.
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Normal
Corticotropin
Low density
lipoprotein
cAMP
Lipid
droplet
Low density
lipoprotein
Corticotropin
Steroid
ATP
ATP
cAMP
Low density
lipoprotein
ATP cAMP
Steroid
Lysosome
Lysosome
StAR
StAR
Lipid
droplet
StAR
?
StAR-independent
cholesterol
flow
Mitochondrion
?
StAR-independent
cholesterol
flow
Nucleus
Endoplasmic
reticulum
Nucleus
Lipid
droplet
Nucleus
Endoplasmic
reticulum
Figure 35-12 Effects of lipoid congenital adrenal hyperplasia in adrenal cells. ATP, adenosine triphosphatase; cAMP, cyclic adenosine monophosphatase; StAR, steroidogenic acute regulatory protein.
chapter
17-Hydroxylase/17,20-Desmolase Deficiency
An essential step in the formation of cortisol and sex steroids is
the 17-hydroxylation of either pregnenolone and progesterone
to 17-hydroxypregnenolone and 17-hydroxyprogesterone,
respectively (see Fig. 35-7). Both enzyme activities are catalyzed by P450c17, a single enzyme bound to the smooth endoplasmic reticulum. In the human testis, P450c17 is encoded
by a single gene, termed CYP17A1, which is localized at
chromosome 10q24.3.112
17-Hydroxylase deficiency was first reported in a 46,XX
female in 1966.113 The first genotypically male patient was
identified 4 years later.114 Over the next 3 decades, about 150
cases were reported in genetic males and females.115 In this
rare form of CAH, diminished 17-hydroxylase activity leads
to deficient production of both cortisol and sex hormones,
resulting in undermasculinization in genetic males and sexual
infantilism in genetic females. In both sexes, the other cardinal
symptoms are hypertension, hypokalemic alkalosis, and carbohydrate intolerance. Most 46,XY patients have been raised
as females because they present with a complete female phenotype and are usually diagnosed at puberty with infantilism.
Rarely, the diagnosis is made in infancy, based on hypertension or ambiguous external genitalia.116 The testes may be
intra-abdominal, in the inguinal canal, or in the labioscrotal
folds. Inguinal hernias are commonly present. Wolffian derivatives are usually hypoplastic. The onset and natural course of
hypertension is variable.
The relative deficiency in cortisol biosynthesis is reflected
by a rise in ACTH, which in turn stimulates steroidogenesis
up to 17-hydroxylation. Plasma levels of pregnenolone and
progesterone are elevated. There is overproduction of 11deoxycorticosterone (DOC) and corticosterone (more than 50
to 100 times normal). Plasma testosterone levels are extremely
low, with a blunted response to hCG.117 Plasma FSH and LH
concentrations are elevated, as they are in agonadal subjects.
The diagnosis should be suspected in cases of male undermasculinization, including 46,XY phenotypic females, who have
hyporeninemic hypertension and hypokalemic alkalosis.
The disease is caused by mutation in the CYP17A1 gene.
Molecular genetic studies showed a marked heterogeneity
in genetic lesions, including mutations, missense, nonsense,
deletions, and insertions.118-120 To date, about 20 different
mutations have been identified, all of them in the coding
region. Substitutive treatment is only to replace the deficient
glucocorticoid production. It will suppress ACTH overproduction, and thus the overproduction of mineralocorticoids,
and improve hypertension. Control of treatment is best
performed on clinical parameters.121 There is no risk of
adrenal crisis. Sex steroid replacement therapy is needed at
puberty.
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this disorder, but management of the disorder has been a matter of controversy.131 A spontaneous change at puberty to the
male gender was observed in several individuals of a large
Arab kindred.132 On this basis, as well as the good response
to exogenous testosterone therapy in infancy, the authors proposed to raise all affected genetic males in the male gender.
The question whether exposure to high 4-androstenedione
levels in utero and postnatally leads to disturbed female gender identity in later life remains largely unsettled, and the best
management will be dictated by the age at diagnosis and the
familial context.
chapter
473
Iatrogenic Causes
Considerable attention is given to the possibility that synthetic
chemicals (xenobiotics) in the environment may pose a hazard to human reproductive health. The endocrine-disrupting
effects of many xenobiotics can be interpreted as interference with the normal regulation of reproductive processes
by steroid hormones. A recent review concluded that there
is evidence that xenobiotics bind to androgen and estrogen
receptors in target tissues, to androgen-binding protein, and
to sex hormone-binding globulin.171 Although environmental
chemicals have weak hormonal activity, their ability to interact with more than one steroid-sensitive pathway provides
a mechanism by which their hazardous nature can be augmented. A given toxicant may be present in low concentration in the environment and, consequently, harmless by itself.
However, numerous potential antagonists working together
through several steroid-dependent signaling pathways could
prove to be hazardous to normal sex differentiation.172,173
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VI: Genitalia
variable and is usually described according to Prader (see Fig.
35-6). Virilization can be quite important, and even a female
fetus with a severe form of the disorder may present with an
apparently normal male phenotype except for bilateral cryp
torchidism. Some children have moderate virilization at birth,
with clitoral enlargement and a partial posterior fusion of the
labioscrotal folds. Such infants may be misdiagnosed unless
careful genital examination is performed. In the nonclassic
forms (late-onset, acquired, cryptic), the affected females are
not virilized at birth.
The key measurement for the diagnosis of 21-hydroxylase deficiency is basal plasma 17-hydroxyprogesterone, the
steroid above the enzymatic block. In most congenital forms,
the elevation is large (30 to 100 ng/mL, 100 to 300 nmol/L).
In the nonclassic forms, an ACTH stimulation may be needed.
End-test values for 17-hydroxyprogesterone are usually
greater than 20 ng/mL (60.5 nmol/L), and in some instances
(3%) they are between 12 and 20 ng/mL (36 to 60.5 nmol/L).
Even if adequate glucocorticoid and mineralocorticoid replacement therapy is given, unsatisfactory or poor cosmetic results,
sexual difficulties, and poor fertility are reported in adult
women.174-176
During pregnancy, suppression of the overproduction of
androgens by the fetal adrenal gland is achieved by giving the
mother a daily dose of 20 g of dexamethasone per kilogram
of maternal weight, split in two or three doses.177,178 However,
such treatment should be initiated after careful genetic counseling and monitored by highly specialized teams of pediatric
endocrinologists, biologists, and gynecologists.
11-Hydroxylase Deficiency
21-Hydroxylase Deficiency
21-Hydroxylase deficiency is the most common variant of
CAH, accounting for about 90% of all cases. The clinical syndrome is a consequence of defective 21-hydroxylation of progesterone and 17-OH progesterone, with resulting deficient
production of both cortisol and aldosterone and excessive
ACTH production (see Fig. 35-7). The disease occurs in a wide
spectrum of clinical variants, including a severe form with
a defect in aldosterone biosynthesis (salt-wasting form), a
form with normal aldosterone biosynthesis (simple virilizing form) (Fig. 35-14), and a mild nonclassic form that
may be asymptomatic or may be associated with symptoms of
androgen excess developing during childhood or at puberty.
In the classic (salt-wasting and simple virilizing) forms,
signs of androgen excess are often prominent. Salt loss occurs
in approximately 80% of cases, whereas virilization of the
female fetus is constant. However, the degree of virilization is
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475
CONCLUSION
There are medical and surgical criteria used to assign gender
in a child with ambiguous genitalia. In the case of 46,XX CAH
or 46,XY CAIS, the decision is easier, and the female gender
is chosen by most. Among patients with ambiguous presentations, the most difficult discussions concern those who are
poor androgen responders. In these cases, the choice of gender
rests on the penile size, the response of the penis to androgen
stimulation, and the presence of mllerian derivatives. Challenging the genital tubercle with androgens could be useful
but does not give evidence that responders during the neonatal period will remain so after puberty.
Anatomic features should allow definition of the potential capacity of penetrative sexual intercourse. The potential
fertility of the patient may influence the decision of gender.
Also to be taken into consideration are the disappointing
and controversial outcomes of genital reconstructive surgery. Clitoral sensitivity has been reported to be affected
in genitoplasty, and early vaginal reconstruction requires
revision at puberty in most cases, leading some surgeons to
defer these reconstructions to a later stage of life.194 Genital
and especially clitoral surgery is often associated with difficulties in adult sexual function, even with newer, nervesparing techniques.
The way the situation is presented to the parents in the
first few days of life and their understanding of the dilemmas
may forge parental insight. The parents instinctive perception
in the final decision is strongly determined by the social and
cultural environment, the sex being commonly considered as
an instrument of reproduction and pleasure as well as a main
identifier for society. Finally, the main paradox is that the only
person who is not party to the decision in the neonatal period
is the patient. This probably explains the controversies raised
by various patient support groups on behalf of those who
considered that their sex was imposed upon them. For the
medical team, the difficulty of the choice of gender is how to
make the least bad choice.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
36
Labial Abnormalities
Because of the influences of maternal estrogens, newborns
often have significant labial edema and may have vaginal discharge or withdrawal bleeding. These changes typically subside by 2 months of age as the hormonal milieu normalizes.
After the neonatal period, the appearance of the labia is fairly
consistent until adolescence.2 Occasional asymmetry or discoloration may occur but is rarely of consequence. An inguinal defect, such as a hernia or gonad, should be considered
in the differential diagnosis of a unilateral labial mass. Labial
lipomas and hemangiomas occur uncommonly in childhood.
Labial hemangiomas usually regress at puberty, and intermittent bleeding responds to compression or silver nitrate cauterization. Labial varices are likewise best managed expectantly
unless bleeding occurs. Labial cysts are rare in the prepubertal child, and symptomatic posterior vestibular cysts can be
incised.3
A variety of dermatologic disorders and infectious lesions
can involve the labia. Dermatitis, candidiasis, and eczema
affect the labia and should be managed with topical agents.
Chickenpox may extensively involve the vulvar region, and
topical antibiotic ointment helps prevent superinfection.
Vitiligo is a patchy, congenital absence of pigment, but disorders such as lichen sclerosus can also result in depigmentation. Lichen sclerosus and erosive chronic dermatologic
conditions can lead to deviation of the urinary stream, painful
paraphimosis, or infection from fusion of the minor labial
folds over the clitoris and urethral meatus. Judicious surgical
release may be required.3
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477
Figure 36-1 Normal hymenal variant: Annular with bump. Crescentic and redundant are other normal variants.
Labial adhesions are most commonly discovered incidentally
in infancy or early childhood; newborns seem to be spared
by the influence of maternal estrogen. Adhesion begins in
the posterior fourchette and progresses anteriorly, forming
an almost translucent midline raphe (Fig. 36-2). The vaginal
introitus and urethral meatus may be completely hidden by
the adhesions.4
Labial adhesions are typically asymptomatic. Symptoms
suggestive of urinary tract infection may occasionally occur if
adhesions deflect or block the normal efflux of urine. Trapping
of urine behind the adhesions makes it impossible to obtain
a valid voided specimen, making the diagnosis of actual urinary infection problematic. Pruritus and postvoid dribbling
can also occur secondary to trapped urine, and dampness
may be minimized by blotting inward with more tissue after
wiping.
The majority of labial adhesions resolve spontaneously
during hormonal changes at puberty. In general, labial adhesions do not warrant treatment. Symptomatic or otherwise
bothersome adhesions can be successfully separated with the
application of estrogen cream (Premarin 0.625 mg/g) twice
daily for 1 to 2 weeks. Use of a cotton swab to apply the cream
with gentle pressure along the line of adhesion increases the
success of treatment. Temporary hyperpigmentation of the
labia may occur during treatment. Prolonged courses of estrogen should be avoided. Incomplete separation is acceptable as
long as the symptoms resolve. Adhesions that have thinned
but not parted can be gently separated with lubricated swab
after the application of a topical anesthetic cream. Forceful
separation is painful and traumatic for the child.
True labial fusion can result from severe chronic vulvar
inflammation, and adhesions that fail to thin with estrogen
therapy may need to be surgically separated. Regardless of the
method of separation, routine application of a bland ointment
to the previously attached tissues minimizes the risk of readhesion. Management of constipation is also beneficial.
Although almost all adhesions are believed to result from
benign inflammation of the vulvar tissues, labial adhesions
have also been linked to sexual abuse. In general, the adhesions related to injury are more dense, as are those created by
repeated manual separation in the office. Posterior fourchette
scars that deviate off midline and neovascularity that does not
cross the midline are other findings of concern. The discovery
of routine labial adhesions should not raise concern for abuse,
but vulvar changes in combination with other signs or symptoms of abuse warrant further investigation.5
Complete labial fusion, without an apparent thin midline
membrane, results in a single anterior orifice that suggests
Labial Hypertrophy
Isolated prominence of the labia minora occasionally occurs
and is likely a normal variant (Fig. 36-3). No clear etiology has
been identified. In general, elongation of the labia is asymptomatic, but irritation of the exposed tissue by chronic minor
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Figure 36-4 Female genital cutting, type III. (Courtesy of Dr. Aseem
Shukla.)
Clitoral Abnormalities
The discovery of an enlarged clitoris (clitoromegaly) in a newborn girl warrants thorough investigation for potentially lifethreatening conditions. A clinical impression may be confirmed
by calculation of the clitoral index, as described by Huffman.15
The clitoral index is determined by multiplying the width of
the glans times the length of the phallus; it is thought to be
normal if less than 4.35 mm and worrisome if greater than
10 mm. In premature infants, a developmentally appropriate clitoris can appear relatively exposed and large.2 Maternal estrogens have less effect on the labial tissues, so there
is less prenatal labial fat deposition to conceal the clitoris. This
disproportion improves as the child matures. Clitoromegaly is
most commonly related to in utero androgen exposure. Neurofibromatosis, hemangioma, lymphangioma, and chronic vulvar irritation are less common causes of clitoral enlargement.6
Complete agenesis of the clitoris is rare. A bifid or duplicated clitoris is found in females with the exstrophy-epispadias
complex. Because of the separation of the clitoral halves, the
labia minora and labia majora also part in the midline, leaving
an anterior cleft. Approximation of the bifid clitoris, labioplasty, and monsplasty constitute one aspect of the complex
genitourinary reconstruction in exstrophy-epispadias (see
Chapter 30).
Interlabial Masses
Identification of a mass between the labia majora can be quite
concerning for a parent, but most of these uncommon lesions
are benign. The lesions emanate from the urethra or vagina
and may be large enough to eclipse the normal interlabial
landmarks. Careful inspection of the position and appearance of the mass, in combination with consideration of the
age, ethnicity, and symptoms of the patient, helps confirm the
diagnosis in most instances. Radiographic evaluation is not
necessary in most cases, although abdominal and pelvic ultrasonography may be helpful if the diagnosis remains unclear.16
Urethral catheterization and endoscopy are rarely required for
diagnosis.
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36: Surgical Management of Female Genital Anomalies and Disorders of Sexual Development
Paraurethral Cyst
Congenital paraurethral cysts are the uncommon result of
ductal obstruction of the Skene paraurethral gland. The cyst
is typically based on the inferolateral aspect of the distal urethra and may result in eccentric displacement of the urethral
479
Figure 36-5 Interlabial masses: paraurethral cyst (A), urethral prolapse (B),
periurethral condyloma (C).
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Urethral Prolapse
Prolapse or eversion of the distal urethral mucosa occurs most
commonly in prepubertal black females at a mean age of 5.4
years.18 Bloody spotting is the most frequent presentation,18-20
and perineal fullness or discomfort may occur as well. Dysuria,
frequency, retention, or other urinary symptoms have been
reported in up to half of the cases.19,20 The cause is uncertain,
although abnormal urethral muscular attachments, hypoestrogenized tissues, and trauma have been implicated.21 Thorough
questioning often reveals a history of coughing, constipation,
or abdominal straining.20,21
The prolapse may be circumferential or partial, with
partial eversion typically involving the posterior urethral
wall.20 Except in the most acute cases, the urethral mucosa
is congested and friable and forms a beefy-red or purple
doughnut around the urethral meatus (see Fig. 36-5B). The
prolapsed tissue may be significant enough to fill the introitus,
but retraction of the labia should allow visualization of the
hymen. If necessary, urethral intubation may be performed
for confirmation.
The symptoms and the prolapse itself may resolve with sitz
baths and a trial of topical estrogen cream, but incomplete resolution or recurrent prolapse is common.18,21 Excision of the
prolapsed mucosa by quadrants, with approximation of the
mucosal edges, is the most definitive management. Surgical
therapy is indicated in the event of thrombosis and necrosis,
recurrent prolapse, failure of medical therapy, or significant
symptoms. A Foley catheter may be left in place overnight as
a convenience for the patient. Amputation of the prolapsed
tissue by ligation over a Foley catheter is not recommended.
Urethral Polyp
Polyps of the female posterior urethra are a rare type of interlabial mass. Blood spotting may be associated with a polyp
that protrudes through the urethral meatus. Excision with fulguration of the base is adequate management.25
Bladder Prolapse
Prolapse of the posterior bladder wall through a patulous
bladder neck is seen uncommonly in female patients with
exstrophy-epispadias. Congestion or ischemia of the mucosa
and ureteral obstruction are the greatest concerns. Manual
reduction is possible, but earlier definitive surgical correction
may be required.
Imperforate Hymen
Imperforate hymen results from failure of distal canalization
of the vaginal plate at the junction between the UGS and the
vagina. The abnormality is usually identified in the newborn
period or during the course of investigation of primary amenorrhea. Under the influence of maternal estrogens, the newborn produces vaginal and cervical secretions. In the setting of
imperforate hymen, efflux of these secretions is not permitted,
and the newborn may present with a whitish bulging mass
filling the introitus (hydrocolpos or mucocolpos). The vagina is
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36: Surgical Management of Female Genital Anomalies and Disorders of Sexual Development
quite distensible and may contain up to a liter of mucous secretions.6 Secondary obstruction of the upper urinary tract can
result from vaginal distention. Bedside incision of the tense
hymen allows drainage of the retained secretions. Although
the upper tracts generally decompress after incision of the
hymen, this should be confirmed by repeat ultrasonography.
If imperforate hymen is missed during the neonatal period, it
may be discovered after the onset of puberty as a bluish, bulging introital mass. Microperforations and hymenal bands are
relatively common and may be addressed before puberty.
Prolapsed Ureterocele
Large ectopic ureteroceles typically are associated with the
upper pole of a duplex system and occasionally manifest as
an interlabial mass with prolapse of the ureterocele through
the urethra. Caldamone and associates26 reported an 11% incidence of prolapse, predominantly in white females. Although
ureterocele prolapse almost always occurs in infancy, we have
treated a 17-year-old with prolapse as the initial presentation.27
The prolapse can be significant, precluding visualization of the
urethra and vagina. Bladder outlet obstruction secondary to
the prolapsed tissue is a urologic emergency. Manual reduction of the prolapse may require an anesthetic and can be difficult. Once the prolapse is reduced, a Foley catheter should
be left indwelling for a short time. Definitive surgical therapy
should follow.
Despite the distortion, the gross appearance of the prolapsed ureterocele is usually easily distinguished from that
of other interlabial masses. The tissue is eccentric, and the
urethral meatus may not be visible. The prolapsed mucosa is
pink in acute cases but exhibits various stages of congestion
later (see Fig. 36-5D). If the diagnosis is in question, renal and
bladder ultrasonography or aspiration with a fine needle is
helpful.16 Subsequent evaluation of the ureterocele includes
an ultrasound study, voiding cystourethrogram (VCUG), and
assessment of upper tract function.
Sarcoma Botryoides
The possibility of a genitourinary malignancy is understandably the greatest concern of the referring physician and parent
when an interlabial mass is discovered. Fortunately, genitourinary malignancies in the pediatric population are uncommon,
and the gross appearance of sarcoma botryoides, in particular,
is quite distinctive. Sarcoma botryoides is a polypoid form of
embryonal rhabdomyosarcoma (RMS). The tumor originates
in the subepithelial layer of a hollow pelvic organ, and it protrudes into the lumen as it grows. In females, the tumors arise
in the bladder or vagina or, rarely, from the uterine cervix. The
polypoid tissue resembles a bunch of grapes and extends or
prolapses into the interlabial region from the urethra or vagina
(see Fig. 36-5E). RMS of the bladder usually occurs in patients
younger than 5 years of age. The mean age at diagnosis for
vaginal tumors is less than 4 years, and uterine tumors manifest in adolescence.28
Cystoscopy and vaginoscopy with biopsy are required
for diagnosis, but there is no role for attempted complete
endoscopic resection. Computed tomography of the chest,
abdomen, and pelvis, as well as nuclear bone scanning
and bone marrow aspiration, complete the tumor staging.
Historically, genitourinary RMS was managed with aggressive or exenterative resection, but contemporary protocols
are multimodal and attempt to minimize acute toxicity, with
preservation of pelvic organs and quality of life.28-30 Vaginal
sarcoma botryoides in children is quite chemosensitive. The
prognosis for a vaginal RMS is better overall than for cervical
481
RMS, but a single polypoid cervical lesion may have the best
prognosis. Polypectomy with or without curettage can be
curative, but limited adjuvant chemotherapy may be advised,
based on prognostic features.31-35
Reassessment of the tumor burden after induction chemotherapy with vincristine and actinomycin D, with or
without cyclophosphamide, leads to further chemotherapy
in responders and surgical excision or radiation therapy
in nonresponders.18,30,31 The most current protocols are
available on the Web site of the National Cancer Institute
(www.cancer.gov [accessed February 2009]).36 The philosophical approach regarding the role of radiation and surgery differs between RMS study groups in the United States
and those in Europe,37 but the groups share a commitment
to longitudinal follow-up of survivors. Organ-sparing protocols after incomplete response to chemotherapy include
radiation, but late surgical intervention for treatmentrelated complications is common after radiation for pelvic
RMS.38
Mllerian Agenesis
Mayer-Rokitansky-Kster-Hauser syndrome is a constellation
of mllerian, renal, and skeletal abnormalities that occurs in 1
of every 4000 to 5000 46,XX females.6,43 Deficiency of the caudal
portions of the bilateral paramesonephric ducts results in failure of formation of the proximal vagina and uterus (Fig. 36-7).
A well-timed embryologic omission or event may explain
the constellation of findings.44,45 Complete agenesis of the
middle and upper vagina uniformly occurs, but the anatomy of the uterus and fallopian tubes is variable. A hymenal
rim and vaginal dimple usually are present, because these
structures are derived from the UGS. The labia and ovaries
are also embryologically distinct and therefore normal.
Although absence of the vagina may be noted on physical
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Uterine
tube
Uterine
septum
Urogenital sinus
Lumen of uterus
Cervix
Caudal tip of
paramesonephric
ducts
Fornix
Vagina
Tissue of
sinovaginal bulbs
(vaginal plate)
Hymen
Figure 36-7 Mllerian agenesis and vertical fusion abnormalities: Top left, Imperforate hymen. Top right, Transverse septum. Bottom, Mllerian
agenesis. (From Yerkes E, Rink RC. What urologists should know about pediatric gynecologic abnormalities. Contemp Urol. 2002;14:12-30. Copyright 2002, Medical Economics.)
examination (Fig. 36-8), primary amenorrhea is the more common presentation.42,43,45,46 Other patients present with dys
pareunia or failed intercourse.46
Two distinct forms of Mayer-Rokitansky-Kster-Hauser
syndrome have been described.46,47 Type A patients have symmetric residual muscular mllerian anlagen and normal fallopian tubes. Type B is the slightly more common atypical
form, with asymmetry of the muscular buds and abnormally
developed fallopian tubes. Up to 10% of patients develop
cyclic abdominal pain from a small amount of functioning
endometrium in a unicornuate uterus. Minor ovarian abnormalities have been reported in 15% of all cases, but only in
type B patients.46
Associated anomalies of the upper urinary tract, most
commonly renal agenesis or ectopia, have been reported
in approximately one third of all cases of mllerian agenesis.42,45,46 Skeletal abnormalities, most commonly involving
vertebrae, have been reported in 10% to 20% of cases.44,45
The renal and skeletal abnormalities seem to occur only in
Vaginal Atresia
Failure of the UGS to form the distal portion of the vagina
results in vaginal atresia. The upper vagina, uterus, fallopian
tube, and ovaries are generally normal. Patients typically pre
sent with primary amenorrhea and pain or a mass related to
retained menses (hematometrocolpos). Treatment involves incision and dissection through the atretic segment with pullthrough of the distended proximal vagina.
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483
VAGINAL REPLACEMENT
A wide variety of techniques for vaginal reconstruction or
replacement in patients with vaginal agenesis have been
employed over the last 2 centuries. Similar principles are applied
to reconstruction of high, thick transverse septa and in cases of
complete androgen insensitivity syndrome (CAIS). Multiple
modifications of several classic procedures have led to a number
of suitable vaginal substitutes. Many reasonable options exist,
and the surgeon should work with the patient to determine the
most appropriate approach (Tables 36-1 and 36-2).50
Timing of reconstruction remains controversial and depends
not only on the nature of the underlying abnormality (e.g.,
obstruction of functioning endometrium versus agenesis) but
also on the type of reconstruction planned. Mature patients
may be more diligent about the routine dilations that often
are required after replacement vaginoplasty. Although pelvic
ultrasonography or computed tomography may have been
performed during evaluation of the mllerian or vaginal abnormality, magnetic resonance imaging (MRI) and transperineal
ultrasonography provide valuable preoperative information.
MRI clearly demonstrates the existing mllerian structures
and hydrometrocolpos, and sagittal views reveal the level and
thickness of a transverse vaginal septum or the length of an
atretic vagina.51 Transperineal ultrasonography provides similar
important information about the extent of the vaginal defect.52
Preoperative knowledge of the level and extent of the vaginal
defect guides surgical therapy and helps prevent inadvertent
injury to surrounding organs during the course of dissection.
Progressive Dilation
Figure 36-10 Coronal magnetic resonance image of obstructed uterine horns in an adolescent who underwent rectal pull-through as an
infant. No vaginal orifice is present on examination of perineum.
In 1938, Frank53 proposed the creation of a neovagina by applying progressive pressure to the perineum or vaginal dimple
in patients with vaginal agenesis. Ingram54 modified the technique with the use of dilators mounted on a bicycle seat. The
dilation occurs over several months. This technique is not
adequate for all patients, but a neovagina can be successfully
created nonoperatively in some highly motivated patients.
The Vecchietti operation, which applies Franks principle via
an abdominal traction device, was introduced in 1965. The dilation procedure is completed over 7 to 9 days with this invasive
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Replacement
Outcomes
Function: natural position, size, sensation, secretions
Need for dilation to achieve or maintain functional size
Risk of prolapse
Risk of malignancy or other secondary change
Patient
Level of satisfaction with function and cosmesis
Morbidity/Disruption of normal daily activities
Time until first intercourse
approach.41 Laparoscopic modifications of the Vecchietti operation have also been described.55,56 Long-term dilation is required
to maintain adequate caliber. Progressive dilation techniques
are not widely used by urologists at this time.
Vulvovaginoplasty
In 1964, Williams57 described a superficial vulvovaginoplasty
for the creation of a neovagina in women with vaginal agenesis. Although a satisfactory channel can be created, the angle
of the vagina is quite abnormal, and voided urine may pool in
the vagina.41 Others have tubularized hairless vulvar flaps and
rotated the neovagina into the bluntly dissected rectovesical
space. The cavity then requires progressive enlargement with
Lucite dilators.58 Johnson and coworkers59 described the use of
labia minora tissue expanders in preparation for vaginoplasty.
They found the outcome satisfactory, without the need for chronic
dilation, but the risk of infection with expansion is significant.
Bowel Interposition
Vaginal replacement with intestine is the method of choice for
most urologists. Pedicled bowel interposition grafts have several distinct advantages over vaginoplasties that utilize skin
grafts or flaps. The need for laparotomy and the risk of pelvic
contamination were previous limitations, but greater facility
with laparoscopic dissection and use of endostapling devices
minimize these concerns in selected patients. Contractures of
the bowel segment are uncommon, and dilation usually is not
required. Intestinal mucus provides lubrication of the neovagina and is easily managed with douching in most patients.
Satisfaction with sexual function is reported by more than 75%
of women after bowel vaginoplasty.68
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485
Figure 36-12 Colon vaginoplasty. A, Dissection of rectovesical space for excluded bowel segment. B, Completed sigmoid vaginoplasty.
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Initial Evaluation
Because most patients with UGS anomalies present as neonates with genital ambiguity, the initial management centers on identifying potentially life-threatening problems and
gathering sufficient data to allow timely assignment of gender. Ideally, a multidisciplinary team consisting of at least
a neonatologist, an endocrinologist, a urologist or pediatric
surgeon, and a consistent child psychologist or social worker
gathers these data and works with the parents. Genetic counseling is appropriate. This is an extremely stressful time for
most parents, and it is the beginning of a critical long-term
relationship between the family and the multidisciplinary
team. The infant is the passive center of the team at this point
but ultimately has the most important voice. The family
will have many questions that the surgeon may not be fully
equipped to answer. The Intersex Society of North America
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487
Techniques
The surgical approach to clitoral hypertrophy has evolved dramatically since the recognition that cosmesis is only one element of the desired optimal surgical outcome. Moving beyond
the initial reports of clitoral resection,80,93,107 various techniques
for clitoral recession were described.108-111 Several contemporary variations share the common objectives of preserving the
neurovascular integrity of the glans clitoris, preventing painful erections and providing feminine cosmesis. These new
procedures have their basis in Schmids efforts to excise corporal tissue while preserving the neurovascular bundle to the
intact glans.112 Most surgeons now use some modification of
Kogans subtunical excision of the erectile tissue.113 Baskin and
associates114 demonstrated that circumferential branches from
the dorsal neurovascular bundles wrap toward the ventrum,
making a ventral approach to the corpora less concerning
(Fig. 36-14). Corporal tissue proximal to the bifurcation is left
intact. Engorgement of this retained but unrestrained corporal
tissue may enhance sexual function, but data are lacking. Opinions vary regarding reduction of the glans clitoris.87,89,115,116 To
maximize the likelihood of preserved sensation and viability,
we believe that the glans should be well concealed but left
intact. Ventral modification, if any, would seem prudent. The
prepuce should be preserved as the clitoral hood, because this
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Figure 36-14 Technique for clitoroplasty. A, Note lateral extension of neurovascular bundle relative to planned incision. B, Excision of erectile
tissue distal to bifurcation.
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489
Figure 36-15 Flap vaginoplasty. A, Flap is mobilized prior to incision of the sinus. B, Note that confluence is not changed, but the sinus is opened
up by insertion of the flap.
Figure 36-16 Sagittal view of low (right) and high (left) vaginal confluence.
Preoperative Preparation
All children undergoing vaginoplasty require at least an
enema, and the high confluence patients receive total bowel
preparation using polyethylene glycol (GoLYTELY; Braintree
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VI: Genitalia
Figure 36-17 Sagittal illustration of total urogenital mobilization or TUM (A) versus partial urogenital mobilization or PUM (B). Note that dissection stops at the pubourethral ligament in PUM.
Operative Details
The following sections detail the approaches to both high and
low vaginal confluence, including flap vaginoplasty, pullthrough vaginoplasty, and TUM or PUM. Our approach in
virtually all cases now is urogenital mobilization.
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491
492
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E
Figure 36-18, contd.
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36: Surgical Management of Female Genital Anomalies and Disorders of Sexual Development
493
from supine (A) to prone (B) position during the surgical procedure.
and
Partial Urogenital
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Figure 36-22 After urogenital mobilization, the vagina is opened over the Fogarty balloon.
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36: Surgical Management of Female Genital Anomalies and Disorders of Sexual Development
CLOACAL ANOMALIES
Evaluation
Although UGS anomalies can be very challenging problems, cloacal anomalies involve another order of complexity,
because the rectum also enters the common channel. These
disorders combine the most challenging aspects of both UGS
and anorectal malformations. The internal and external anatomic anomalies occur on a wide spectrum. The genitalia may
appear ambiguous and warrant an intersex evaluation. Other
anomalies are common. These malformations occur in only 1
in 40,000 to 50,000 patients132 and make up less than 15% of all
anorectal malformations.133 The evaluation is similar to that
described for UGS abnormalities, but several important differences are noted here.
These children may be quite ill, with severe abdominal distention and ascites causing respiratory compromise. Cardiac
malformations, renal abnormalities, and sacral anomalies are
commonly present and should be addressed early.
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Figure 36-23 Spectrum of external appearance of cloacal malformation, from nearnormal (A) to genital transposition (B), to a urethral type channel (C).
chapter
36: Surgical Management of Female Genital Anomalies and Disorders of Sexual Development
Address comorbidities
Diverting colostomy
Address hydronephrosis and hydrocolpos
(CIC vaginostomy/vesicostomy)
MRI spine/pelvic floor
3D MRG
Surgical planning/prognosis
Address GU anomalies
Definitive repair
Surveillance and management
(Renal/bladder/gynecologic)
CIC, clean intermittent catheterization; GU, genitourinary; MRI, magnetic resonance imaging; 3D MRG, three-dimensional magnetic resonance genitography.
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Outcomes
Although repair is technically demanding, the reported
results have been satisfactory, particularly when one recognizes that many cases potentially have a neuropathic component. An abnormal sacrum has been noted in roughly 50% of
cases.148,149 In Hendrens experience, 59% of patients voided
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36: Surgical Management of Female Genital Anomalies and Disorders of Sexual Development
CONCLUSION
Abnormalities of the female genitalia range from straightforward and easily managed cases to extremely complex, lifethreatening anomalies. External genital anomalies, particularly
499
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
37
ADOLESCENT UROGYNECOLOGY
Louise C. Strawbridge and Sarah M. Creighton
VAGINAL ANOMALIES
The vagina can be absent entirely or shortened. This may occur
as an isolated abnormality or as part of a recognized disorder
of sexual development such as AIS. Vaginal agenesis is usually
associated with an absent or poorly developed uterus. It can
also occur together with complex pelvic anomalies such as cloacal exstrophy and anorectal agenesis (Fig. 37-1). Patients can
present during childhood, particularly if their vaginal absence
is part of a complex condition. Vaginal agenesis can also be
diagnosed in an adolescent who presents with primary amenorrhea. If a uterus is present but the vagina is absent, atretic, or
imperforate, nondrainage of menstrual loss can cause urgent
presentation and serious sequelae.
500
The vagina is also affected in CAH, in which the main clinical features are clitoromegaly and fusion of the lower vagina
and labia. Current management is to perform a feminizing
genitoplasty in early childhood, as described in Chapter 36.
The vagina may be inadequate for sexual intercourse in later
life and will need further assessment and probable further
surgery in adolescence.
Mayer-Rokitansky-Kster-Hauser Syndrome
Mayer-Rokitansky-Kster-Hauser syndrome is a rare condition, with an estimated incidence of 1 in 20,000 females. The
most common presentation is with primary amenorrhea.
The external genitalia and pubertal development are normal.
The vagina and uterus are absent, and the diagnosis is made
on ultrasonography and magnetic resonance imaging. Laparoscopy is rarely necessary. Occasionally, the uterus exists as
very rudimentary horns lying on either side of the pelvic wall.
Further investigations reveal a normal female karyotype and
normal ovarian function. The cause of this condition is not yet
known, although familial cases have been described. Up to
40% of these women also have urinary tract malformations,
which may be minor or significant. In addition, skeletal anomalies are present in up to 12%.
As with AIS, the patient is not able to menstruate or to carry
a pregnancy. Initial management should be geared toward
exploring and trying to come to terms with the diagnosis.
The vagina is often short, and further intervention is usually
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501
E
F
Figure 37-2 Williams vulvovaginoplasty. A, Before surgery. B, Incision. C, Dissection. D and E, Sutures. F, Final result.
Surgical Treatment
Surgical intervention is indicated if vaginal dilators have been
unsuccessful. Patients without previous surgery achieve the
best results with dilation. Those patients with previous pelvic
surgery causing scarring of the genital area often require surgery as a first choice, because dilators are ineffective.
Nonsurgical Treatment
Williams Vulvovaginoplasty
Vecchietti Technique
The Vecchietti technique combines elements of surgery and
vaginal dilation. The technique relies on the principle of continuous pressure to form a vagina. The pressure is applied by
an acrylic olive placed at the vaginal dimple. Threads from
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Amnion
Other tissues, such as amnion, have been used to line the neovagina.12 Amnion can be obtained at elective cesarean section
and avoids the disadvantage of scarring at the donor site,
although dyspareunia is a problem. However, amnion donation is controversial and complicated to organize. Because of
the risk of infection, the collected amnion should be frozen and
stored. It is then cultured and, if sterile, can be used. Because
the practical logistics of amnion donation are considerable,
this technique is rarely used nowadays.
Peritoneum
Davydov13 first described the use of peritoneum to line the
neovagina. A neovaginal space is created as in the McIndoe
procedure, and then an abdominal approach is used to free
a cylinder of peritoneum and bring it down to line the neovagina. The top end of the vagina is then closed by suturing
bowel, usually colon, across it for a vaginal roof. This procedure can now be performed laparoscopically and is suitable
for patients in whom previous surgical scarring prevents dilation or the Vecchietti procedure.14
Intestinal Transposition
Different parts of the intestine in varying surgical modifications have been used as vaginal replacement. Baldwin, in 1904,
used a loop of ileum.15 The complications surrounding the first
few cases included death, and this led to the procedures being
abandoned for almost 60 years. Pratt16 modified the operation and used sigmoid colon with success. Cecum and ileum
have both been used to replace the vagina. All bowel segment
vaginoplasties require an abdominal and perineal approach,
and a loop of bowel is brought down while its blood supply
is retained. The distal end is sutured to the introitus, and the
proximal end is closed. Gut continuity is restored. This type of
surgery is indicated for patients who have undergone extensive pelvic surgery and in whom dissection to form a neovagina by any other means is impossible. This includes patients
with major pelvic anomalies such as cloacal exstrophy as well
as those who have failed with other methods such as McIndoe
procedures.
The major advantage of this procedure is that contracture
does not occur and dryness is not a problem. A good length of
vagina can be achieved. The patients do need to douche regularly, because mucous discharge is a persistent and sometimes
distressing problem. The vagina can prolapse outward and
can have an unsightly stoma-like appearance. Symptomatic
diversion colitis may occur and raises concerns about the use
of colovaginoplasty in children.17 Adenocarcinoma of bowel
segment vaginoplasties has also been reported.18
CLITORAL HYPERTROPHY
The most common cause of clitoral hypertrophy in XX females
is CAH. The 21-hydroxylase deficiency accounts for about 90%
of cases.19 Presentation is usually at birth, although patients
with mild disorders caused by decreased enzyme activity
rather than enzyme deficiency can present in the peripubertal period with premature adrenarche and hirsutism. Clitoral hypertrophy can also occur in rarer conditions, including
maternal ingestion of androgens or progestins during pregnancy. Androgen-secreting tumors can also cause virilization.
They are rare and include arrhenoblastomas and pregnancy
luteomas.
Clitoral hypertrophy is also a feature of incomplete AIS.
The etiology of incomplete AIS is similar to that of CAIS,
although the genitalia are partially responsive to the effects of
testosterone in utero. This gives rise to a spectrum of clinical
features ranging from a slightly virilized female appearance
to normal male anatomy with impaired spermatogenesis or
impaired virilization at puberty or both. Several classifications have been proposed.20 If the gender of rearing is female,
surgery is most frequently performed in childhood but may
need later revision.
Testosterone biosynthetic defects also lead to ambiguous
genitalia. These include conditions such as 5-reductase
deficiency, in which mutations in the gene for 5-reductase
type II isoenzyme lead to disruption of sexual development
in utero. Children are usually born with ambiguous genitalia
and reared as female. At puberty, virilization occurs, causing
growth of the phallus and sometimes descent of the testes
into the scrotum (Fig. 37-3). Several populations around the
world with a higher prevalence of this disorder have been
described, including the Dominican Republic,21 Papua New
Guinea,22 and Turkey.23 Successful change into the male gender has been described in large cohorts of affected patients,
and some have fathered children.24 However, some affected
patients prefer to remain female and may request surgical
intervention.
Other defects anywhere within the biosynthetic pathway
from cholesterol to dehydroepiandrosterone will cause a
defect in testosterone production. Patients present with variable degrees of genital ambiguity. The most common block
in testosterone biosynthesis affects 17-ketosteroid reductase
(also called 17-hydroxysteroid). Presentation at birth is similar to that of PAIS. Surprisingly, these women do show signs
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503
DUPLICATION ANOMALIES
Duplication anomalies arise from failure at some point of the
fusion of the paired mllerian ducts. The true incidence of such
anomalies is unknown, because many are entirely asymptomatic and found by chance. The incidence is higher in women
with infertility and recurrent miscarriage. Uterine anomalies
can be isolated but are also associated with an increased incidence of renal anomalies. Uterine anomalies, in particular
duplication, are very common in girls with cloacal anomalies.
Diethylstilbestrol exposure also leads to an increased risk of
mllerian anomalies.
Vaginal Duplication
Management of duplication anomalies depends on the type
of anomaly and the symptoms. A longitudinal vaginal septum can cause painful intercourse. This condition is usually
diagnosed on examination, because it can be missed on ultrasonography. Resection of the septum is straightforward and
curative. Vaginal duplication is, however, often associated
with a double uterus and cervix.
Figure 37-3 A 16-year-old XY female with 5-reductase deficiency
before clitoral reduction.
of virilization at puberty, and the mechanism is unknown.
Aproportion of affected women opt to change gender assignment at puberty.
Types of Surgery
Several surgical techniques have been described. Clitorectomy
(removal of the whole clitoris) was used in the past but is not
now an acceptable option. The clitoris is recognized as an
important sensory organ involved in sexual response. Later,
surgeons aimed to preserve as much of the enlarged clitoris
as possible and buried the corpora under the skin.25 However,
this meant that the erectile tissue was concertinaed under the
skin and, when erect, was very painful. Further modifications
of the technique described excision of corporal tissue and
preservation of the glans and the neurovascular bundle to
reduce any loss of sensation.26,27 Gearhart and colleagues28
performed pudendal evoked potentials during feminizing
genitoplasty on six young children. They demonstrated
Uterine Duplication
A double uterus is not usually an indication for surgery.
Successful pregnancy can occur, and surgery to remove one
uterus may compromise the remaining uterus. However, in
some cases, there is a bicornuate or septate uterus, which may
possess a noncommunicating uterine horn. In this situation,
when menstruation starts, the noncommunicating horn will
fill with blood, resulting in a hematometra. This causes severe
dysmenorrhea and is also associated with an increased incidence of endometriosis. If the communicating uterus is of an
adequate size, resection of the obstructed horn is the treatment
of choice and can be done laparoscopically. If both horns are
very small, a metroplasty may be considered to unite them.
The Strassmann procedure has been used in treatment of a
bicornuate uterus. In this procedure, a transverse incision is
made exposing both cornu. The septum is excised, and the
uteri are reunited. The Tompkins procedure involves a vertical
incision in the back of the uterus over the septum. The septum
is removed, and the cavity is closed without loss of space; this
is most suitable for a septate uterus. If the septum is thin and
easily visualized hysteroscopically, then hysteroscopic resection is possible, and this procedure is increasingly used.
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CONCLUSION
It is becoming more clear to specialists in the field of reconstructive genital surgery that long-term success rates in relation to sexual function are highly variable. Whereas some
patients seem to have good results, others obviously do
not. The emergence of patient support groups has increased
awareness of patient dissatisfaction. The range of types of
surgery available is large, but success rates are unpredictable and complications are not uncommon. The decision to
undergo surgery is a difficult one to make, although a decision not to do so may mean, in effect, a decision not to have
a conventional sexual relationship. The only person who
can make the final decision is the patient, with our support
and advice. It is our role to provide as much information as
possible to allow that decision to be a fully informed one. If
surgery is the correct choice, then the timing of it also needs
consideration. In some cases, such as feminizing genitoplasty
for CAH, better results may be obtained by delayed surgery,
because it would reduce the number of procedures required
and allow the patient greater input into the decision. Whether
or not this is true may be explained by better long-term
follow-up data.
REFERENCES
F
or complete list of references log onto www.expertconsult.com
CHAPTER
38
C.R.J. Woodhouse
The current revolution, led in part by adult patients themselves, questions previously held notions, requires a flexible
approach to allow a gender change in later life, and draws
attention to the larger number of affected adults than was previously known. Despite the difficulties in assessing quality of
life and management success in a broader context than surgical outcome, changes in the management are demanded. It
remains to be seen whether the changes will be for the better.
THE PENIS
Micropenis
In disorders of sex development (DSD), those with an inadequate penis are usually undervirilized males, most of whom
have an XY karyotype. The policy for many years has been to
advise a male sex assignment, especially if the hormonal environment in utero has been androgenic. Occasionally, infants
who have a 46,XX karyotype but are heavily virilized are raised
as males, but almost by definition they will have an adequate
penis (Fig. 38-1).
A micropenis is defined as one with a stretched length that
is more than 2 standard deviations (SD) below the norm. Some
are responsive to androgens and, particularly with intermittent doses of testosterone, may grow into the 10th to 25th
percentile range. For many, however, growth is limited to that
which would be expected of nonandrogen-sensitive organs
(Fig. 38-2).
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reverted to the male gender, and 7 of those living as females
had gender dysphoria. Therefore, female gender was successfully maintained in only 64%, and only 8 patients had reached
adulthood.12
There is no right answer for sex assignment in many
DSD conditions, but it is reasonable to question previously
held beliefs in light of the limited adult data available. A decision to raise a child as female should not be based exclusively
on the notion that it is easier for the surgeon to create female
genitalia than male genitalia, especially if the infant has the
potential for fertility as a male.
SURGICAL ENLARGEMENT
chapter
509
B
Figure 38-2 Clinical photographs of patients with micropenis in childhood (A) and after puberty (B).
18
16
Centimeters
14
12
10
8
6
4
2
0
8 10 12 14 16 18 20 22 24 26 28 30 32
Age in years
solid line indicates the 50th percentile, and the dotted lines describe
the 90th and 10th percentiles for the stretched penis. (From Schonfeld
WA. Primary and secondary sexual characteristics. Am J Dis Child.
1943;65:535-549.)
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It seems, therefore, that an abnormal or rudimentary
phallus can form the basis for sexual activity in a male role.
Nothing is known of the satisfaction of the sexual partners,
but it would be unreasonable to base decisions as to the gender of rearing of a baby on the opinions of a putative partner
some years in the future.
FERTILITY
forearm skin flap (above) piggy-backed onto a micropenis. (Courtesy of D.R. Ralph.)
Medical Enlargement
The early management of any case of ambiguous genitalia is
that of the underlying condition. With endocrine correction,
there may be some growth of the penis. Further growth is possible when puberty is induced. Dihydrotestosterone cream has
been used to stimulate penile growth. Both the penis and the
prostate show rapid growth. In a series of 22 children, there
was a mean increase in length of 53% in the first month and
a further 18% in the second month of treatment. The series
included 4 boys who had failed to respond to testosterone
treatment.24 Late treatment of a 12-year-old and a 17-year-old
boy has been reported, but the responses were poor.25 The
cream is not freely available.
Klinefelters Syndrome
Karyotype abnormalities are eight times more common in men
with nonobstructive azoospermia than in the normal population. Of these men, 83% have Klinefelters syndrome.30
Klinefelters syndrome is surprisingly common, occurring
in 1 of every 500 male live births. It is seldom diagnosed until
adolescence, because the genitalia are normal. At puberty,
some secondary sexual characteristics develop, but the testes
remain small and soft. Characteristically, the boys grow tall
(with particularly long legs), have gynecomastia, and appear
eunuchoid. The karyotype is 47,XXY in 85% of cases and mosaic
(46,XY/47,XXY) in the remainder. In the past, all patients with
the complete form were thought to be azoospermic, and testicular biopsies showed the presence of hyalinized seminiferous
tubules and Leydig cell hyperplasia; mosaics were known to
have some spermatogenesis. It is now clear, however, that there
is a spectrum of germ cell function (Table 38-1).31
Until recently, patients with Klinefelters syndrome were
considered to be infertile. There have been successful pregnancies using testicular sperm for intracytoplasmic sperm
injection (ICSI). Preimplantation genetic analysis of embryos
has not shown a recurrence of Klinefelters syndrome, the
karyotypes being 46,XX or 46,XY.31-33
5-Reductase Deficiency
Three men born with 5-reductase deficiency have been
reported to have fathered children. In one case, two boys and
one girl were produced in two pregnancies by intrauterine
insemination. The other two men fathered one child each by
intercourse.34,35
Hypogonadal Hypogonadism
Hypogonadal hypogonadism is rare and produces a wide
spectrum of phenotype. Kallmanns syndrome is but one
group. Some have severe micropenis. In adults, it is useful to
divide these men into those with testicular volumes greater
than or less than 4 mL. Long-term treatment with human chorionic gonadotropin (hCG) raises the serum testosterone, but
not into the normal range. The larger testes respond better.
chapter
Testis
Sperm
ICSI
Pregnancy
Normal baby
GONADAL NEOPLASIA
Both male and female gonads are at risk of neoplasia. If
there were no prospect of fertility, it would be reasonably easy
to suggest removal of all gonads even when the risk is small.
Now, a more accurate assessment of risk is essential.
The greatest risk is in those with a Y chromosome (although
without a Y chromosome male fertility is improbable). It also
seems likely that the common precursor of neoplasms is carcinoma in situ arising from primordial germ cells (intratubular
germ cell neoplasia, or IGCN). Although follow-up is incomplete, it is already known that 50% of men with IGCN will
develop a germ cell tumor within 5 years, but it is probable
that all would in time.38 About 25% of DSD patients with a
Y chromosome, especially if it is structurally abnormal, have
IGCN on biopsy.
Several types of disorders of sex development carry an
increased risk of testicular neoplasia, and management is frequently dictated by this possibility. The majority are germ cell
neoplasms, so some germ cells must be present in the gonad,
even if primitive and small in number. The more dysplastic
the germ cells, the higher the risk of neoplasia.
The highest risk is in patients with mixed gonadal dysgenesis who may have a 46,XY or a mosaic 46,XY/45,XO karyotype. Ninety percent have undescended gonads which either
are streaks or contain some testicular tissue and may be different on the two side. Gonadoblastoma is rare in patients with
46,XX karyotype and dysgenetic gonads; this is not surprising,
because the gonadoblastoma locus is on the Y chromosome.39
The usual tumor is a gonadoblastoma. This is a mixed
tumor of Sertoli cells and germ cells, with occasional Leydig
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REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
39
chapter
Prenatal
Infancy
Toddler
4 -7 Years
8 -10 Years
11 Years
Neurons
develop
Early
vocalizations
2 -3 Word
sentences
Good vocabulary
Poor comprehension
Knows when
not understanding
Good vocabulary
and comprehension
513
Prenatal
Infancy
Toddler
4 -7 Years
8 -10 Years
11 Years
Anxiety formation,
affective vulnerability
Doctor/hospital
anxieties/phobias
Behavioral problems,
demoralization,
compliance problems
Mood - anxiety
problems vs.
learning to cope
Figure 39-2 Potential effects of chronic illness and medical interventions on development, by age at insult.
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Prenatal
Infancy
Toddler
4 -7 Years
8 -10 Years
11 Years
Spontaneous
erections
Sensorimotor:
finds/stimulates
genitals/perineum
Touches genitals/
masturbates
Enjoys nudity;
genital pride
Modesty; interested
in others sexuality
encounter significant psychological repercussions of incontinence, sensorimotor dysfunction, and later issues of sexual
function, fertility, and the implications of these for sexual
relationships.11 Adult studies imply that female patients may
sometimes adapt better than males,12 perhaps because genital
issues are less problematic.
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515
DEVELOPMENTAL VULNERABILITIES
Early and multiple hospitalizations create developmental
risks and the potential for developmental delays or deficits.
A genitourinary diagnosis in the prenatal period is likely to
affect the parents in particularly complex psychological ways.
Mothers may be more vulnerable to guilt feelings. Both parents are likely to experience anxieties surrounding prenatal or
neonatal diagnoses. Neonatal hospitalizations and surgeries
impair bonding and engender parental perceptions of an ill or
defective child. Marital stresses may proliferate.
Similarly, maternal problems with bonding can lead to
infant problems with bonding. The implications and ramifications of such early infancy situations are not all clear. However,
disruptions of the typical parent-child relationships are likely
to occur. Multiple hospitalizations and chronic illness, along
with frequent doctor visits and outpatient procedures, can
similarly induce strains in the relationship between parent
and child or parent and parent. It is important for the treatment team to recognize that such developmental disruptions
may occur. If a child or parent behaves in the medical setting
in an inexplicable manner, the treatment team should consider
that developmental delays or deficits or misperceptions by the
child or parent may be orchestrating the observed reactions.
Because the framework for future development is laid
down in the past and present, one must surmise that at least
some developmental insults are likely to occur in a child with
chronic illness. Development stages may lag or psychosocial
stages may be bypassed or delayed to the point of creating
long-term psychosocial vulnerabilities. Therefore, it is important to gather an updated psychosocial history in these children at regular intervals. Many children will benefit from a
psychosocial rehabilitation program aimed at their specific
needs.
PSYCHIATRIC VULNERABILITIES
In addition to vulnerabilities already noted, the urologist
needs to be sensitive to the development of major anxiety or
mood (affective) disorders in patients. In some cases, anxiety
can be pervasive. Disruptive behavioral disorders, relationship disorders, and insults to typical family relationships can
also be problematic.
Hospitalization, procedures, and surgeries stress children
of all ages. The autonomic nervous system responds to pain,
fear, touch, sound, and so on. Blood pressure and pulse, for
example, demonstrate obvious changes and effects. The HPA
and HPG axes are also likely to endure profound effects that
can transform their basic functions and may bias a childs
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Prenatal
Infancy
Toddler
4 -7 Years
Abnormal
hormone
exposure
Failure to
find genitals
from pain or
surgeries
Learned aversion
due to genital pain
and/or anxiety
Genital fear/shame,
poor genital image
or sense of male
or female self
8 -10 Years
11 Years
Maturing sexual
brain accentuates
sexual/relationship
anxieties
Educational Interventions
Family, parent, and patient educational materials can be verbal,
written, pictorial, presented by video, or available on the Internet. Access to written materials is extremely helpful to parents
and may be the only way to provide accurate information that
parents will easily recall. Resources should include age- and
stage-appropriate information that will answer general questions while providing a framework for specific questions.
Materials for the parents of children who are approaching
puberty or already saturated with adolescence should include
a realistic appraisal of the childs potential sexual function
and fertility and realistic approaches for the achievement of
psychosexual developmental milestones.
The child or adolescent requires simple but specific and
complete information. Although it can be quite helpful to
provide written materials, children and adolescents respond
best to face-to-face interactions that are private, frank, and
confidential, as appropriate for age. Coping strategies develop
only slowly throughout childhood. The psychiatrist and
psychologist can educate the parents about coping skills that
the parents can then teach gradually to their child. Supportive
therapy for self-esteem and sexual self-esteem should bedi
rectedto the child. Body image, genital image, acceptance of
the genitalia, and self-genital contact may all require strong
supportive, intermittent, short-term therapy as the clinical
situation demands.
Pharmacologic Interventions
For many psychiatric problems, psychopharmacologic interventions become necessary. Many urologists already use psychopharmacologic preparationsfor example, the tricyclic
antidepressants (TCAs) such as imipramine (Tofranil). However, few in the pediatric field are aware of the variety of TCAs
nor of their full spectrum of uses, side effects, and risks. Child
psychiatrists recommend the use of TCAs only after a baseline
electrocardiogram (ECG) has been obtained, because of their
potential cardiac effects.39 Effectiveness for enuresis or incontinence has clearly been shown to correlate directly with the
serum level; serum levels must be monitored and maintained
in the therapeutic range for symptomatic urinary control to
be achieved.40 Additionally, about 5% to 10% of the population are slow hydroxylators and will have increased serum
levels with a relatively small TCA dose when compared with
the general population. These levels may be well into the toxic
range for cardiac function in such children. Desipramine, the
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517
Behavioral Interventions
For older children and for parents, cognitive behavioral
therapy (CBT) can be very helpful as an adjunct to treatment
interventions for anxiety, mood problems, self-esteem, sexual
self-esteem, and sexual dysfunction. CBT can be useful as an
intervention for specific psychiatric and behavioral problems
and as a preparatory adjunct to procedures. For adult patients
who grew up with genitourinary problems, CBT and insightoriented therapy may be especially useful and especially
appreciated.
For many genitourinary conditions, sex therapy and sex
counseling can be very therapeutic. Many of these children
and adolescents need to learn to be verbally intimate in
order to adapt to the sexual and psychosexual implications
of their conditions. Similarly, verbal intimacy can be vital to
the ultimate development of sexual intimacy. For the adolescent genitourinary patient, learning verbal intimacy as the
initial step in sexual relationships can greatly aid normal
psychosexual development and may evolve to more nearnormal sexual intimacy. When the urologist discusses with
the child his sexual situation, function, and realities, openly
and, preferably, alone, the child will benefit clinically and
psychosexually and will learn important communication
skills about intimate subjects as well. Without such an intervention, many adolescents may face a great obstacle to sexual
relationships.
Similarly, children and adolescents with major genitourinary conditions may have to be educated about the importance as well as the function of their own genitalia. They may
require education that it is safe to touch or handle their genitalia and that masturbation is a normal activity. Males with
significant penile anomalies may require education about
sexual positions that permit successful and satisfying sexual
intercourse. Some girls with vaginal anomalies may similarly
require education. Written and pictorial materials can be very
helpful, especially if the treating physician has high levels of
embarrassment about frank sexual discussions.
Adults who have endured congenital genitourinary anomalies may require counseling before or during marriage.
Interventions for adults may include education about sexual
functioning, sexual pleasure, satisfactory sexual intercourse,
positions for intercourse, masturbation, verbal intimacy, sexual intimacy, and the importance of intimate activities other
than intercoursetouching and sexual touching. Because
of improved abilities to cope and to deal with embarrassing
and difficult material, adults are likely to require less education and fewer intervention sessions in a given therapeutic
approach than children or adolescents.
Children, adolescents, and adults all may require psychosocial habilitation and rehabilitation to develop and adapt
despite their significant genitourinary conditions. Major pediatric genitourinary anomalies tend to affect anatomic regions
and perceptual areas of such intimacy that few patients are
likely to develop and mature without suffering at least some
psychosocial insults and psychosexual hurdles. It is essential
that the treatment team recognize these vulnerabilities within
the patient population in order to provide their patients the
best possible overall care, overall prognosis, and outcome.
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Table 39-1 Summary of Some Important Developmental Milestones and Difficulties by Age
Prenatal
Infancy
Toddler
4-7 Yr
8-10 Yr
11 Yr
Language
Development
Neuronal
development
Early
vocalizations
2- to 3-word
sentences
Good
vocabulary, poor
comprehension
Good vocabulary
and comprehension
Chronic Illness
Vulnerabilities
Affects brain
development
Brain
development,
maternal-child
bonding affected
Anxiety
f ormation,
affective
vulnerability
Doctor/hospital anxieties/
phobias
Reactive behaviors,
demoralization,
noncompliance
Mood-anxiety
problems vs learning
to cope
Psychosexual
Developmental
Milestones
Spontaneous erections
(vaginal lubrication?)
Sensorimotor:
finds, stimulates
genitals and
perineum
Touches/holds
genitals,
masturbates
Genital pride,
enjoys own
nudity
Modesty; interested
in others sexuality
Abnormal
Psychosexual
Development
Abnormal
hormone
exposure/
developmental
anomalies
Postsurgery
f ailure to touch
or enjoy genitals
Learned
a version due to
genital pain or
anxiety
Genital fear/
shame, poor
genital image
Hides sexual
interest, poor sense
of self as male or
female
Maturing sexual
brain accentuates
sexual/relationship
anxieties
REFERENCES
For complete list of references log onto www.expertconsult.com
S E C T I O N
40
FORESKIN
Peter M. Cuckow
NORMAL DEVELOPMENT
During its early development, the tip of the genital tubercle,
which will subsequently develop into the mature glans, is
uncovered. At about 12 weeks of gestation, a fold of skin forms
at the base of the glans, which migrates distally to cover it.
Initially, this skin fold is more prominent on the dorsal surface, but as it advances, it also migrates ventrally and fuses to
form a midline raphe. By 5 months, the glans is surrounded
by a sleeve of skin whose inner surface fuses with the outer
epithelium of the glans itself.1 From about 6 months of gestation, a process of keratinization occurs between these two layers, bringing about their separation and depositing a variable
amount of keratin between them, often referred to as keratin
pearls.2 This process continues throughout the latter part of
gestation.
At birth, it is unusual for the foreskin to be retractable,
because of incomplete separation of the epithelial layers and
also the conical shape of the foreskin, whose tip is too narrow to permit retraction behind the glans. Only about 4% of
newborns have a fully retractable prepuce, and in a further
54% the tip of the glans may be revealed by gentle retraction.3
Evolution to a fully retractile, widened, and separated foreskin proceeds at a variable rate during childhood. In a study
of foreskin development between birth and 3 years of age,
Gairdner3 found nonretractability in 80% of boys at 6 months,
50% at 1 year, 20% at 2 years, and 10% at 3 years. In an older
cohort of boys, Oster4 documented a change from 8% nonretractability to 1% between 6 and 17 years of age. During the
same period, glanular adhesions decreased from 63% to 3%,
and visible smegma production increased significantly, from
1% to 8% by puberty.
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VI: Genitalia
including applying granulated sugar to the penis,8 adding
multiple punctures to the edematous foreskin before compression,9 and injecting hyaluronidase beneath the narrow band to
release it.10 With this last approach, DeVries and colleagues10
found that wrapping the distal penis in a gauze swab soaked
with saline solution and squeezing gently but firmly for 5 to
10 minutes invariably sufficed to permit reduction without
anesthetic. After reduction, the edema subsides. Acute surgery is almost never indicated in this situation. Application of
lubricating jelly and local anesthetic creams may be counterproductive in that they decrease the ability to grasp the penis.
Later, a circumcision may be offered, but this is not mandatory,
because the foreskin will continue to develop normally.
allows him to relax and void. Most patients have only a single
severe episode, although recurrent balanitis is said to be a relative indication for circumcision. Acute surgery should usually
be avoided, and in particular the dorsal relieving slit of the
prepuce. Although balanitis is less common, it is still seen in
the circumcised population7 and therefore is not eliminated by
the operation. The decreasing frequency in older boys almost
certainly reflects foreskin maturation and the better penile
hygiene this affords. There is very little evidence to suggest
that balanoposthitis is a precursor to scarring at the tip of the
prepuce and subsequent true phimosis.5
Paraphimosis
Paraphimosis occurs when the narrow tip of the prepuce is
withdrawn behind the glans and constricts the penile shaft,
leading to edema of the distal penis (Fig. 40-3). This swelling
prevents repositioning of the prepuce over the glans. Complications include urinary retention, ulceration of the glans, and
ischemic necrosis of the glanular mucosa. Reduction is usually
possible within the first few hours by first reducing the edema
of the distal penis. Various techniques have been described,
Figure 40-2 Ballooning of the foreskin, before (A) and during (B) voiding when turbulent urine flow causes distention.
chapter
40: Foreskin
521
r etracted behind the glans, where it obstructs the lymphatic drainage from the end of the penis, which swells. As a result, the foreskin
cannot be easily replaced.
Figure 40-5 Webbed penis. The scrotal skin is fused along the shaft
of the penis.
the dartos, the fusion of scrotum and shaft skin extends more
distally, and the impression may be that of a micropenis.13 In
fact, the penis is of a normal size and is simply concealed, buried, or hidden (all terms used to describe the anomaly). A buried
penis is readily confirmed by careful examination with palpation through the prepubic tissues. In some cases there is a
physiologic phimosis at the preputial meatus and a very capacious inner preputial sac, which has been termed the megaprepuce. This balloons dramatically during voiding and empties
by dribbling.
Many operations have been described for correction of
these more severe fusion anomalies, and most authors agree
that simple circumcision is contraindicated.14 Release of the
penile shaft from its restricting deep attachments to prevent
reburying is well recognized, but there is variation in the
approach to providing its skin cover. Use of a tailored inner
preputial sleeve15 or a rectangular island flap of inner mucosa16 has been described, but neither technique gives a normal
circumcised appearance. As with the simpler webbed penis,
the line of demarcation between scrotal and shaft skin can be
demonstrated, suggesting that a similar surgical approach can
be taken.12,17 Incision along this line and deep dissection to the
penile root release the shaft and unfurl the redundant inner
prepuce. Removal of the inner prepuce leaves a rectangle
of skin that is sufficient to provide cosmetic skin cover and
the appearance of circumcision. The scrotum is closed in the
midline, giving it a more caudal appearance. This technique
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VI: Genitalia
Figure 40-6 Buried penis. Left, The scrotal skin and penile shaft skin have failed to separate. The penile shaft is tethered to the deep fascia. There
is a phimosis and a large inner preputial sac, which balloons during micturition. Right, Same patient, after surgical correction.
has been successfully applied to more than 20 boys with good
cosmetic results and no recurrent burying (Fig. 40-6).18
Penile Lymphedema
Primary lymphedema of the prepuce is a rare condition caused
by abnormal development of the lymphatic drainage of the
genital skin (Fig. 40-7). The skin is thickened with chronic
edema, whereas the underlying glans and corpora are usually
unaffected. In rare instances, the edema regresses spontaneously, but surgery, consisting of circumcision and removal of
the bulky subcutaneous tissue, gives reasonable results.19 An
alternative approach is to excise all the affected skin and subcutaneous tissue and reclothe the penis in split-skin grafts.20,21
Secondary lymphedema is more common, and worldwide the
most common cause is filarial infection in the tropics.22 Other
causes include trauma, previous penile surgery,23 a redback
spider bite,24 and an extraintestinal manifestation of Crohn
disease.25,26 In the last example, the genital manifestations may
predate overt bowel symptoms, but a high index of suspicion
and persistence will eventually lead to the underlying diagnosis. Urethral involvement may complicate the management of
this difficult clinical problem.26
Trauma
Injury of the prepuce is uncommon, and physicians should be
alert to the possibility that it may be nonaccidental. In a survey
of 32 foreskin injuries, the mechanism seen most commonly
(in 6 boys) was a zipper injury.27 The foreskin can be easily
released if the zipper is cut close to the point of its entrapment,
enabling it to be pulled apart easily.28
chapter
Figure 40-8 Balanitis xerotica obliterans. There is recognizable scarring at the tip of the prepuce and no pouting inner mucosa (compare
Figure 40-1).
the glans itself, and the meatus can be involved in the scarring process, resulting in meatal stenosis. Rickwood and
coworkers30 reviewed 23 patients operated on for clinically
diagnosed true phimosis and found that 21 had histologically
proven BXO with thickening, edema, and lymphocytic infiltration of the dermis. The etiology of BXO is unknown, but it
may be of viral origin.
It is unclear whether the lesion of BXO responds to the
local application of steroid creams, because many patients
with physiologic phimosis have been included in most studies. Lindhagen32 compared steroid cream with placebo in
patients with nonretractable foreskin and showed that all of
the failures had histologically proven BXO. The operative
management is circumcision, which removes all the affected
tissue in most childhood cases. One series of 10 boys monitored for 5 years after circumcision showed no recurrence or
regression of glanular lesions,33 although BXO is often cited
as a precursor to postcircumcision meatal stenosis.34 Authors
vary on this association, and different series of patients with
meatal stenosis have shown either 10 of 12 patients with previous BXO35 or, in contrast, 0 of 12 patients previously affected.36
In the context of hypospadias and other urethral conditions,
the urethra and glans may be severely affected. In such cases,
the condition poses an extra difficulty in achieving a satisfactory long-term result of reconstruction.
40: Foreskin
523
Circumcision Techniques
Neonatal circumcisions are usually performed with the
patient under local anesthesia with a clamp or Plastibell
device.41,49 With the Gomco clamp, the foreskin is retracted,
congenital preputial adhesions are separated, and the
appropriate-sized bell of the clamp is placed over the glans.
The foreskin is replaced over the bell, and the clamp is
assembled. Closure of the clamp crushes the skin, allowing
the distal prepuce to be excised and producing a suture-less
524
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VI: Genitalia
anastomosis just below the corona. The Plastibell is similarly placed over the glans, and the foreskin is replaced over
it. A suture is tied around the foreskin, crushing it against
a groove on the outer circumference of the device, and the
distal foreskin is excised. The bell remains in situ until skin
necrosis allows it to separate and fall off, after a mean of
9 days.50 In the meantime, the infant voids through the open
end of the bell. Jewish ritual circumcisions are usually performed with a Mogen clamp. This has a slit through which
the foreskin is pulled and then crushed above the glans.
The distal foreskin is excised before the inner prepuce is
retracted, and a circumferential dressing is applied.51,52
In older children, it is usual to perform circumcision under
general anesthesia with the addition of a local anesthetic
penile or caudal block to provide good analgesia during and
immediately after the operation.34 Although larger sizes of
the clamp devices are available, most circumcisions are performed by the freehand or sleeve techniques. For the freehand
technique, the foreskin is held in clips, and a dorsal slit made
with scissors to just below the corona. The incision is carried
forward on both sides to the frenular aspect of the penis, leaving a cuff of inner prepuce below the glans. The edges are
separated, and hemostasis achieved with bipolar diathermy
or absorbable ligatures. The edges are then opposed with
interrupted absorbable sutures. In the sleeve technique, the
foreskin is retracted and a circumferential incision is made
in the inner prepuce, 0.5 cm below the glans. The foreskin is
replaced, and a matching outer incision is made at the level
of the corona. The sleeve of skin between the incisions is then
removed, hemostasis is achieved, and the operation is completed as for the freehand technique.
Circumcision Complications
Given the prevalence of circumcision, any complication of
the procedure, however uncommon, will affect a significant
number of patients. A wide range of complications is reported,
although there are few prospective long-term studies. Historically, there have been significant numbers of deaths following
the procedure, due to anesthesia, hemorrhage, and infection.3
Figure 40-9 Meatal stenosis. A narrow meatus after circumcision (left), compared with a normal meatus in an uncircumcised boy (right).
chapter
40: Foreskin
525
Neonatal Circumcisions
(Patel)55
Circumcisions in Childhood
(Europe, Australia)34,38,50,58-60
No. of patients
116,841
100
1192
Type of study
Retrospective
Prospective
Prospective
Hemorrhage (%)
0.4
Infection (%)
0.16
4.3
0.15
2.1
5.1
0.17
>2
5.0
0.72
>35
20.1
Preputial Plasty
Although the best way to avoid the complications of circumcision is not to perform the operation, simpler foreskinpreserving techniques have been proposed. Preputial plasty,
which widens the narrow preputial tip, is advocated as an
effective way to produce a retractable foreskin that has few
complications.60 Various techniques have been described,
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
41
HYPOSPADIAS
Pierre D.E. Mouriquand, Delphine Demde,
Daniela Gorduza, and Pierre-Yves Mure
chapter
41: Hypospadias
527
Preputial hood
Urethral plate
Ectopic urethral meatus
Hypoplastic urethra
(not surrounded by spongiosum)
Normal urethra
(surrounded by spongiosum)
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VI: Genitalia
a limited part. Very little is known about the ground workers, those molecular agents such as tissue proteins, growth
factors, vascular factors, and tissue destructors (apoptosis),
which need to be well balanced to establish an equilibrium
between constructive and destructive factors.
sum, a line is drawn on each side along the border between the inner
and outer aspects of the preputial hood. Where the two lines cross is
the division of the corpus spongiosum.
The Genes
Among the genetic disorders affecting the child and his genital construction, two groups can be distinguished: the isolated
gene mutations and the syndromic genetic disorders (Table 41-1).
In a series of 205 hypospadiac patients compared with
205 controls, the risk of having another child with hypospadias
was 17-fold.7 In a Swedish series of 2500 patients, 7% reported
at least one additional family member with hypospadias.8
The Hormones
In a 1997 report,9 defects of the testosterone biosynthetic pathway in boys with hypospadias determined the incidence of
defects in three major enzymes (3-hydroxysteroid dehydrogenase, 17-hydroxylase, and 17,20-lyase) in 30 boys with fully
descended testes but with proximal hypospadias. One half of
the boys had evidence of impaired function of one or more
of these enzymes, suggesting that there was an underlying
defect in the biosynthesis of testosterone. This paper surprised
many, and another study screening 32 consecutive hypospadias patients did not confirm the same findings.10
chapter
41: Hypospadias
529
Figure 41-6 Anterior hypospadias with a distal division of the corpus spongiosum.
Shima and colleagues showed that the more severe the
hypospadias was, the less satisfactory was the response to
stimulation by human chorionic gonadotropin (hCG).11 Here
again, this was not found in Feyaerts and associates paper.10
Mutations of the androgen receptor are rarely found in
hypospadias.12
In total, fewer than 5% of hypospadias patients have an
identified endocrine disorder, although it is most likely that
some hormonal impairment occurred during gestation and
led to the insufficient virilization of the genital tubercle.13
The Placenta
The placenta probably plays a major role in virilization of
the genital tubercle during the first part of gestation. Fredell
and colleagues8 examined discordant monozygotic twins and
found that the birth weight of the twin with hypospadias was
significantly lower than the birth weight of the twin without
hypospadias.14-16 Another study found that boys with hypospadias had a lower placental weight than control boys.17
Hypospadias is also more common with mothers who are very
young or relatively old.18 In these groups of pregnant women,
the placenta is often less developed. These findings clearly
point out the essential role of the placenta in genital construction, although very few markers can attest to this hypothesis.
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part
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MOTHER
CHILD
PLACENTA
ANOMALIES
Mesoderm
Karyotypes:
46,XY
45,XO; 46,XY
Y-Deficient patients
46,XX; 46,XY
46,XX
WT1
SF1
Hormonal
disorders
Tumors
Treatment
hCG
Aromatase
Undifferentiated
gonad
Pituitary
gland
FSH
LH
SRY
SOX9
Genes:
Isolated gene mutation
syndromes
Testis
LH receptor anomaly
Gonadotropin insufficiency
Sertoli Leydig
WT1
SF1
SOX9
AMH
ENVIRONMENT
Disruptors
Promotors?
with Hypospadias
DHT
Target tissues
Androgen
receptors
Gonadal dysgenesis
Pure
Mixed
Ovotesticular DSD
SF1
LHR
5 -Reductase deficiency
Protein platform
Structuring and
destructuring
proteins
CAIS
PAIS
HYPOSPADIAS
chapter
41: Hypospadias
531
Dialogue
Mesenchymal cells
Hormonal balance:
Androgens
Estrogens
Endocrine disruptors
Epithelial cells
or
or
Structuring
proteins
Growth factors, anti-proteases,
extracellular matrix components,
adhesion, tight junction proteins,
transcription factors
Construction
Hormonal balance:
Androgens
Estrogens
Endocrine disruptors
Destructuring
proteins
Balance
Normal tissues
Hypospadias
Proteases
Apoptosis factors
Waste proteins
Destruction
higher risk of urethral stricture, they are perfectly valid for the
most severe forms of hypospadias. The use of buccal mucosa
instead of skin may improve their results.
SURGICAL PRINCIPLES
In general, hypospadias surgery involves three main steps:
(1) straightening of the penis (i.e., correction of chordee);
(2) reconstruction of the missing urethra (i.e., urethroplasty);
and (3) reconstruction of the tissues forming the ventral radius
of the penis (i.e., glans, corpus spongiosum, and skin).
Correction of Chordee
Degloving of the penile skin and freeing of the ventral tissues
sitting on each side of the urethral plate usually sorts out the
penile chordee related to tethering of the ventral skin and the
two spongiosal pillars. If the chordee persists after this first
maneuver, freeing of the urethral plate from the ventral surface
of the corpora cavernosa, from the glans cap down to the normal urethra surrounded by normal spongiosum, is an alternative advocated by some (Fig. 41-10). In fewer than 5% of cases,
the chordee still persists after these two procedures, and a dorsal plication of the corpora cavernosa is then needed.41 Some
authors do not like to free the urethral plate, arguing that this
step may jeopardize its blood supply. They prefer to perform
a dorsal corporeal plication straightaway. In the most severe
form of hypospadias, when a Koyanagi procedure is chosen,
the urethral plate is divided behind the glans and detached
down to the base of the penis.37 This complete detachment of
urethral tissues from the ventral aspect of the corpora is usually sufficient to straighten the penis, although the procedure
is used only for the most severe forms of hypospadias.
Urethroplasty
The choice of urethroplasty depends on the quality and width
of the urethral plate (the strip of urethral mucosa extending
from the ectopic urethral meatus up to the glans cap).33 If the
Figure 41-10 Freeing of the urethral plate to release the chordee. The
plate remains attached distally to the glans cap and is continued proximally by the urethra.
532
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VI: Genitalia
D
Figure 41-11 The Thiersch-Duplay procedure. A, Incision lines. B and C, Incisions are made along each edge of the urethral plate. The urethral plate is tubularized around an 8F (2.64-mm) to 10F (3.30-mm) catheter. D, A Firlit collar, glans plasty, circumcision, and skin cover are
performed.
chapter
41: Hypospadias
533
B
E
Figure 41-12 The onlay procedure. A, Incision lines. B, Dissection of a rectangular preputial flap. C and D, The rectangle of preputial mucosa
is positioned as an onlay on the urethral plate, avoiding circular anastomosis. E and F, The pedicle is mobilized to cover the suture lines. A Firlit
collar, glans plasty, circumcision, and skin cover are performed.
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VI: Genitalia
Figure 41-13 The Mathieu procedure. A, Incision lines. B, Dissection of the Mathieu flap and incision along each edge of the urethral plate.
C, Suture of the Mathieu flap along the edges of the urethral plate over an 8F (2.64-mm) to 10F (3.30-mm) catheter. D, A Firlit collar, glans plasty,
circumcision, and skin cover are performed.
Penile Covering
Once the penis is straight and the urethra has been fully
reconstructed, many would advocate covering the neourethra
withsome healthy tissue, such as the two pillars of spongiosum sitting laterally (spongioplasty) or some cellular tissue
taken from the dorsum of the penis or the scrotal region.
The next steps are the reconstruction of the new meatus
(meatoplasty), the creation of a ventral glans (glanuloplasty),
chapter
41: Hypospadias
535
Rolling the glanular urethral plate (Thiersch-Duplay procedure)27,28 and covering the reconstructed urethra by means of
the two glans wings is a possibility if the glans groove is deep
enough. The urethral plate is freed with two vertical incisions
following its edges. The two glans wings are deeply dissected
laterally. The urethral plate is then rolled around a urethral
catheter using fine resorbable sutures (6-0 to 7-0 polydioxanone or polyglactin).
The Snodgrass35 procedure is an alternative if the distal urethral plate is too narrow to be rolled. A longitudinal midline incision is made on the urethral plate, which is then rolled around
a urethral catheter, leaving a raw area inside the urethra, which
one hopes is subsequently epithelialized. Snodgrass showed that
this procedure was potentially applicable in all cases of primary
distal hypospadias, regardless of urethral plate configuration or
width.49 The results are good with a fistula rate of 2% and a glans
dehiscence rate of 3%. A general review of literature reported a
9% rate of complications, including meatal stenosis (3%), fistula
(5%), partial glans dehiscence (9%), and stricture (2%).50
Koff Procedure
B
Figure 41-14 A, A rectangle of buccal mucosa is harvested from inner aspect of the lower lip. B, Buccal graft urethroplasty.
A complete mobilization of the penile urethra (Koff procedure45) is another possibility to position the urethral meatus
at the right place, although this procedure may look quite
extensive to some. The whole penile urethra is detached from
the anterior aspect of the corpora cavernosa and then moved
forward to bring its opening at the tip of the glans. A gain in urethral length of 5 to 15 mm is possible with this technique. More
length can be obtained if a more proximal freeing of the urethra
is achieved using the Turner-Warwick procedure,46 although it
is rarely needed in these types of hypospadias. The Koff repair
has a very low fistula rate, but meatal stenosis appears in about
20% of cases, probably because of a distal ischemia.51
These three procedures are attractive because they do not
use any nonurethral tissues to repair the missing urethra.
Many variations of these procedures have been described,
such as the glans approximation procedure52 or the granular reconstruction and preputioplasty procedure.53 Barcat54
described a reconstruction of the distal urethra using one
cutaneous flap and one glanular flap.
Mathieu Procedure
In the Mathieu29 procedure (see Fig. 41-13), two parallel incisions are made on either side of the urethral plate, up to the tip
of the glans and deep down to the corpora cavernosa. The incision line delimits a perimeatal-based skin flap that is folded
over and sutured to the edges of the urethral plate. The lateral
wings of the glans are generously dissected from the corpora
cavernosa. The rest of the procedure follows the recommendations given earlier.
Distal strictures are rare (1%), and fistulas are met in 4% of
the cases55 (0.5% meatal retraction and 1% urethrocutaneous
fistulas).56
The half-moonshaped meatus is sometimes disappointing,
but an extensive dissection of the two wings of the glans allows
a nice glanuloplasty. The overall results remain satisfactory.
536
part
VI: Genitalia
Figure 41-15 The Asopa-Duckett procedure. A, Incision lines. B and C, Dissection of a rectangle of preputial mucosa with its pedicle. D, The flap
is tubularized around an 8F (2.64-mm) to 10F (3.30-mm) catheter, and a proximal circular anastomosis with the native urethra is performed. E and
F, The pedicle covers the suture lines. A Firlit collar, glans plasty, circumcision, and skin cover are performed.
F
Figure 41-16 The Koyanagi procedure. A and B, Incision lines. C, The preputial mucosa is incised at the 12-oclock position to form a Y-shaped
flap. D, The medial edges of the two preputial flaps are sewn together to form the back wall of the neourethra. E, The neourethral plate is tubularized around an 8F (2.64-mm) to 10F (3.30-mm) catheter. F, A Firlit collar, glans plasty, circumcision, and skin cover are performed.
538
part
VI: Genitalia
Figure 41-17 End results. Note the mucosal (Firlit) collar surrounding the glans.
chapter
41: Hypospadias
539
Figure 41-18 The Bracka procedure. Stage 1: A, incision lines; B, removal of the urethral plate and dissection of a rectangular preputial flap;
C, positioning of the rectangle of preputial mucosa as an onlay on the ventral aspect of the penis; D and E, suturing of the graft to the penile shaft,
with circumcision and skin cover. Stage 2: F, incision lines; G and H, urethroplasty using the preputial graft and skin cover.
540
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VI: Genitalia
is a potential option. A preoperative course of -hCG or testosterone or dihydrotestosterone cream can be helpful to improve
the blood supply of penile tissues. In all cases, the experience of
the pediatric urologist is of paramount importance.
The Snodgrass incised plate urethroplasty has been
reported to be an option with successful outcome after failed
procedures.89 Previous incision of the urethral plate was not
a contraindication in these selected cases in which the plate
appeared supple. However, TIP repair should be avoided in
repeat hypospadias surgery if the plate has been resected or is
obviously scarred.90
Buccal graft urethroplasties in redo cases have a complication rate of approximately 30% in our experience,87 and 20%
in the report of Baskin and Duckett.91 These complications
are mainly represented by fistulas and urethral breakdowns
of variable length. However, the plate left after urethral
breakdown is usually wide enough to allow a subsequent
Duplay urethroplasty. In the severe hypospadias cripple, composite urethroplasty can be indicated.
Multistage Procedures
Multistage procedures have their best indications in cases of
severe posterior hypospadias in which the urethral plate cannot be preserved. Some plastic surgeons, such as Bracka40 (see
Fig. 41-18), have reported better cosmetic results using twostage procedures inspired by Cloutiers39 technique. The main
concern raised by these two-stage procedures is the use of skin
to repair the urethra. In the last decades of the 20th century,
skin appeared to be a poor material to replace the urethral
tissue, because it has an unacceptably high rate of urethral
strictures. This is the reason why two-stage procedures using
buccal mucosa might provide better long-term results.
The stage-one repair includes an axial incision on the
glans, which is completed by a ventral dissection; then a
full-thickness graft of preputial skin or buccal mucosa is
harvested, sutured in place, and immobilized with a tieover pressure dressing. Six months after the first operation,
the stage-two repair is the tubularization of the urethral
plate. Although graft manipulation requires an appropriate learning curve, this procedure may be a valid alternative for reconstruction, especially for severe and crippling
hypospadias.92 In his personal series (600 operations in 457
children), Bracka reported a 5.7% fistula rate, and strictures
were seen in 7%.93 The author suggested that, if balanitis
xerotica obliterans is present in the genital skin, a buccal
graft should be used instead. In a recent series of 62 boys
who underwent a two-stage procedure, 1patient developed
a hematoma, 3 patients had a partial glans dehiscence,
3 others kept a residual mild curvature, and 3 boys had a
meatal stenosis.94
COMPLICATIONS
Complications are common and should be treated at least
6 months after the initial procedure, to allow the tissues to heal
properly.
Hypospadias Cripple
chapter
41: Hypospadias
541
Mucosal Ectropion
The complication of mucosal ectropion is less common nowadays with the use of onlay urethroplasties. It was commonly
observed with bladder mucosal graft urethroplasties82 and
was often associated with pseudopolyps requiring a resection.
Recurrence is common, as is secondary meatal stenosis.
Urethrocele
Figure 41-19 Urethral fistula.
Fistulas
Fistulas (Fig. 41-19) are the second most common complication
of hypospadias repair. The patient presents with an abnormal
stream or drops coming from the undersurface of the penis.
Although late fistulas exist, this is usually an early complication (first month postoperatively). A fistula that is small
and not associated with a urethral stricture can heal spontaneously. If it persists after 6 months, another procedure is
required. The fistula rate varies with the technique used96: 4%
for the Mathieu procedure but 15% for the onlay procedures in
our hands, going up to 20% in cripple hypospadias.55,71 This
complication is more common with free graft urethroplasties
than with vascularized grafts.
The location of the fistula varies, but it is often found
proximal to the glans corona in a lateral position. If the fistula
persists longer than 6 months after the initial procedure, the
fistula tract should be excised and sutured and covered by
several layers of tissue. Large fistulas are unusual and attest
that the original urethroplasty was not satisfactory. They
usually require a full reconstruction of the urethra. A combination of fistula and urethral stenosis is common, and therefore
the urethroplasty needs to be checked cautiously before deciding on a simple fistula closure. Fistulas located just behind
the corona are not easy to close and tend to recur if the usual
excision-and-coverage procedure is performed. For this reason, it is often recommended in these cases to redo the distal
urethroplasty using a Mathieu flap.
Strictures
Strictures are less common nowadays, because pediatric urologists tend to avoid circular anastomosis and prefer onlay
urethroplasties. Meatal stenoses are usually simple to handle
Urethrocele is often related to a difference in urethral compliance between the native urethra and the reconstructed urethra. It is therefore important to support the penile urethra
with several layers of well-vascularized tissue, to reduce the
difference in tissue elasticity. It is also important to check
that the urethrocele is not associated with a urethral stenosis.
This complication was particularly common with bladder
mucosal urethroplasty. Excision of the redundant urethral
tissues and treatment of the distal stenosis are required
(Fig. 41-20).
Hairy Urethra
Hairy urethra should no longer be seen with modern techniques, although it may reappear with the Koyanagi pro
cedure,because proximal skin is often kept to reform the
urethra. This complication is caused by the use of scrotal skin
and requires a new urethroplasty. Urethral stones may develop
in the hairy segment of the urethra.
Persistent Chordee
Persistent chordee is quite rare. The long-term outcomes of plication of the tunica albuginea of the corpora are unknown, and
dorsal plication of the corpora at an early age may predispose
the patient to secondary penile deformities as the penis grows
considerably in the adolescent period. One should therefore
be very cautious with these dorsal-shortening procedures, and
patients should be followed up through puberty.
542
part
VI: Genitalia
B
Figure 41-20 A, Urethrocele (associated with a meatal stenosis).
B, Urethrography of the same patient as in A.
LONG-TERM OUTCOMES
Few publications exist regarding long-term outcomes of modern procedures. The long-term results available today mostly
concern procedures that have now been abandoned. The Denis
Browne procedure does not provide satisfactory long-term
results. In most cases, the meatus remained proximal to the
glans at the middle third of the penile shaft,100-102 and a quarter of these patients had difficulty in urinating while standing.
Two thirds had a spraying stream. Bracka103 reported that half
of the patients who underwent a Denis Browne procedure104
or an Ombredanne procedure105 needed further surgery. More
than 30% of posterior hypospadias patients had complex longstanding problems.106
Although early outcome data are widely available, little
has been reported on the long-term problems. Data suggest that most men have no lasting effects, but up to 40% of
those with severe hypospadias have some degree of voiding
problems. Recently, Khoury and coworkers107 described longterm follow-up of the TIP repair: 69% of patients had normal
urinary peak flow rates, and 46 of 48 patients had a postvoid
residual of less than 10%. In a study of island tube and island
onlay repairs with a mean follow-up period of more than
14 years, Snyder and colleagues108 found normal urine flow
rates in all patients, although this result does not match what
other authors have published. Long-term urinary outcomes in
patients undergoing a free flap repair were recently reported.
In a review of 44 boys who had undergone two-stage repair
for severe hypospadias, 40% described urinary spraying, and
40% milked the urethra after voiding.109 The result was similar
in a group of patients after buccal mucosa grafts, with 26%
describing problems with urinary spraying.110
An objective assessment of the cosmetic appearance after
hypospadias is difficult. In a recent objective study, 32 boys
had their penis photographed after three different types of
repair: TIP, Mathieu, or onlay. The TIP repair was believed
to have the most cosmetically appealing result.111 Lam and
colleagues, in their long-term review of two-stage repairs,
reported that 92% of patients were pleased with the outcome,
and 88% considered their penis to be normal.109 In contrast,
Nelsons group reviewed single-staged buccal urethroplasty
for severe cases of hypospadias and found that only 28% were
very satisfied with the appearance of the penis.110
Concerning sexual outcome, problems affecting erection,
ejaculation, and sexual sensation have been reported in more
than 20% of men, in several studies.110,112,113
TECHNICAL TIPS
Most surgeons use magnification glasses for this surgery. Endless debates exist about the use of antibiotics, coagulation,
tourniquets, types of urine drainage, dressings, and sutures.
Each surgeon has his or her own habits, and each needs to
compare honestly his or her results with others.
Surgical repair can be carried out starting from 6 months
of age, and before 2 years if possible. Children younger than
2 years of age have reflex micturitions that facilitate the postoperative period. Among children who have bladder control,
first micturitions after surgery might be more difficult to
initiate.
Preoperative penile hormonal stimulation is an issue for
discussion, and there is no agreement about the dose and
type of stimulation that should be used. -hCG, systemic
testosterone administration, local dihydrotestosterone cream,
local testosterone cream, epidermal growth factor, and growth
hormone are regularly discussed as means to improve the size
of the penis and its ability to heal. Little is known about the
long-term effects of these hormonal treatments, particularly
concerning growth and precocious puberty. Recent publications from dermatologists114 showed that androgens may
slow down the healing process. A publication to come from
our department shows that patients who received preoperative androgen stimulation have a significantly higher rate of
chapter
CONCLUSIONS
Hypospadias surgery remains very challenging, with a significant complication rate even in the best hands. This surgery
should be performed by experienced pediatric urologists who
handle at least 40 to 50 cases per year per surgeon.
41: Hypospadias
543
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
42
with the median raphe on the ventral aspect of the penis. The
scrotum is located below the penis and varies greatly in size
and appearance.
PENILE ANOMALIES
Congenital penile or scrotal anomalies can be isolated variations
of external genitalia development, or they can represent significant underlying malformations. Prompt diagnosis and potential
surgical planning are essential to allay the anxieties of parents
as well as to identify other, potentially clinically significant conditions. Congenital penile anomalies have been shown to be
increasing in incidence. The weighted incidence of anomalies
including hypospadias has increased from 7 of every 1000 newborns (1988-1991) to 8.3 of every 1000 newborns (1997-2000),7
but this may be a result of increased reporting. Multiple etiologies in abnormal development have been proposed, including
genetic, hormonal, and environmental influences.8 Whereas
molecular pathology has aided in the identification of key steps
in abnormal development, modern imaging techniques continue to refine the evaluation and treatment of such anomalies.
Aphallia
Aphallia (Fig. 42-3) is very rare, with only about 70 cases
reported in the medical literature. Its estimated incidence is
1 in 10 million births. This devastating abnormality is thought
to result from a failure of the genital tubercle to develop
normally.
Classification
Two classification schemes have been proposed. Skoog and
Belman9 based their classification system on the opening of the
urethral meatus. In type 1 aphallia, the urethral meatus opens
below the urinary sphincter or is postsphincteric. In type 2, it
is at the level of the prostatic urethra with a communication
to the rectum in the form of a fistulous tract. In type 3, it is at
the level of the bladder, with no urethra seen, and a vesicorectal fistula allows for urinary drainage. Evans and colleagues10
classified aphallia based on the severity of associated anomalies. Patients with severe cases present with renal aplasia or
dysplasia and other caudal anomalies. A less severe form is
associated with low mortality and few associated anomalies.
chapter
545
Abdomen
Penis
Scrotum
Rump
Spine
Figure 42-1 Schematic (A) and ultrasound (B) sagittal views of male genitalia at 18 weeks. Note how the penis points up toward the head.
(Courtesy of Dr. Douglas S. Richards.)
in patients who have some degree of urethral development.
Associated anomalies include testicular maldescent, renal
anomalies, vesicoureteral reflux, imperforate anus, and musculoskeletal and pulmonary abnormalities.10
Vesicorectal fistula occurs in patients with no urethral
development. This is caused by very early bladder outlet
obstruction. In these cases, associated anomalies are much
more frequent (an average of four per patient), and mortality
rate is closer to 100%.
Evaluation
Prenatal diagnosis has not been reported to our knowledge.
A karyotype may not be necessary, because invariably these
patients are XY. Further evaluation is required to determine
the presence of associated anomalies and should be tailored to
the physical findings. MRI has been helpful in further defining the lower urinary tract and gastrointestinal tract and in
demonstrating the presence of erectile tissues.11 The presence
of erectile bodies may help in planning the reconstructive procedure, but, in general, corporal bodies are absent or severely
hypoplastic.
Treatment
Gender reassignment has been recommended in the past,
given the formidable obstacles to surgical reconstruction of a
functional penis and urethra. However, a recent report questioned the option of gender reassignment because of the early
impact of testosterone imprinting on the brain, which leads
to significant psychosocial difficulty as the gender-reassigned
child matures. In 16 patients assigned to the female gender at
birth or reassigned to female during early childhood, 2 lived
as males later in adolescence or adult life. In 17 patients raised
as males, all continued to live as males.12
Prior to this report, the standard of care had been removal
of the male gonads and creation of a functional female genital
and urinary tract. This approach must be still considered an
Micropenis
Micropenis is unusual but can result from multiple hormonal abnormalities. It constitutes 1.8% of all congenital
penile anomalies.17 True micropenis is unusual and should
546
part
VI: Genitalia
Genital tubercle
Early
penis (glans)
Ectoderm
Urogenital folds
Urogenital membrane
Urogenital
fold
Urethral groove
Cross-section
Urethral
groove
Urogenital
folds (fused)
Labioscrotal
folds
(fused)
Labioscrotal folds
A
Glans of
penis
Fusion of
urogenital
folds
Scrotum
C
Figure 42-2 Normal anatomic development. A, External genitalia at 7 weeks (undifferentiated). B, External genitalia at 9 weeks. C, External
genitalia at 12 weeks. (Courtesy of Dr. Eugene Daniels.)
Classification
Figure 42-3 Aphallia. (From Perovic S, Djakovic N, Hohenfellner M.
[Penile and urethral anomalies]. [German] Urologe A. 2004;43:394-401.)
be distinguished from a buried or webbed penis. As discussed earlier, normal penile development requires the
appropriate timing and secretion of testosterone from Leydig cells. During the first 3 months of gestation, the process
is mediated through placental hCG. In the 4th month, with
chapter
547
Hypogonadotropic Hypogonadism
1. Isolated, including Kallmanns syndrome
GnRH
Anterior
pituitary
4. Laurence-Moon syndrome
5. Bardet-Biedl syndrome
6. Ruds syndrome
FSH
LH
Testicles
Primary Hypogonadism
1. Anorchia
2. Klinefelters and poly-X syndromes
3. Gonadal dysgenesis (incomplete form)
4. Luteinizing hormone receptor defects (incomplete forms)
Evaluation
7. Trisomy 21
8. Robinow syndrome
Treatment
The initial management of true micropenis is dictated by the
presence of associated hormonal disturbances, as seen in cases
of pituitary insufficiency. In these cases, emergent correction
of the biochemical abnormality is warranted. Subsequently, it
is important to determine whether the penis will grow with
androgen stimulation. Observation of the response to hCG
during the diagnostic evaluation may give an idea of the
9. Bardet-Biedl syndrome
10. Laurence-Moon syndrome
548
part
VI: Genitalia
Diphallia
The incidence of diphallia (Fig. 42-5) is 1 in 5 million live
births.28 A good embryologic explanation does not exist, given
the fact that the genital tubercle is believed to arise as a single
structure.
Classification
A widely accepted classification separates true diphallia from
bifid phallus. These two groups are further subdivided into
partial or complete duplication. True complete diphallia refers
to complete penile duplication, each penis having two corpora
cavernosa and a corpus spongiosum. If only one corpus is
present in each penis, the term bifid phallus applies. This is the
more commonly seen variant associated with the exstrophyepispadias complex.
Evaluation
Evaluation should include imaging of the urinary tract with
a voiding cystourethrogram and upper imaging with a renal
ultrasonogram. Ultrasonography may also be helpful in evaluating the phallic anatomy.32 Cavernosography may be useful
Treatment
Treatment of diphallia should be approached on an individual
basis and should take into account the associated anomalies.
Early treatment is advocated, with the goal of obtaining appropriate function (urination and erection) and adequate cosmetic
results. Treatment often includes removal of one of the penises.
Buried Penis
The true incidence of buried penis (Fig. 42-6) is unknown,
because there is a constant debate regarding the definition of
this condition. Inconspicuous penis, hidden penis, cryptic penis,
pseudomicropenis, and concealed penis have all been used as
overlying terms.33 Hidden penis was reported in 0.4% of 4.84
million newborns in the Nationwide Inpatient Sample covering
20% of hospitals in the United States from 1988 to 2000. This
condition can cause recurrent balanitis and spraying of urine.34
A number of etiologies have been proposed: (1) failure of
dartos fascia to develop into the normally elastic configuration
that allows skin to slide freely on the deep layers of the shaft,
(2) deficiency of penile shaft skin, (3) abnormal attachments
of the tunica albuginea to Bucks fascia, (4) insufficient attachment of the dartos fascia and penile skin to Bucks fascia,
(5) excessive prepubic fat pad, (6) loose skin, and (7) low position at which the crura unite to form the penile shaft.
The term trapped penis refers to cicatricial scarring after
penile surgery, especially neonatal circumcision, which can be
considered a separate entity.
Evaluation
In general, these patients have a normal scrotum with a very
small-appearing penis, which becomes palpable when one
presses down on the pubic fat pad and on the base of the penis.
chapter
549
Figure 42-6 Physical appearance (A) and schematic view (B) of a buried penis. (From Shankar KR, Rickwood AM. The incidence of phimosis
in boys. BJU Int. 1999;84:101-102.)
Treatment
The indications for and timing of surgery are controversial and may depend on the cause (Table 42-2). Indications
for surgery include difficulties with hygiene, phimosis,
balanitis, and psychosocial stressors. Current recommendations are to perform surgical correction after the child has
started to walk and has lost most of the prepubic fat pad.
Often, buried penis is secondary to obesity, and treatment of
this underlying condition takes precedence. Watchful waiting is an option, but spontaneous resolution does not always
occur.
The main complications after surgical correction include
recurrent buried penis and redundant penile skin.34 This surgery can be performed safely in children from 3 months of age.
Webbed Penis
Webbed penis (Fig. 42-7) is rarely an isolated congenital anomaly. In this condition, a web or fold of skin obscures the penoscrotal angle. It can be iatrogenic, occurring after circumcision
or penile surgery. Alternatively, it is postulated that a disturbance in the development of the prepuce may leave the ventral
Treatment
Surgical repair is recommended only if the cosmetic appearance is of great concern.37 Many descriptions of surgical repair
have been published, including simple incision, excision of
redundant skin with closure, multiple Z-plasties, and excision
of skin with mobilization of triangular skin flaps. Rarely, the
urethra is hypoplastic, requiring urethral surgery in conjunction with skin rearrangement.
Phimosis
The incidence of true pathologic phimosis (Fig. 42-8) has been
estimated to be 0.4 cases per 1000 boys per year.38 The incidence
cannot be clearly determined, because a certain proportion of
boys of any age group have a physiologic nonretractable foreskin. Oster found phimosis in 96% of boys at birth, in 80% at
6 months, and in 50% at 3 years.39 These numbers are comparable to those recorded by Herzog and Alvarez.40 This should
550
part
VI: Genitalia
Surgical Intervention
Timing
Trapped penis
If indicated*
If indicated*
If indicated*
*Indications
for surgery include difficulties with hygiene, phimosis, balanitis, and psychosocial stressors.
angle.
Classification
Table 42-3 describes the classification of phimosis.
Treatment
There is still considerable debate on the handling of phimosis.
True pathologic phimosis requires a circumcision. Physiologic
phimosis can be simply observed; the age at resolution is an
uncertainty, although the vast majority resolve. Recent data
showed efficacy for a 6-week course of topical steroids in up to
87% of boys ages 1 to 16 years.42 Parents of boys who are uncircumcised should be encouraged to teach their sons to gently
retract their foreskins by age 3 years.
Treatment
At the time of surgical repair, use of the Gittes artificial
erection test will determine the degree of curvature.47 The
goal of surgical correction is to achieve corpora of similar
size. Various techniques have been described, ranging from
complete penile disassembly, to corporal rotation, to use of
free dermal or tunica vaginalis grafts, to simple degloving
and plication.48-50
chapter
551
Description
Full retraction
Absolutely no retraction
A. Retractability of Foreskin
B. Appearance of Foreskin
0
Normal
Penile Torsion
Torsion of the penis is reported to be common, although
its incidence as an isolated condition is unknown. Usually, the torque is in a counterclockwise direction toward
the left. Penile torsion may be caused by an abnormal
arrangement of the penile shaft skin early in development, secondary to aberrant attachments of the suspensory ligaments at the base of the penis. Pressure from the
heel of the fetus during early development may also play a
role.
Median raphe cysts can occur anywhere from the meatus to the
anus. They can be glomus tumors, dermoid cysts, pilonidal cysts,
epidermal cysts, urethral diverticula, or steatocystomata.53
Treatment
Treatment
Aspiration and simple drainage may carry a risk of recurrence. Simple complete excision followed by primary closure
has generally been regarded as the treatment of choice.54 If no
malignancy is evident, simple observation may be the best
treatment option.
Classification
Meatal Stenosis
Meatal stenosis is one of the most common complications after
circumcision and has been reported in up to 7.3% of circumcised patients presenting to a pediatrician.55 It can also occur
in patients with coronal or subcoronal hypospadias who have
undergone hypospadias repair or, rarely, BXO. Meatal ischemia
secondary to ligation of the frenular artery during circumcision or recurring meatitis and local irritation at the junction of
552
Incision
part
VI: Genitalia
Posterior flap
(Dartos Fascia)
(From Fisher C, Park M. Penile torsion repair using dorsal dartos flap
rotation. J Urol. 2004;171:1903-1904.)
Treatment
Meatotomy can be performed in the office after topical
application of anesthetic cream (EMLA or LMX) for 30 to
45minutes. A straight crushing hemostat can be used for 1 to
2minutes along the ventral web with subsequent incision.56
SCROTAL ANOMALIES
Congenital Absence and Hypoplasia
Complete absence of the scrotum (Fig. 42-12) is extremely rare,
with only four cases reported. It is caused by failure of the
labioscrotal fold to develop.
Evaluation
A thorough maternal and family history may demonstrate a
possible teratogen exposure or other etiologic factor. Attempting to identify the location of the testes and other congenital
Treatment
With agenesis, neoscrotal construction should be preferentially
performed using a preputial skin flap.57 If the child is circumcised, perineal tissue expanders offer an alternative. Orchiopexy may be performed during or after construction.
chapter
pic right inguinal scrotum and testes. (From Hoar RM, Calvano CJ,
Reddy PP, et al. Unilateral suprainguinal ectopic scrotum: the role of
the gubernaculum in the formation of an ectopic scrotum. Teratology.
1998;57:64-69.)
Ectopic Scrotum
Ectopic scrotum (Fig. 42-13) is extremely rare, with approximately 22 cases reported in the literature. Two theories have
been proposed to account for this anomaly: (1) abnormalities
in the development of the gubernaculum with its secondary attachment to the skin covering the genital tubercle, and
(2) failure of fusion of the outer genital folds secondary to heel
compression during intrauterine life.59
553
If the phallic tubercle also is intrinsically abnormal, development of the corporal bodies and the urethral groove and
folds may be affected; this explains the frequent occurrence
of the other genital abnormalities.65 Some reports suggest a
chromosomal etiology. In a review of 53 patients, 13% had a
familial link.66
Classification
Penoscrotal transposition is also referred to as doughnut scrotum, prepenile scrotum, and Shawl scrotum. It can be complete,
with the penis covered entirely by the scrotum, or incomplete,
in which case the scrotum does not fuse above the penis.
There is a high incidence of associated anomalies. Renal dysplasia or agenesis, imperforate anus, central nervous anomalies, cardiac abnormalities, and upper-limb defects have been
reported. Some small series have reported associated anomalies in up to 100% of patients, but the largest review to date
found that 32% had associated organ system anomalies.66 The
genitourinary system was most commonly affected, with vesicoureteral reflux occurring in 9%. Most patients with penoscrotal transposition had an associated hypospadias (79%) or
chordee (81%).
Treatment
Evaluation
Evaluation
Penoscrotal Transposition
Penoscrotal transposition (Fig. 42-14) is usually associated
with other anomalies. Abnormal positioning of the genital tubercle in relation to the labioscrotal swellings during
the critical fourth to fifth week of gestation may affect the
inferomedial migration and fusion of the scrotal swellings.
Treatment
Repair of penoscrotal transposition can be carried out at the
time of hypospadias repair or at a different time. Timing of
the surgery should correspond to that of the genital surgery
(before 18 months of age). Several techniques for scrotoplasty
have been described. The aim of the procedure is to free the
penis by moving the skin flaps (Fig. 42-16).
554
part
VI: Genitalia
Bifid Scrotum
Approximately 5% of patients with posterior hypospadias
have a bifid scrotum.68 Bifid scrotum (Fig. 42-17) occurs along
the same spectrum as penoscrotal transposition, withabnor
malpositioning of the genital tubercle in relation to the
labioscrotal swellings. However, the labial scrotal folds are
completely separated, and no median raphe is present.
Evaluation
A renal ultrasonogram is recommended, given the risk of renal
abnormalities.
Treatment
Surgical repair is usually carried out at the time of hypospadias repair. It is performed in a manner similar to penoscrotal
transposition, and rotation of flaps of scrotal tissue may be
required.
Scrotal Hemangioma
Genital hemangioma accounts for approximately 1% of all
hemangiomas.69 Fifty cases have been reported in the literature, although the distinction between the two subtypes is
not always mentioned.70 Awakura and coworkers reported
37 cases specific to Japan.71 Table 42-4 lists the types and
causes of scrotal hemangioma.
Figure 42-15 Prenatal diagnosis of penoscrotal transposition. Axial
ultrasound scan shows the penis between the caudal aspects of the bifid scrotum. (From Gotoh M, Tsai S, Sugiyama T, et al. Giant scrotal
hemangioma with azoospermia. Urology. 1983;22:637-639.)
Figure 42-16 Glenn-Anderson repair: bilateral rotational advancement flaps with relocation of the scrotal compartment. (From Glenn JF,
chapter
Evaluation
Cutaneous hemangiomas are fairly evident on examination.
Cavernous hemangiomas (Fig. 42-18) require careful delineation, because scrotal arteriovenous malformations have also
been reported in association.73 Scrotal ultrasound may be useful
in delineating the extent of the mass. Because an absence of flow
on Doppler studies does not exclude the diagnosis of hemangioma, MRI may provide more useful information for differentiation of scrotal hemangioma from other lesions (Fig. 42-19).74
Evaluation
Patients usually have no symptoms except for minimal scrotal
discomfort which causes a waddling gait. Edema can affect the
penis, the perineum, and the inguinal region. In a recent series
by Klin and associates, 90% of the patients had unilateral
555
Treatment
The edema usually resolves within 72 hours, but up to 20%
of patients experience some type of recurrence.79 Management
includes reassurance, activity restriction, scrotal support, and
close observation. The process resolves without long-term
sequelae.
Splenogonadal Fusion
Approximately 150 cases of splenogonadal fusion have been
reported in the literature.80 Continuous and discontinuous
forms occur with equal frequency81 (Table 42-5). Most of the
reported patients were younger than 20 years old; fusion was
found on the left side in 98%, and 95% of the patients were male.
The cause is unclear. For some unknown reason, the two
organs fuse during the 5th to 8th week of embryonic life.
During this period, the splenic anlage and the left urogenital
fold that contains the gonadal mesoderm are in close proximity. This explains the high incidence of limb defects. The
discontinuous form (Fig. 42-20) may represent a rare variant
of accessory spleen.82
Evaluation
Figure 42-17 Bifid scrotum. (From Chadha R, Gupta S, Mahajan JK,
Exploration is commonly performed to look for an undescended testicle, inguinal hernia, or scrotal mass. Although
ultrasonography can reliably demonstrate the extratesticular
Cause
Presentation
Treatment Options
Cutaneous (strawberry)
hemangioma
Subcutaneous (cavernous)
hemangioma
556
part
VI: Genitalia
Figure 42-18 Preoperative (A) and postoperative (B) views of cavernous hemangioma. (From Ferrer FA, McKenna PH. Cavernous hemangioma
of the scrotum: a rare benign genital tumor of childhood. J Urol. 1995;153:1262-1264.)
location of a palpable mass, it cannot provide a definitive histologic diagnosis. Scintigraphy with a technetium 99m (99mTc)
sulfur colloid can identify ectopic uptake within the scrotum
or tail of the functioning splenic tissue and add specificity to
the imaging diagnosis.84
Treatment
Surgical exploration is generally needed to rule out malignancy, but orchiectomy is usually not indicated, because the
splenic tissue can be dissected away from the tunica albuginea in most cases.85 Laparoscopic management has also
been performed during exploration for intra-abdominal
testes.86
ACUTE SCROTUM
age shows mass of lower scrotum, dilated testicular vein, (long arrow),
and punctuate foci of hypointense thrombi (short arrows). (From
Aizenstein RI, Wilbur AC, ONeil HK, Gerber B. Clinical image: MRI
of scrotal hemangioma. J Comput Assist Tomogr. 1996;20:888-889.)
chapter
Clinical Presentation
The history and physical examination can significantly narrow the differential diagnosis of acute scrotum (Table 42-6).
The combined background information and physical findings
can frequently suggest the correct diagnosis.89 The age of the
patient is important. Testicular torsion is most common in neonates and postpubertal boys, although it can occur in males of
any age. The onset and duration of the pain must be carefully
determined. Torsion can manifest with sudden or gradual
onset of severe testicular pain. Nausea, vomiting, and fever
may occur, but urinary symptoms are unusual.90 A history of
trauma does not exclude the diagnosis. Recurrent severe pain
of rapid onset and spontaneous resolution is suggestive of
intermittent torsion.91 The physician needs to be aware that an
embarrassed child may state that he has lower abdominal pain
or inguinal pain rather than scrotal pain.
Physical Examination
A general abdominal examination should be performed, with
particular attention given to flank tenderness and bladder
distention. Next, the inguinal regions should be examined for
obvious hernias and any swelling or erythema. The genital examination begins with inspection of the scrotum. The two sides
Table 42-5 Classification of Splenogonadal Fusion
Continuous fusion
Discontinuous
fusion
557
Differential Diagnosis
Vascular Causes
Testicular Torsion
Testicular torsion or torsion of the spermatic cord is a surgical
emergency. This condition results from an abnormally mobile
testicle twisting on its vascular pedicle (the spermatic cord),
Figure 42-20 A, Discontinuous splenogonadal fusion: left testicle with ectopic spleen (arrows) attached to the upper pole. B, Seminiferous tubules can be seen on the upper left, and splenic tissue is present on the lower right. (A, From Cirillo RL Jr, Coley BD, Binkovitz LA, Jayanthi RV.
Sonographic findings in splenogonadal fusion. Pediatr Radiol. 1999;29:73-75. B, Courtesy of Dr. Dharam M. Ramnani.)
558
part
VI: Genitalia
Inflammatory
Rare
Henoch-Schnlein
purpura
Testicular torsion
Torsion of vestigial
appendages
Trauma
Varicocele
Epididymitis
Idiopathic scrotal edema
Orchitis
Appendicitis
Familial Mediterranean fever
Hydrocele
Inguinal hernia
Lymphangioma
Spermatocele
Tumors
Thrombophlebitis
Ventriculoperitoneal
shunt herniation
Bell
clapper
Tunica
vaginalis
Figure 42-21 Abnormal (left) and normal (right) insertion of the tunica vaginalis. (From Dogra V. Bell-clapper deformity. Am J Roentgenol.
2003;180:1176.)
Torsion
of
Vestigial Appendages
The most common cause of testicular pain, torsion of a vestigial appendage, occurs primarily in boys between 2 to 12 years
of age. With the acute scrotum, it comprises between 24% to
46% of cases.111,112 The vestigial appendages of the testicle
are embryologic remnants of the mllerian or wolffian duct
(Fig. 42-22).
The appendix testis, or hydatid of Morgani, is an anatomic
vestige of the mllerian duct. This pendulous structure lies
within the tunica vaginalis and arises from the superior poles
of the testis. It is found in 90% of males, and bilaterally in 60%.
The other appendices infrequently are reported as culprits in
the etiology of the acute scrotum. Approximately 91% to 95%
of twisted testicular appendices involve the appendix testes.
Symptoms mimic those of testicular torsion but are insidious
in onset and less severe. There is often an associated localized
upper pole hydrocele and an inflammatory reaction in the epididymis, which is often enlarged.111 The infarcted appendage
is visible and palpable in up to 21% of patients (blue-dot
sign).112 Often the entire testis is mildly tender, and the cremasteric reflex should be intact.
Sonographic evaluation of torsion of the appendages
of the testes usually reveals a circular mass with variable
echogenicity adjacent to the testis or epididymis. A reactive
chapter
hydrocele may also be present and may help with the ultrasound diagnosis, because the appendage may be seen in the
fluid of the hydrocele. Increased peripheral flow may be seen
around the torsed appendage on color Doppler ultrasound,
with normal flow to the ipsilateral testis. If the diagnosis is
certain, bed rest and analgesis with oral nonsteroidal antiinflammatory drugs are sufficient. The pain usually resolves
in 5 to 10 days. If the findings at the time of initial evaluation
are equivocal, immediate exploration is indicated.
Paradidymis
Appendix epididymis
Appendix testis
Henoch-Schnlein Purpura
Henoch-Schnlein purpura (HSP) is a rare cause of acute, painful groin swelling. It is characterized by nonthrombocytopenic
purpura and is the most common systemic vasculitis of unknown
origin diagnosed in children. It is usually accompanied by a
palpable skin rash, colicky abdominal pain, and arthralgia, and
it sometimes involves the kidneys, leading to nephritis and
hematuria.113 It occurs in approximately 3% of all cases of acute
scrotum,114 and between 2% to 38% of children with HSP experience scrotal involvement. The symptoms of involvement of
the external genitalia are painful swelling and ecchymosis. The
most commonly involved sites are the scrotal wall, epididymis,
testis, testicular appendage, and spermatic cord, but the glans
and shaft of the penis can also be involved.115 In general, scrotal
symptoms of HSP seem milder than those observed in testicular torsion. In some cases, sudden onset of acute scrotal pain
may be the initial manifestation of the disease, preceding the
systemic symptomatology by several days.
HSP occurs within the first 2 decades of life.116
Histopathologically, HSP is characterized by vascular deposits of immunoglobulin Adominant immune complex.117
HSP is self-limited and is responsive to steroid therapy. Most
cases resolve within 1 month, although the opposite side may
become involved. Although scrotal exploration is unnecessary,
many patients undergo exploration in this setting because of
the clinical suspicion of testicular torsion. Scrotal scintigraphy
and color Doppler sonography are quite reliable in documenting normal blood flow in these patients. Expectant management should be followed if the study shows either normal or
increased perfusion.
Trauma
Blunt scrotal trauma can cause significant injury which, if
not correctly diagnosed and treated, may result in loss of
the testicle.118 The testicle may suffer a hematoma or contusion, rupture of the tunica albuginea, traumatic dislocation from the scrotum, hematocele, or delayed hydrocele or
pyocele.119 The cause is usually a direct blow to the testicle
in a sports-related injury, motor vehicle accident, or violent
assault.
Patients present with post-traumatic pain, variable swelling,
and scrotal ecchymosis which may extend into the penis. In a
series of 65 patients presenting with scrotal trauma, ultrasound
was shown to have excellent sensitivity (100%) and specificity
(94%) in diagnosing testicular rupture120 (Fig. 42-23).
If a rupture is present, it should be repaired surgically to
prevent secondary infection, abscess, and eventual atrophy
with loss of spermatogenesis. Cass and Luxenberg121 reported
a 20-year experience comparing primary conservative management (before 1971) with the new and now standard
approach of early operative exploration and repair. They
found a 45% orchiectomy rate in the delayed surgical intervention group, versus a 9% rate in the early surgical exploration group (defined as within 3 days after the injury). Any
compromise to the testicular blood supply should also lead to
surgical exploration.
559
Vas aberranus
Figure 42-22 The vestigial appendages. (From Sidhu PS. Clinical and imaging features of testicular torsion: role of ultrasound.
Clin Radiol. 1999;54:343-352.)
Varicocele
A varicocele is an abnormal dilation and tortuosity of the
pampiniform plexus within the spermatic cord. Varicoceles
are usually left-sided and rarely bilateral.122 Although most
varicoceles are asymptomatic, some boys experience significant testicular pain, particularly during exercise. Patients with
intratesticular varicocele may have pain related to passive
congestion of the testis, which eventually stretches the tunica
albuginea.123
The physical examination is usually sufficient to diagnose
a varicocele. Classically, palpation of the scrotum reveals a
bag of worms. The mass of veins disappears when the child
lies down, but transmission of pressure through the plexus
may be perceived with a Valsalva maneuver.124 Treatment is
usually unnecessary unless the child has testicular pain or
shows testicular atrophy, in which case varicocelectomy is
indicated.125
Inflammatory Causes
Epididymitis
The exact incidence of epididymitis is unknown but has been
estimated to range from 28% to 64% of acute scrotum cases.126
The onset of pain associated with epididymitis typically is
more gradual than of torsion of the testis, and fever and irritative urinary symptoms are more common. The peak incidence
of epididymitis is between 9 and 14 years of age.127 Epididymitis in younger males and infants has been correlated with
anorectal128 and genitourinary malformations.129 As a result,
its presence in prepubescent males should prompt an evaluation for congenital anomalies. The etiology and management
of epididymitis are still subject to controversy. Several causes
have been proposed, including ascending infection, urethro
vasal reflux, nonbacterial inflammation, and amiodarone
use.130 There is also a recent report suggesting a postinfectious
etiology with elevated viral titers compared to controls.131
Bacteriuria is relatively uncommon, representing only 15.8%
of cases.132
The physical examination varies from slight scrotal swelling to marked edema, intense pain, fever, and pyuria.132 Color
560
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VI: Genitalia
Figure 42-23 Scrotal ultrasonography of blunt testicular rupture. A, Preoperative view. Note heterogeneous echo pattern of testicular parenchyma. B, Postoperative view. Note excellent preservation of parenchyma with homogeneous appearance. (From Caldamone AA, Valvo JR,
Altebarmakian VK, Rabinowitz R. Acute scrotal swelling in children. J Pediatr Surg. 1984;19:581-584.)
Doppler ultrasonography shows hyperemia of the epididymis
with a diagnostic sensitivity approaching 100%.133,134 Equivocal
findings warrant surgical exploration.97 For boys with acute
epididymitis who have no urinary tract anomalies, no pyuria,
and no positive urine culture, antibiotics are not indicated.135
Systemic and local signs and symptoms resolve gradually in
1 to 7 days.
Hydrocele
Fluid between the parietal and visceral layers of the tunica
vaginalis forms a hydrocele. Normally, the processus vaginalis
is obliterated in utero; if it does not obliterate, fluid can pass
between the scrotum and the peritoneal cavity (communicating hydrocele). A hydrocele may manifest as chronic or sudden
swelling of the scrotum without pain or tenderness. A hydrocele may also develop acutely after testicular torsion, torsion
of the appendix, testis epididymitis, or trauma.
Physical examination shows a tense scrotum that may
have a bluish hue but is rarely tender. Hydroceles may exhibit
diurnal variation in size, being larger in the evening, after
the child has been upright all day. The majority of hydroceles
transilluminate, but bowel fluid and air transmit light similarly to hydrocele fluid. Hematoceles may also manifest as
acute scrotum but are usually the sequelae of blunt abdominal
trauma.136 Meconium-filled hydrocele sacs can cause acute
scrotum in newborns.137 There have been rare reports of torsion of communicating hydroceles.138 High ligation of the
hydrocele through an inguinal incision is curative, but diagnosis can be difficult. Sonographic imaging may not clearly
diagnose this phenomenon139 (Fig. 42-24).
Inguinal Hernia
Indirect inguinal hernia is the protrusion of an abdominal
organ into a patent processus vaginalis extending into the
inguinal canal. A hernia in a child is seldom symptomatic
unless it is incarcerated. Physical examination may reveal a
reducible, firm bulge in the groin and scrotum. Incarceration
of the hernia sac and its contents occurs when the contents
become stuck beyond the internal ring; this tends to occur in
younger patients. Prompt reduction is required; otherwise,
chapter
561
Figure 42-25 Examination performed 2 hours after onset of left scrotal pain. A, T2-weighted magnetic resonance image (MRI) shows slightly
low signal intensity of left testis. B, On dynamic subtraction MRI, the left testis showed no contrast enhancement. (From Ameh EA. Morbidity and
mortality of inguinal hernia in the newborn. Niger Postgrad Med J. 2002;9:233-234.)
Imaging Techniques
Ultrasonography
Scrotal ultrasonography is essential for the evaluation of scrotal and testicular pathology. It is performed with the patient
lying in a supine position and the scrotum supported by a
towel placed between the thighs. Color and power Doppler
techniques have obvious advantages over gray-scale sonography, allowing early diagnosis to the extent that they highlight
perfusion changes from the very beginning.142 It is possible to
detect the absence of blood flow in the symptomatic testicle,
whereas flow is normally present in the contralateral testis. Major limitations to color Doppler include the required
technical skill of the sonographer and difficulty in assessing
blood flow in some boys younger than 13 years old. Ingram
and Hollman noted that 38% of normal boys aged 10 weeks
to 13 years had no flow detectable with color Doppler ultrasound.143 Diagnosis can also be problematic with partial or
incomplete torsion or with rotation of less than 360 degrees in
which there is complete obstruction of venous flow, although
arterial flow is still detected. In these cases, spectral analysis
shows an increase in the resistive index with inversion of diastolic flow.
Testicular Scintigraphy
Medicolegal Aspects
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REFERENCES
For complete list of references log onto www.expertconsult.
com
CHAPTER
43
CRYPTORCHIDISM
TESTICULAR DESCENT
Testicular descent is necessary for normal spermatogenesis, which requires the 2 C to 3 C cooler scrotal environment. Embryonic testicular descent can be divided into three
phases:
1. Transabdominal migration of the testis to the internal
inguinal ring
2. Development of the processus vaginalis and the
inguinal canal
3. Transinguinal descent of the testis to the scrotum
Transabdominal Migration
During the 6th gestational week, the testis is located ventromedial to the mesonephros, relatively close to the inguinal region.
As the fetus and abdominal cavity enlarge, the testis remains
relatively stationary, whereas the ovary ascends. To achieve
this differential movement, the key structure in humans is the
gubernaculum (or caudal genital ligament). Before gonadal
differentiation, the male and female gubernaculum is a short,
thin ligament extending from the lower pole of the undifferentiated gonad and its duct to the genital swellings, the precursors of the male scrotum and female labia majora. After
testis formation, the male gubernaculum masculinizes via
outgrowth, with mesenchymal proliferation and increased
hyaluronic acid content, anchoring the testis. In females, the
gubernaculum remains thin and lengthens in proportion to
fetal growth, allowing ascent. This sexually dimorphic outgrowth of the mesenchymal gubernacular cone in males, the
hallmark event during the male transabdominal phase, is not
dependent on androgens3 but is stimulated by the testis hormone, INSL3 (also known as Leydig insulin-like hormone or
relaxin-like hormone) (see later discussion).
Because rodent models are frequently used to study testicular descent, it is noteworthy that, in these animals, the
testis and ovary are suspended to the abdominal wall by a
second ligament, the cranial gonadal suspensory ligament.
In male rodents, testosterone stimulates cranial gonadal
suspensory ligament regression, thereby permitting caudal
testicular mobility. In females, this ligament persists due to
the absence of testosterone, and caudal ovarian mobility is
thus prevented.4 The cranial gonadal suspensory ligament is
present but becomes vestigial in humans.
In summary, INSL3 causes the early masculinizing gubernacular swelling reaction in males, and androgen causes
regression of the cranial suspensory ligament (in mice). The
coordinated result of masculinization of the gubernaculum
during transabdominal migration in humans is positioning
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Processus Vaginalis
In gestational month 3, an elongated pocket of peritoneum,
called the processus vaginalis, grows along and partially
encircles the gubernaculum, creating a potential space in the
inguinal canal and scrotum. Although the testis is stationary
between the 3rd and 7th months of fetal life, the gubernaculum and the processus vaginalis together distend the inguinal
canal and scrotum,5 creating a path for testicular descent.
Transinguinal Descent
This final phase of testicular descent occurs very rapidly, usually between weeks 24 and 35 of gestation.6 During this time,
testosterone shrinks the enlarged, masculinized gubernaculum by decreasing its turgidity and viscoelastic properties,
yielding the gubernacular ligament.3 Normally, the processus
vaginalis obliterates completely before birth, but if the testis
does not descend, the processus vaginalis usually remains patent, resulting in an open internal ring to the inguinal canal.
About two thirds of cryptorchid neonates have spontaneous postnatal testicular descent, typically within 6 months.7
If the testis is undescended at birth, descent is presumably
caused by the burst of testosterone (mini-puberty) that occurs
during the first 3 months postnatally,8 secondary to activation
of the hypothalamic-pituitary axis by loss of negative feedback
from the maternal endocrine environment. Some data suggest
that the postnatal rise in serum testosterone is lower in boys
with cryptorchidism than in those with normal testicular
descent, possibly because of a primary deficiency in pituitary
secretion of luteinizing hormone (LH).9 However, Barthold
and colleagues recently reported conflicting data showing no
significant hormonal differences between these groups.10
is associated with a complete female phenotype or male pseudohermaphroditism, which is not observed in most cases of
human cryptorchidism. Similarly, anti-androgens prevent testicular descent (by blocking gubernacular regression) in 50%
of prenatally exposed rodent and porcine models.14,15 Lastly,
prenatal exposure of rodents to estrogenic compounds induces
cryptorchidism, and this effect can be overcome by simultaneous treatment with dihydrotestosterone or human chorionic
gonadotropin (hCG). These observations support the role of
androgens in descent. However, the variability in testicular
position among children with abnormal androgen actions and
the partial success of anti-androgeninduced cryptorchidism
in animal models shed a negative light. In addition, this clinical situation and this animal model are both associated with
genital ambiguity. Prenatal estrogenic exposure can induce
partial persistence of the mllerian structures. However, most
children with cryptorchidism have unilateral disease, no genital ambiguity, and no persistence of the mllerian structures.
In summary, these clinical and experimental observations suggest a partial role of androgens in testicular descent.
For more than 30 years, it has been recognized that (1) exogenous androgens are unable to stimulate outgrowth of the
gubernaculum in female fetuses, (2) anti-androgens fail to
block outgrowth of the gubernaculum in male fetuses, and
(3) gubernacular outgrowth is normal in humans or animals
with testicular feminization.16 In contrast, androgenic stimulation clearly induces the regression phase of the gubernaculum
after the initial outgrowth phase. These observations and animal experiments in which fetal orchiectomy induced failure
of gubernacular growth led to the theory of descendin,17 a
testicular hormone with specific local effect on gubernacular
cell growth. In 1993, this hormone, now called INSL3, was
first discovered. Its function was identified in 1999, when
INSL3-knockout mice18,19 were found to have bilateral intraabdominal undescended testes due to absent gubernacular
outgrowth phase yet had normal androgenization of the other
male internal and external genitalia.
INSL3 is produced by the fetal testis and not by the fetal
ovary. The gubernaculum, which expresses the INSL3 receptor, LGR8, is stimulated to outgrow in males by INSL3; females
do not make INSL3 during fetal life. Therefore, INSL3 and its
receptor, LGR8 (a member of the G proteincoupled receptor
family, sometimes called GREAT), are the critical regulators of
the transabdominal phase of masculinizing gubernacular outgrowth. Approximately 2% of patients with isolated cryptorchidism have functionally deleterious mutations in the INSL3
or LGR8 gene, but further study is needed to identify other
regulators of the INSL3 signaling pathway in humans.
Hormonal Factors
Estrogens
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43: Cryptorchidism
565
Anti-mllerian-Inhibiting Substance
The observation that patients deficient in AMH (also called
mllerian inhibiting substance, or MIS) typically have intraabdominal testicles led to the suggestion that AMH may
play a role in testicular descent.26 However, AMH deficiency
in humans probably prevents testicular descent indirectly,
through the obstruction produced by the persistent mllerian
structures, rather than by a direct lack of hormone.27,28 In addition, most males with intra-abdominal cryptorchid testes have
no persistent mllerian structures. Other pieces of experimental evidence refute the role of AMH in testicular descent,
including prenatal exposure to anti-AMH antibodies29 and the
phenotypes of AMH or AMH receptor knockout mice.30
Mechanical Factors
First described and named by John Hunter in 1762,37 the term
gubernaculum means helm or rudder, and this structure
was thought to guide the testis into the scrotum. Perhaps the
most important mechanical factor, the gubernaculum begins
as a mesenchymal band that originates on the lower pole of the
testis/mesonephric duct and inserts in the scrotum. Separate
extrascrotal bands or tails were described by Lockwood,38
which may explain the occurrence of testicular ectopia. Its morphogenesis includes an outgrowth phase mediated by INSL3
and a regression phase mediated by androgens, as detailed
earlier. The exact mechanism through which the gubernaculum mediates testicular descent is debated and may involve
traction, muscular contraction, or differential growth around
a fixed point. Most likely, the gubernaculum, in conjunction
with the processus vaginalis, serves to dilate the inguinal canal
and thereby facilitate descent of the testis into the scrotum.16
Palpable Testes
Undescended Testis
A true undescended testis is a testis halted along its normal path
of descent. Depending on its location, it may or may not be
palpable. Inguinal testes are an excellent example because they
have halted along the normal path of descent in the inguinal
canal, but they may or may not be palpable. When viewed
laparoscopically, peeping testes move in and out of the
internal inguinal ring (Fig. 43-2). An emergent or gliding
566
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VI: genitalia
testis. (From Baker LA, Lorenzo A, Jordan GH, Docimo SG. Laparoscopy and cryptorchidism. In: Docimo SG, ed. Minimally Invasive
Approaches to Pediatric Urology. London: Taylor & Francis Publishers;
2005:161-176. Used by permission from Taylor & Francis.)
Ectopic Testis
An ectopic testis is one that is located in an aberrant position off
the path of normal descent (Fig. 43-3). The most common site
of palpable ectopia is the superficial inguinal pouch of DenisBrowne, located between Scarpas fascia and the external
oblique fascia above the external inguinal ring. Less common
ectopic sites include the femoral, pubic, penopubic, penile,
and perineal positions. In crossed or transverse ectopia, a testis
crosses the scrotal septum or descends into the opposite inguinal canal. Nonpalpable ectopic sites include anterior abdominal wall, retrovesical, and other intra-abdominal positions.
Ectopic descent is thought to result from overdevelopment of
one segment of the gubernaculum (i.e., a tail of Lockwood)
or from scrotal inlet obstruction. An ectopic testis is fixed in
position by fibrous attachments and therefore cannot spontaneously descend; only surgery will correct this position.
Retractile Testis
A retractile testis is one that has completed the process of descent
but may be found in the groin because of an overactive cremasteric reflex. The cremasteric reflex is a function of the genitofemoral nerve (L1) and is present in all boys older than 2 years
of age.46 When the reflex is elicited by tactile stimulation of the
thigh, the cremaster muscle contracts and draws the testis out of
the scrotum toward the inguinal canal. Teleologically, the cremaster reflex protects the testis by drawing it out of harms way, but
it may cause a normal testis to mimic an undescended testis.
A retractile testis should be suspected in the 2- to 12-yearold child with a possible undescended testis. A retractile testis
can be manipulated into the scrotum, where it will remain
(at least temporarily) after its release. In contrast, the undescended testes retracts into the groin immediately. Retractile
testes are typically normal in size and consistency, whereas
undescended testes may be smaller and softer than normal.
Figure 43-3 Empty left hemiscrotum with scrotal right testis. The left
testis is located in a laterally ectopic position.
Nonpalpable Testes
Approximately 20% of all cryptorchid testes are nonpalpable.
Between 50% and 60% of these are intra-abdominal, canalicular (within the inguinal canal), or peeping (just inside the
internal inguinal ring). Approximately 20% of nonpalpable
testes (4% of all cryptorchid testes) are absent, and another
30% (6% of the total) are atrophic or rudimentary.
Intra-abdominal Testes
Intra-abdominal testes are located in a variety of intra-abdominal
positions, the majority less than 2 cm from the internal ring.
However, a testis can be adjacent to the kidney, on the anterior abdominal wall, retrovesical, and in other intra-abdominal
positions. In rare cases, the wolffian ducts do not connect with
the gonad (epididymal disjunction), leading to a large space
between the cranial testis and the caudal epididymis/vas.
Intra-abdominal testes may be associated with a closed or an
open internal ring. In the closed ring variant, the processus vaginalis does not develop, the gubernaculum is absent, and the
internal inguinal ring is closed. This is the typical configuration
seen with the prune-belly syndrome. In the open ring variant, a
patent processus vaginalis exits the internal inguinal ring, and
the gubernaculum is present. With the open ring variant, the
testis may be peeping into the inguinal canal, depending on
the length of the processus vaginalis and the testicular vessels.
Absent Testes
Although unilateral absence (monorchidism) occurs in 4% of
patients with cryptorchidism, bilateral absence (anorchidism)
occurs in fewer than 1%. Testicular agenesis and atrophy after
intrauterine torsion are two mechanisms for testicular absence.
chapter
43: Cryptorchidism
567
Cryptorchidism
Anorchidism
Female
Pseudohermaphroditism
46,XY
46,XY
46,XX
Baseline
Normal
Low
Variable
Positive
Negative
Negative
Gonadotropins
Normal
Increased
Normal
AMH/MIS
Positive
Negative
Negative
Normal
Normal
Increased
Gonads
Testes or negative
Negative
Ovaries or negative
Internal ducts
Negative
Negative
Uterus/mllerian system
Genitogram
Male urethra
Male urethra
Gonads
Testes
Blind-ending vessels
Ovaries
Internal ducts
Wolffian
Wolffian
Mllerian
Karyotype
Serum testosterone
Ultrasonography
Laparoscopy
Vanishing Testis
The term vanishing testis indicates that the testicular vessels
and a vas deferens are found on surgical exploration, but a testis is absent. In utero infarction of a normal testis by gonadal
vessel torsion after gestational weeks 12 to 14 is hypothesized,
because ipsilateral wolffian duct differentiation and mllerian
duct regression, both of which require ipsilateral testicular
hormones, occur normally. Supporting evidence for testicular
infarction includes the common finding of hemosiderin and
calcium deposits in testicular remnants (nubbins) found on
exploration.48 Contralateral compensatory testicular hypertrophy, defined as a testis length of 1.8 cm or greater, has been
found to be 90% accurate in predicting monorchia49 but does
not eliminate the need for surgical exploration.
In the evaluation and surgical treatment of nonpalpable
testes, the presence of palpable ipsilateral scrotal appendages
(i.e., tunica vaginalis, gubernaculum, or vas deferens) and a
contralateral descended testis with no hypertrophy is associated with a 93% likelihood of discovering a testis that can
be successfully relocated to the scrotum. Conversely, if the
ipsilateral scrotal appendages cannot be palpated and the
contralateral descended testis is hypertrophied, there is a 96%
probability that the impalpable testis is vanished.50
Testicular Agenesis
Testicular agenesis may result from failure of the testicular
blood supply to develop or from abnormal gonadal ridge
differentiation. An example of the latter is 46,XY complete
gonadal dysgenesis. However, these individuals are characterized by streak gonads, either female or ambiguous genitalia,
and persistence of mllerian structures. The variable phenotypic appearance, including the presence and form of the
external genitalia, relates to the time during gestation when
the testis differentiation becomes abnormal. True congenital
absence of a testis is extremely rare, and absence of both testes
results in a female phenotype.
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VI: genitalia
Figure 43-4 A and B, Newborn infant with bilaterally nonpalpable testis, normally formed scrotum, 3-cm phallus with mild chordee, and
urethral meatus at the tip of the glans with complete foreskin. This child is a Prader 5 severely virilized 46,XX female with congenital adrenal
hyperplasia resulting from 21-hydroxylase deficiency.
mllerian structures. In equivocal cases, diagnostic laparoscopy and/or open surgical exploration with gonadal biopsy
may be required to confirm the diagnosis of anorchia (see
Table 43-1).
TESTICULAR ASCENT
An ascended testis refers to a cryptorchid testis, usually one
that is palpable, that was previously identified as descended
in the scrotum. In the past, this was considered a misdiagnosis caused by an error in physical examination,57 but the
cumulative experience of qualified examiners suggests that it
is a real phenomenon.58 The risk of ascent may be as high as
32% to 50% in cases in which one testis is significantly retractile.59,60 Ascended testes are typically unilateral (77%), identified in mid-childhood, and located distal to the inguinal canal
(77%).59 Ascended and significantly retractile testes may be
prone to the same germ cell maldevelopment seen in congenital cryptorchidism.59 Ascent is thought to be caused by relative
shortening, or lack of elongation, of spermatic cord structures
as the affected child grows.61 The finding of a fibrous remnant
within the spermatic cord, possibly an obliterated processus
vaginalis, may limit cord growth.62 Patients younger than
7 years of age who have tight, inelastic spermatic cords appear
to be at highest risk for acquired cryptorchidism and should be
examined annually until puberty.60 Ascent may also be iatrogenic after an inguinal hernia repair.63
chapter
RISK FACTORS
Maternal, Paternal, and Gestational Factors
Maternal obesity, cesarean section, low birth weight, and prematurity have been associated with cryptorchidism, each independently doubling the relative risk over that of the general
population.64 In addition, shorter menses and later menarche
were noted in mothers of cryptorchid boys versus controls.65
Davies and colleagues noted an increased tendency toward
threatened abortions, prior miscarriage, and decreased fertility.66
These observations suggest that the maternal-placental-fetal
hormonal state may be abnormal in affected individuals. Cryptorchidism was associated with paternal exposure to pesticides,
which may indicate an effect on the paternal germline.67 Race
does not appear to be a significant risk factor.
Genetic Factors
Cryptorchidism frequently has strong familial clustering, and
14% of cryptorchid boys come from families in which other
males are cryptorchid. Cryptorchidism is transmitted in a
multifactorial pattern; fathers are affected with an incidence
of approximately 4%, and siblings with an incidence of 6% to
10%. The increased incidence of cryptorchidism in first- and
second-degree relatives warrants counseling and monitoring
of families with cryptorchidism for its appearance in subsequent male children, including nephews and cousins. The frequency of sporadic and familial cryptorchidism suggests that
genetic factors are involved.
With the recent increase in mutant mouse models of cryp
torchidism, several investigators have performed candidate
gene mutation screenings in cryptorchid patients. Mutations
have been identified in the following genes: INSL3,68-70
LGR8,70,71 androgen receptor polymorphisms,72 HOXA10,33
and HOXD13.34 Some of these mutations have been proved to
be causal in cryptorchidism.
Environmental Factors
Some literature suggest that the incidence of cryptorchidism
is increasing. One possible explanation is prenatal environmental exposure to a growing group of compounds termed
endocrine disruptors. Such compounds include DES (synthetic
estrogen), DDT (pesticide), nonylphenol (industrial surfactant), bisphenol-A and certain phthalates (plastics additives),
and natural phytoestrogens (common in soy products).73
These chemicals act as estrogen or androgen agonists or
antagonists. Ample data from animal and human exposures
demonstrate a causal relationship between such chemical exposures and cryptorchidism.74 The necessary level of
exposure (range of parts per billion) is probably very low,
so exposure is commonplace. The future challenges lie in
defining whether certain individuals are more susceptible,
43: Cryptorchidism
569
ASSOCIATED ANOMALIES
Multiple factors are involved in normal testicular descent. As
a result, many clinical syndromes that affect genetic integrity
or the endocrine, musculoskeletal, and nervous systems can
be associated with this condition. For example, abnormalities
in chromosome number, such as autosomal trisomy, triploidy,
and Klinefelters syndrome (XXY), are commonly associated
with cryptorchidism. Deficiencies in pituitary function, testosterone production, 5-reductase activity, and androgen
receptor sensitivity effectively interrupt androgen activity
and can result in cryptorchidism. Infants with abdominal
wall defects such as omphalocele, gastroschisis, or umbilical
hernia, as well as prune-belly syndrome or bladder or cloacal
exstrophy, often have undescended testes. Cryptorchidism is
commonly present with an anomalous central nervous system, as in cerebral palsy, mental retardation, and spinal cord
abnormalities. Overall, 15% of males with myelomeningocele
are cryptorchid, with a 50% incidence among those affected
above L4.
When hypospadias is accompanied by bilateral or unilateral cryptorchidism, a thorough investigation to exclude
underlying genetic or endocrine abnormalities causing an
intersex condition must be undertaken,75,76 because disorders
of sex development (DSD) are present in approximately 30%
of these children. If the undescended testis is palpable, there
is a 15% risk of intersex; if the undescended testis is nonpalpable, the risk is increased to 50%.76
Wolffian duct abnormalities have been reported in approximately 50% of those with undescended testes, including vasal
and epididymal agenesis, segmental atresia, and elongation.
Frank discontinuity may occur between the testis and epididymis. An elongated, or long-looping, vas deferens is
usually associated with an intra-abdominal testis but may also
be seen with an inguinal testis. Patients with bilateral or nonpalpable undescended testes have a higher incidence of such
anomalies, and the more proximal the location of the testis,
the more severe the epididymal malformation.77 Epididymal
abnormalities are clinically important for three reasons. First,
an abnormal vas deferens and epididymis may preclude the
option of orchiopexy based on vasal and epididymal collateral blood supply. Second, in cases of disjunction between the
testis and epididymis, epididymal tissue in the scrotum may
be mistaken for an atrophic testis if surgical exploration is not
performed. Third, epididymal anomalies may cause future
infertility despite a technically successful orchiopexy.
DIAGNOSIS
History
Maternal and paternal prenatal risk factors, including hormone exposures, should be ascertained when evaluating a
cryptorchid newborn. A family history of cryptorchidism or
genetic or hormonal disorders might suggest further evaluation. In an older child, a history of previously descended
testes suggests testicular ascent57,58,78 and should not prompt
criticism of previous examinations. A history of prior inguinal surgery suggests secondary cryptorchidism, though
occasionally an inguinal hernia has been repaired without
orchiopexy in an infant with an undescended testis, with the
erroneous thought that the testis will descend spontaneously.
570
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VI: genitalia
Physical Examination
A general physical examination is carried out, and any abnormalities are noted. If a testis is not in the scrotum, the cryptorchid testis is sought by gently advancing the examining fingers
along the inguinal canal toward the pubic tubercle. This examination is best facilitated by applying lubricant to the groin. The
inguinal testis will be felt to pop under the fingers. The child
may be examined in sitting or squatting position, which occasionally results in identification of a palpable testis that was
not palpable in the supine position. If the testis is not found
in the inguinal canal, all ectopic sites should be thoroughly
examined. Some testes that seem retractile at a young age actually are ectopically attached testes that will ascend with linear
growth.57 Differentiating the true undescended testis from a
retractile testis can be challenging, and a second examination
in the office is often quite helpful. With experience, these can
be delineated, prompting close observation or surgical repair,
depending on the certainty of the diagnosis. Nevertheless, in
some cases of retractile testes, the diagnosis is confirmed only
after examination with the child under anesthesia.
If bilateral nonpalpable cryptorchidism exists, any evidence of intersexuality, including genital ambiguity and scrotal hyperpigmentation, should prompt further evaluation. In
cases of unilateral or bilateral cryptorchidism, hypospadias
may be a sign of an intersex condition.75,76 In cases of unilateral nonpalpable cryptorchidism, the contralateral descended
testis is examined. Any enlargement may suggest testicular
absence or atrophy, although this sign is not specific enough
to preclude surgical exploration.
Localization Studies
If a testis is not palpable, radiographic studies are often
employed to localize and assess the presence or absence of a
testis. Frequently, cryptorchid patients are referred to the pediatric urologist after an ultrasound study has been obtained.
Elder found that 66% of ultrasound studies performed were
unnecessary, because he was able to palpate the testis in question during the office visit.79 Radiographic localizing studies
cannot determine with certainty that a testis does not exist,
and they cannot rule out the presence of an intra-abdominal
testis.80 Therefore, laparoscopy is the diagnostic procedure of
choice for the nonpalpable testis because of its superior accuracy compared to other modalities.81-83 However, radiographic
imaging studies may be useful in certain clinical circumstances,
such as the overweight boy with a nonpalpable inguinal testis
and in follow-up of cryptorchid boys who, because of comorbid conditions, are not surgical candidates.
TREATMENT OF CRYPTORCHIDISM
Age
Therapy for cryptorchidism is usually carried out between
6 months and 1 year of age. Histologic deterioration of the cryp
torchid testis has been noted as early as 12 to 18 months. Because
testes rarely descend after 6 months,7 there may be surgical
advantages to orchiopexy within the first 6 months, especially
in patients with high undescended testis. Decisions regarding
orchiopexy after 1 year of age are based on the benefit of the testis
to the individual. Although an undescended testis may function
poorly for fertility, the usefulness in terms of androgen production must be considered, especially in cases of a solitary testis.
Indications
The four commonly cited indications to treat cryptorchidism
are reduced fertility, testicular cancer, inguinal hernia, and testicular torsion.
Fertility
At birth and into the first year of life, undescended testes
have normal histology, including a normal population of
germ cells. Beyond 18 months of age, both light and electron
microscopy demonstrate histologic changes suggesting deterioration of the germ cell population of the testis.85,86 Such histologic changes can also be seen in a contralateral, descended
testis after 2 years, suggesting that both the undescended and
the scrotal testes can be intrinsically abnormal.86 Grossly, this
deterioration may result in testes that are smaller and softer
than normal. Retractile testes are believed to be intrinsically
normal, although there has been some debate on this point,
possibly because of varying definitions of the term retractile
and the selection of patients with infertility for adult testicular
biopsy, which introduces bias.87
Clinically, decreased fertility is a well-recognized consequence of cryptorchidism. Data derived from orchiopexies
performed in the 1950s to 1970s indicate that paternity is
impaired in approximately 10% to 13% of boys born with
one undescended testis and in 33% to 35% of those born with
two undescended testes.88,89 These rates are not significantly
different from the control infertility rate of 7% in unilateral
cryptorchids but are significantly lower than control in bilateral cryptorchids.89 Although histologic deterioration was
thought to be worse with higher-positioned testes, paternity
(which does not necessarily correlate with histology of the
undescended testis in cases of unilateral maldescent) may
be similar in both abdominal and extra-abdominal unilateral
undescended testes.90 The serum level of inhibin B, an indicator of Sertoli cell function and seminiferous tubule integrity,
is lower in boys with a history of cryptorchidism. This may
predict impaired spermatogenesis later in life, although there
is much overlap of hormone levels between fertile and infertile
men.89 Therefore, it is still not clear whether early orchiopexy
ultimately improves fertility, but serum inhibin B levels are
suggestive of this trend.91 Without treatment, bilateral cryptorchidism ultimately results in infertility. Antisperm antibodies,
abnormalities of the epididymis and vas deferens, and surgical
injury to the vas deferens during orchiopexy may also contribute to infertility in patients with a history of cryptorchidism.
Malignancy
Given that in all men the lifetime risk of testicular cancer is
0.3% to 0.7%,92 there is a 3.7- to 7.5-fold increased risk in individuals born with an undescended testis.93 Approximately
chapter
Inguinal Hernia
About 90% of undescended testes are associated with an occult
inguinal hernia, especially those with minimal descent and
those coupled with epididymal abnormalities. Ectopic testes
are associated with an inguinal hernia in about 50% of cases.
Conversely, up to 6% of inguinal hernias are associated with
an undescended testis.101 Repair of the hernia, if present, is an
integral part of orchiopexy.
Risk of Torsion
Testicular torsion occurs more frequently than normal in undescended abdominal testes and is associated with poor surgical
salvage rates (~10%).102 Torsion of the testis in the inguinal
canal is unusual. If an undescended testis undergoes postnatal
torsion, it can indicate the presence of testicular tumor.103 Torsion in an undescended testis should be suspected in any male
with groin or abdominal pain, an empty hemiscrotum, and a
negative surgical history.
Risk of Trauma
An inguinal testis is subject to blunt traumatic injury by compression against the pubic bone. This risk is prevented by
orchiopexy or orchiectomy.
Psychological Factors
Preoccupation with a solitary scrotal testis, uncertainty regarding the presence and location of a cryptorchid testis, embarrassment with peers and sexual partners, a tarnished body image,
fear of sterility, and other adverse concerns and personality
43: Cryptorchidism
571
NONSURGICAL THERAPY
Medical treatment for cryptorchidism is based on the hormonal dependence of testicular descent.105 Both hCG and
gonadotropin-releasing hormone (GnRH) or luteinizing
hormonereleasing hormone (LHRH) have been used to
induce testicular descent. Systemic testosterone has not been
used, because the key factor in testicular descent is a high local
level of androgens (a paracrine effect).
Agents
Human Chorionic Gonadotropin
hCG is structurally similar to LH and stimulates endogenous
testosterone production by the testis. An example of a therapeutic dose is 1500 units given intramuscularly per square
meter of body surface area twice a week for 4 weeks. The total
dose should not exceed 15,000 units. In the United States, hCG
is the only approved medication for use in cases of undescended testis. A testicular descent rate of 25% is achieved
with hCG, and 18% with GnRH.
Buserelin
Buserelin, a synthetic LHRH superanalogue, is administered in
very small doses, such as 10 g every other day for 6 months. It
induces testicular descent in 17% of cryptorchid boys,108 which
is similar to the results achieved with either LHRH or hCG.
Buserelin may also improve germ cell histology and spermiograms obtained after spontaneous descent or orchiopexy.109
It is available in Europe but it is not approved for use in the
United States. Another GnRH analogue, naferelin, has demonstrated preliminary results similar to those of buserelin.110
Success of medical therapy is better for lower testes,111
although inclusion of retractile testes in some studies may
overestimate the success of medical therapy. After successful therapy, the patient should be reexamined periodically,
because approximately 15% of successfully treated testes
reascend. If a course of medical therapy is unsuccessful, an
additional course with the same or another agent is not likely
to be beneficial.
Hormone administration is contraindicated in newborns,
in patients who are unlikely to respond (e.g., those with postoperative undescended testes or ectopic testes), in patients
who cannot anatomically respond (e.g., boys with prune-belly
syndrome), and in patients beyond puberty who are endocrinologically normal.
Penile enlargement, frequent erections, scrotal rogation
and pigmentation, increased appetite and weight gain, and
aggressive behavior are all seen to some degree with hormonal
572
part
VI: genitalia
SURGICAL THERAPY
Surgical Anatomy
The testis is supplied by the spermatic cord, which contains
the ilioinguinal (L1) and genital branches of the genitofemoral
nerve (L1-L2), the cremaster muscle, the testicular vessels, the
vas deferens, sympathetic and parasympathetic nerves, and
the remnants of the processus vaginalis. The fascial layers of
the spermatic cord and scrotum include the external spermatic
fascia (an extension of the external oblique fascia), the cremasteric or middle spermatic fascia (an extension of the internal
oblique fascia), and the internal spermatic fascia (an extension
of the transversalis fascia).
The testicular artery, also termed the gonadal or internal spermatic artery, is a branch of the abdominal aorta. The testis also
receives blood supply via the cremasteric (external spermatic)
artery and the artery of the vas deferens, which are branches of
the inferior epigastric and inferior vesical arteries, respectively.
Venous drainage of the testis is via the pampiniform plexus of
veins, which drains through the gonadal vein into the renal vein
on the left and the inferior vena cava on the right. The gonadal
vessels course in the retroperitoneum ventral to the ureter before
entering the internal inguinal ring just lateral to the inferior
epigastric vessels. In 1960, Prentiss and colleagues described the
indirect course of the testicular vessels in the retroperitoneum
and methods to achieve length by releasing the lateral attachments, thus creating a straight course to the inguinal canal.112
Lymphatic drainage of the testis is to the retroperitoneal lymph
nodes adjacent to the aorta and vena cava but may be altered after
orchiopexy to include the superficial inguinal lymph nodes.
Inguinal Orchiopexy
Examination under anesthesia is performed before any orchiopexy to confirm the choice of incision site. For an inguinal
orchiopexy, an inguinal incision is made in the lower abdominal skin crease. After Scarpas fascia is opened, dissection
should be done carefully in case the testis is in the superficial
inguinal pouch between the external oblique and Scarpas fascia. The inguinal ligament and external ring are exposed, and
the external oblique is opened in the direction of its fibers. The
ilioinguinal nerve is carefully preserved. Cremasteric muscle
fibers are separated sharply to expose the spermatic cord. As
the testis is drawn out of the wound, the gubernaculum is carefully thinned and divided, with care taken to prevent injuring a
looping vas deferens that may precede the testis into the canal.
The anterior wall of the tunica vaginalis is opened to expose
the testis. Typically, any testicular or epididymal appendages
are excised. The spermatic cord is freed proximally to the internal inguinal ring, and all tethering cremaster muscle fibers are
teased off the cord or divided. The hernia sac is separated from
for Cryptorchidism
Type of Surgery
74
82
Inguinal
87
Prepubic
92
89
Transabdominal orchiopexy
81
67
77
Microvascular autotransplantation
orchiopexy
84
Data from Docimo SG. The results of surgical therapy for cryptorchidism:
a literature review and analysis. J Urol. 1995,154:1148-1152.
chapter
43: Cryptorchidism
573
my, including vas and testicular vessels exiting a closed internal ring.
Transscrotal Orchiopexy
Testes that are low in the canal and are believed to be ectopic
are good candidates for a transscrotal approach.115,116 In this
approach, the inevitable scrotal incision is made at the beginning of the procedure. The testis is manipulated through the
incision, and a stay suture is placed. The ectopic gubernacular
attachments are divided, looking for the course of the vas deferens. Any testicular or epididymal appendages are excised.
The processus vaginalis is probed to check for patency. In 20%
of cases, an inguinal incision will be needed to correct the hernia.116 The testis and cord are mobilized through the scrotal
incision until enough laxity is obtained to achieve orchiopexy
without tension. Fixation is achieved as described previously.
The technique has been especially useful for reoperative orchiopexy after prior inguinal hernia repair when the testis is close
to the scrotum.
Laparoscopic Surgery
Diagnostic Laparoscopy
As in adults, pediatric diagnostic laparoscopy requires placement of a nasogastric tube and a Foley catheter. Peritoneal
access for carbon dioxide insufflation is achieved with the
use of techniques specific to the infant and young child.119
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VI: genitalia
Ports
5 mm
3 mm
3 mm
l ocalization, radiographic imaging to look for a testis postoperatively has limited value.
When an intra-abdominal testis is found, the appearance
of the testis and its position in relation to the internal inguinal
ring are noted. Testes lying more than 1 to 2 cm above the ring
may not reach the scrotum without division of the testicular
vessels.82 Abnormal testes and those that are clearly dissociated from the vas deferens and epididymis may be removed
as the primary form of therapy, depending on the clinical situation and the wishes of the family.
Preoperative administration of hCG has been used by some
to try to stimulate descent of the testis to a palpable position
and thereby obviate the need for laparoscopy.124,125 However,
approximately 50% of these patients can receive no potential
benefit from hormonal therapy because they have an absent or
atrophic testis. Virtually all patients with nonpalpable testes
will require surgical intervention, even if there is a response
to hCG, so the value of hormonal therapy in this situation is
debatable.
Therapeutic Laparoscopy
There are three laparoscopic procedures that are commonly
performed to treat the intra-abdominal testis:
1. Primary one-stage orchiopexy with preservation of the
spermatic vessels
2. Orchiectomy
3. Division of the spermatic vessels as the first stage of a
two-stage Fowler-Stephens orchiopexy126
The second stage of a two-stage Fowler-Stephens orchiopexy
can also be performed laparoscopically. In addition to these
procedures, laparoscopic-assisted microvascular autotransplantation has been described.127
chapter
43: Cryptorchidism
575
Medial
umbilical
ligament
Vas deferens
Testis through
internal ring
Path of
dissection
Iliac artery
and vein
Colon
Spermatic
vessels
Despite common belief, on a population basis, initial laparoscopic evaluation of the clinically nonpalpable testicle has been
shown to have a cost-saving advantage over initial inguinalscrotal exploration when reusable laparoscopic equipment is
primarily used, disposable equipment costs are kept low, and
operating room time for diagnostic laparoscopy meets national
standards.130
Open Surgery
Diagnostic laparoscopy for the intra-abdominal testis can be
followed by open surgical orchiopexy. An option is the Jones
approach, an extraperitoneal approach that utilizes a higher
incision than the standard inguinal orchiopexy, extending
from the anterior superior iliac spine medially.131,132 The retroperitoneum is explored through a muscle-splitting incision,
and orchiopexy is performed in the usual fashion if a testis
is found.
Fowler-Stephens orchiopexy129 is useful for the short testicular vessels. The testicular vessels are divided, and the testicular blood supply relies on collateral circulation of the artery of
the vas deferens and the cremasteric artery. This method can
be performed as an open procedure or laparoscopically in one
or two stages. However, an open one-stage Fowler-Stephens
procedure must be planned in advance before the cord is skeletonized. Temporary occlusion of the gonadal vessels, incision
of the tunica albuginea, and inspection of the testis for color
and arterial bleeding can be used to confirm adequate collateral blood supply (the Fowler-Stephens test), although this
does not necessarily correlate with lack of testicular atrophy.133
Traditionally, division of the testicular artery has been performed near its origin, but an alternative recently proposed by
Koff and Sethi is to divide the testicular artery close to the testis, to preserve collateral blood flow to the vasal artery from the
proximal spermatic vessel.134 The Fowler-Stephens approach
requires a vas deferens with adequate length to extend the
testis into the scrotum. Contraindications include segmental
vas atresia or a detached epididymis, which may interrupt
the collateral blood supply to the testis. The Fowler-Stephens
technique must be performed meticulously. Testicular atrophy
may occur in 20% to 50% of the cases.134 Although the use of
hCG before Fowler-Stephens orchiopexy has been suggested
to improve collateral blood flow,125 there is no experimental
or clinical evidence to support this approach.135
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part
VI: genitalia
Table 43-3 Success Rates* of Open versus Laparoscopic Orchiopexy from Two Large Published Series
Primary Orchiopexy
One-Stage F-S
Two-Stage F-S
Open133
80
81.3
321
66.7
56
76.8
Laparoscopic141
178
97.2
27
74.1
58
87.9
*Success
COMPLICATIONS OF ORCHIOPEXY
Complications of orchiopexy are relatively uncommon. The
most important surgical complication of orchiopexy is testicular atrophy, which may result from four causes:
1. Injury to the spermatic vessels during standard
orchiopexy
2. Tension on the spermatic vessels with subsequent
ischemia
3. Inadvertent torsion of the spermatic vessels when
passing the testis into the scrotum
4. Intentional ligation of the vessels as part of a FowlerStephens orchiopexy
Any of the complications of inguinal hernia repair can also
occur during orchiopexy. Testicular retraction may result from
short testicular vessels, inadequate mobilization of the testicular
vascular pedicle, incomplete division of the cremasteric muscle
fibers to the testis, or improper scrotal fixation of the testis.
CONCLUSION
The etiology of testicular maldescent remains unknown,
although recent advances in molecular understanding of testicular descent are shedding some light. Whatever the underlying
cause, the undescended testis deserves treatment early in life to
prevent loss of spermatogenic potential and to allow early detection of testicular malignancy, should it occur. Treatment can be
through hormonal manipulation or surgery, and the choice
depends on age and testicular location. Surgery for the palpable
testis remains most commonly an inguinal approach with retroperitoneal dissection as necessary. The nonpalpable testis is most
commonly approached laparoscopically, and the success rate of
laparoscopic orchiopexy may exceed that of more traditional
open approaches. In the future, a more complete understanding
of the biology of testicular descent may allow more specific nonsurgical therapy or decrease the need for orchiopexy.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
44
EMBRYOLOGY
The development of the PV is related to the descent of the
testis.1 A PV is identified in all species where there is migration of a male gonad through the inguinal canal.2 Testicular
descent is understood to occur in two sequential phases, the
transabdominal and the inguinoscrotal phase, each under different hormonal controls.3 A key structure in the transabdominal phase is the gubernaculum, which is seen as a short, thin
column of mesenchyme connecting the ambisexual gonad and
the urogenital ridge to the inguinal region. In the male fetus,
the caudal end of the gubernaculum enlarges (the swelling
reaction) by mitosis and deposition of hyaluronic acid.4,5 This
swelling reaction holds the testis closely to the future internal
inguinal ring. The gubernacular swelling reaction is under the
hormonal control of insulin-like peptide 3 (INSL3), which is
produced by fetal testicular Leydig cells, augmented by antimllerian hormone (AMH, also called mllerian inhibiting
substance, or MIS), and androgen.6,7
The PV results from an outpouching of mesothelial cells
from the coelomic cavity into the substance of the gubernacular mesenchyme. The proximal part of the PV is first visible at
about the 8th week of intrauterine life.8 The gubernaculum is
divided by the invading PV into three parts: the plica gubernaculi, the column of mesenchyme that extends from the
caudal pole of the testis to the distal extremity of the PV; the
pars vaginalis, a thin layer of mesenchyme surrounding the
PV, from which the cremaster muscle develops; and the pars
infravaginalis, the gubernacular mesenchyme distal to the processus, into which it continues to grow (Fig. 44-1).9
Heyns showed that the bulb of the gubernaculum is the
same size as the testis and its caudal end lies loose under
Scarpa fascia during the inguinoscrotal phase of descent.10
The distance to the scrotum is several times longer than
the size of the gubernaculum itself, indicating that active
migration of the gubernaculum to the scrotum is necessary for
inguinoscrotal descent of the testis.11,12 Histologic examination of the neonatal rat gubernaculum revealed that cell division occurred most rapidly at the tip of the gubernacular bulb
and its contained PV, consistent with active elongation.13,14
This has been shown to be at least partly influenced by calcitonin gene-related peptide (CGRP), which is released by the
sensory neural component of the genitofemoral nerve.15-17
Androgen blockade abolishes the increased rate of cell proliferation within the gubernacular tip, indicating that androgens are necessary to permit the proliferative response of the
gubernaculum to CGRP.18
HISTOLOGY
Histopathologic examination of the PV demonstrates an inner
surface of mesothelium supported by loose connective tissue
containing blood vessels and peripheral nerves.8,20 An inguinal
hernia sac has an additional layer of irregularly arranged
smooth muscle, which is also present in a patchy distribution
in the patent PV associated with a hydrocele but is absent in
the obliterated PV. The significance of this smooth muscle is
uncertain, but failed apoptosis of this muscle may have a role
in the persistence of a PV.21
The tiny, bright yellow nodule seen on the outer surface of
some processus sacs in boys at the time of surgery is a benign
adrenal rest.22,23 In one study, ectopic adrenocortical tissue
was found in 4% of boys at ligation of a patent PV for communicating hydrocele.24
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part
VI: Genitalia
Epididymis
M. cremaster
Mesorchium
Testis
Vas deferens
Pars vaginalis
gubernaculi
M. cremaster
Plica gubernaculi
Processus vaginalis
Pars
infravaginalis
gubernaculi
Figure 44-2 Left-sided hydrocele. Note the slight bluish discoloration of the scrotum and absence of an ipsilateral groin swelling.
At a molecular level, CGRP may be a key component in
closure of the PV. In an organ culture system of human infant
hernial sacs, Hutson and colleagues showed that CGRP can
induce PV fusion and that CGRP receptors are present on
PV mesenchymal fibroblasts but not on PV epithelial cells.36
CGRP present in the genitofemoral nerve may therefore trigger the release of another factor that results in subsequent
fusion of the PV. One hypothesis is that hepatocyte growth
factor (HGF) may act as an intermediary in this way, because
receptors for this growth factor can be found in the PV and
HGF can also cause PV fusion in vitro.37 Understanding the
molecular mechanisms of PV obliteration could lead to the
development of nonsurgical treatment of patent PV through
local administration of agents that promote fusion.
There is additional evidence that androgenic stimulation
may indirectly be required for PV closure. In a prospective
analysis of PV patency, epididymal anomalies, and cryptorchidism in boys undergoing inguinal surgery, Barthold and
Redman found that closed, partially closed, and open PVs
were associated with an abnormal epididymis in 14%, 36%,
and 69% of the cases, respectively.38 Epididymal anomalies
were associated with patency of the PV regardless of testicular position. The authors concluded that, because androgenic
stimulation may be required for epididymal development,
it may also be necessary for PV closure. The subtle or nonfunctional nature of many of these epididymal anomalies is
emphasized by the fact that PV patency per se in boys is not
associated with germ cell maldevelopment or infertility.39,40
CLINICAL FEATURES
Many authors regard a patent PV as a potential hernia; additional factors, such as increased intra-abdominal pressure,
excess peritoneal fluid, or, rarely, an underlying connective tissue deficiency, are involved in the development of a clinically
apparent inguinal hernia. Consistent with the high incidence
of PV patency in newborns, a hernia or hydrocele commonly
manifests soon after birth and may be bilateral. Both inguinal
hernias and hydroceles are more common in boys than in girls
(approximately 6:1), more commonon the right side (approximately 2:1), and more common in premature infants.
Typically, a hydrocele manifests as a painless scrotal swelling of variable size (Fig. 44-2) and an inguinal hernia as an
intermittent inguinal swelling. A hydrocele may give a bluish
discoloration to the scrotum. Hydroceles may be classified as
chapter
579
Content of
Hydrocele
Primary Pathology
Reference
Nos.
Meconium
Antenatal intestinal
erforation with meconium
p
peritonitis
47, 48
Pus
49-51
Hematocele
52
Cerebrospinal
fluid
25, 53-55
Peritoneal
dialysate
56, 57
Bile
Biliary ascites
58
Chyle
Chylous ascites
Urine
Urinary ascites
Air
Intestinal perforation
59, 60
Malignant
tumor
Intra-abdominal malignancy
61
Splenic tissue
Splenogonadal fusion
62
ATYPICAL PRESENTATIONS
Because the patent PV is an extension of the peritoneal cavity into the scrotum, a variety of intra-abdominal pathologies
may manifest with or be accompanied by scrotal signs (Table
44-1 and Fig. 44-3).25,47-62
A meconium hydrocele resulting from in utero perforation of the bowel is typically lax at birth. The infant may
have no gastrointestinal symptoms if the perforation has
healed. Meconium induces an inflammatory reaction, and the
hydrocele tends to harden and may become calcified in the
neonatal period.48 The presence of abdominal calcification on
the plain abdominal radiograph and hyperechogenic areas
on scrotal ultrasonography should establish the diagnosis in
most cases.
A hydrocele has been described as the presenting feature
of acute appendicitis, with or without perforation.49-51 Rarely,
a suppurative hydrocele complicates the postoperative course
of a child with generalized peritonitis; early exploration in
such cases may prevent testicular loss.50,51 Idiopathic neonatal
pyocele has been described and may be mistaken for testicular torsion.63 Hematoceles may occur secondary to intraabdominal bleeding, such as after blunt abdominal trauma
with splenic rupture,52 or secondary to scrotal trauma. There
is one report of a newborn with a hematocele secondary to
adrenal hemorrhage.64 Very rarely, a patent PV can be the conduit for metastatic spread from intra-abdominal malignancy.
For example, paratesticular Wilms tumor metastasis has been
described.61 Tuberculosis of the sac may develop in association with tuberculous peritonitis.29
A variety of structures can become incarcerated within an
inguinal hernia, including intestine (small bowel, large bowel,
appendix, Meckels diverticulum), uterine adnexa, omentum,
bladder, and an intra-abdominal catheter.55 In splenogonadal
fusion, the PV contains splenic tissue. This congenital anomaly is seen more often in boys and typically affects the left side.
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VI: Genitalia
MANAGEMENT
The natural history of the patent PV indicates that spontaneous closure is uncommon after the age of 2 years.27 This is the
rationale for advocating surgical repair of a hydrocele that persists or is detected after this age. Early surgery is indicated if
there is suspicion of a concomitant inguinal hernia or underlying testicular pathology.
Surgical treatment consists of high ligation of the PV and
partial excision of the distal sac. The operation is usually performed as an elective day-case procedure under general anesthesia. Effective postoperative analgesia may be achieved by
caudal or inguinal infiltration of a long-acting local anesthetic
such as bupivacaine.
Operative Procedure
The operative procedure is shown in Figure 44-4. After antiseptic skin preparation and draping of the child in a supine position, a short incision is deepened through Scarpa fascia, the
chapter
581
External
oblique
aponeurosis
Spermatic cord
at external ring
D
Patent
processus
vaginalis
Patent processus
vaginalis transfixed
and ligated at level
of internal ring
Figure 44-4 Ligation of patent processus vaginalis. A, A skin crease inguinal incision is made
to expose the external oblique aponeurosis.
B, The external oblique is incised above the
inguinal ligament and lateral to the external
ring. C, The spermatic cord is identified in the
inguinal canal. Cremasteric muscle fibers are
separated from the cord to expose the patent processus, vas, and vessels. The processus
is gently teased off adjacent cord structures
(D) and divided between hemostats (E). F, The
processus is freed proximally as far as the internal ring, where it is doubly ligated, and redundant tissue is excised. The distal processus is left
open.
582
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VI: Genitalia
herniotomy,73 and each is probably less than 1% after PV ligation. A recurrent hydrocele that persists is probably the result
of failure to dissect a complete processus, tearing of a friable
sac, or a slipped ligature. The groin should be re-explored,
with a scrotal procedure reserved for cases in which this
exploration is negative or if there is a further recurrence.
The recurrence rate after laparoscopic repair of an inguinal
hernia in children is reported to be higher than after open
surgery in some series; a three-center experience with 933
laparoscopic repairs yielded a 3.4% recurrence rate during
a follow-up period of up to 7 years,75 compared with a rate
of 1% after open surgery.73 Recurrence rates are higher after
neonatal repair.76 Intraoperative complications such as visceral injury or bleeding may arise from the insertion of trocars
or instruments during laparoscopic repair. Port site herniation
has also been described.
In the United Kingdom, the value of routine follow-up after
PV ligation has been questioned.77 In a series of 386 boys who
underwent inguinal herniotomy or PV ligation, 83% attended
a follow-up appointment 6 weeks later. After a total of 440 outpatient appointments, only 8 boys (1.8%) were found to have
a significant abnormality (testicular malposition in 4, contralateral inguinal hernia in 4). A similar proportion of boys who
were not offered routine review were subsequently referred
back by their family doctor for similar problems. Early routine
follow-up appears to be inefficient and not cost-effective. Two
studies from North America supported this conclusion.78,79 In
one of these, a randomized trial of routine outpatient followup at 4 weeks after operation was compared with no routine
visit; parents were equally reassured by clear verbal and
written postoperative advice.79
Sclerotherapy
Obliteration of a hydrocele through the injection of a sclerosant such as tetracycline is a moderately effective and welldescribed technique for the treatment of hydroceles in older
adults.101,102 However, because of the communicating nature
of congenital hydroceles, uncertainty about the potential longterm hazards of sclerotherapy at this site (including the potential for epididymitis and infertility), the specific hazards of
tetracycline in children, and the fact that some adults experience pain for several days after such treatment, there has been
a justifiable reluctance to adopt this approach in children.
Recurrence is more common after sclerotherapy than after
operative repair.
The considerable advances in understanding of the natural
process of occlusion of the patent PV made by Hutson and colleagues may yield nonoperative therapies in the future.36
SPECIAL CONSIDERATIONS
Ventriculoperitoneal Shunts
In most children with hydrocephalus, a ventriculoperitoneal
shunt is inserted to divert cerebrospinal fluid into the peritoneal
cavity. These shunts are frequently associated with the development of a hydrocele or inguinal hernia.25,53,54 The reported
incidence of this complication is about 15% to 20%, and it
occurs more commonly in infants. Increased intraperitoneal
fluid, a raised intra-abdominal pressure, and changes in the
absorption characteristics of the peritoneum due to the effects
of cerebrospinal fluid in conjunction with a patent PV have
chapter
583
Peritoneal Dialysis
Chronic peritoneal dialysis is an effective and popular alternative to hemodialysis in the management of end-stage renal
disease. The technique has been progressively adapted for use
in smaller children, and inguinal hernias and hydroceles are a
recognized complication of therapy in such cases. Between 20%
and 37% of children develop an inguinal hernia or hydrocele
soon after insertion of a peritoneal dialysis catheter57,103-106; this
complication is most common in male infants. Pathogenesis is
related to a patent PV in combination with the high volumes of
dialysate leading to raised intra-abdominal pressure.107
Some authors have recommended prophylactic bilateral
groin exploration and ligation of a patent PV in male infants
at the time of insertion of the peritoneal catheter56; others have
performed prophylactic ligation of any patent PV identified at
peritoneography carried out after insertion of the catheter.104
Meticulous operative repair is required in those patients who
present after commencing peritoneal dialysis, once any lifethreatening problems have resolved. Although most surgeons
perform a standard PV ligation, some have advocated a more
formal inguinal canal repair to avoid recurrence.105 The use of
small volumes of dialysate for 2 or 3 days after surgery may
help to reduce the chance of recurrence.
Abdominoscrotal Hydrocele
Although this condition was first described by Dupuytren in
1834, it was Bickle in 1919 who coined the term abdominoscrotal
hydrocele.108 Syme is credited with the first reported case in a
child, in 1861.109
This variety of hydrocele is rare in children, accounting for
1% of all pediatric hydroceles in one study.110 It occurs most
often in infants and is usually unilateral, although bilateral
cases have been documented.111,112 There is a scrotal hydrocele
with a dumbbell-shaped extension through the deep ring into
the abdomen that forms an intra-abdominal cystic mass (Fig.
44-5). The clinical picture is usually that of a boy with a preexisting scrotal hydrocele who develops an abdominal mass.
Rarely, the hydrocele is present at birth.113 The child may be
asymptomatic, but if the hydrocele becomes infected it may
mimic a strangulated inguinal hernia.114 A clinical diagnosis
is possible if cross-fluctuation can be demonstrated between
the intra-abdominal and the scrotal components of the hydrocele. Ultrasonography is particularly valuable and reveals
a cystic, unilocular abdominal mass in continuity with the
scrotal hydrocele. If the diagnosis is still in doubt, magnetic
resonance imaging clearly defines the lesion.115
Several theories have been suggested to explain the
pathogenesis of abdominoscrotal hydroceles, which may
be different in children than in adults.116-118 They include
(1) intra-abdominal herniation of the inguinoscrotal hydrocele as a result of upward distention and back-pressure along
Squire.)
Ascending Testis
The ascent of the testis from a normally descended scrotal
position to an undescended position was first described by
Villumsen and Zachau-Christiansen in 1966.124 In 1985, Atwell
584
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VI: Genitalia
inguinal canal with growth was postulated as an additional
factor. Subsequent reports have supported the concept of the
ascending testis,126-128 but some authors have suggested that
adhesions surrounding a retractile testis might explain some
cases.
A prospective study of boys with acquired undescended
testes showed that the majority experienced spontaneous
testicular descent after puberty; fewer than 20% required
an orchidopexy.129 Reassuringly, histopathologic studies on
testicular biopsy specimens obtained at orchidopexy have
shown no significant differences between ascended testis and
normally descended testis.130
CONCLUSION
reported on 10 children in whom ascent of the testis was carefully documented.125 In nine of these children, a complete
hernial sac was found at the time of orchiopexy, which was
undertaken at a mean age of 9.4 years. None of the boys had
a clinically apparent inguinal hernia. Atwell proposed that the
absence of complete regression of the PV leaves a fibrous and
nonelastic tissue in its place. This vestigial structure may prevent elongation of the spermatic cord in response to somatic
growth, thereby anchoring the testis, which would then
assume a higher position.125 Alteration in the length of the
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
45
INCIDENCE
Varicoceles occur more commonly in adolescent boys than
was previously suspected. Various studies indicate an
approximate frequency of 16% (Table 45-1). Clinical observation indicates that puberty-associated testicular enlargement, with its concomitant increased blood flow, is the factor
causing most varicoceles to appear. Screening studies demonstrate a paucity of varicoceles in prepubertal boys, with a
significant progressive increase in frequency as puberty progresses. The incidence of pediatric varicocele may actually
be underestimated, because many varicoceles either are not
detected by primary care doctors and are discovered later in
adult infertility clinics or never materialize as fertility problems and are not reported. Pediatric varicoceles are often
associated with a unique body habitus: Various studies have
demonstrated a clear association with increased height and
weight and lower than normal body mass index in adolescent boys and adult men with varicocele.2-5 Varicocele frequency appears to be prevalent in first-degree relatives of
index patients with varicocele. One study demonstrated a
56.5% prevalence of varicocele among first-degree relatives
of adult male varicocele patients (as determined by physical
examination), with the highest frequency among the sons of
fathers with varicocele (67%).6
Studies in adults show that between 80% and 90% of
varicoceles occur on the left side. Right-sided varicoceles
are uncommon, are usually noted only when bilateral varicoceles are present, and seldom occur as an isolated finding. These observations hold true for pediatric varicoceles
as well, although new information indicates that subtle
right varicocele may coexist with clinical left varicocele
far more frequently than previously described (see later
discussion).
*In this chapter, the term growth arrest is used to describe more accurately
the smaller testis associated with the varicocele rather than atrophy, which
suggests shrinkage from an already normally achieved size.
585
586
part
VI: Genitalia
Boys
Study
Horner,
196059
Oster, 197160
Steeno et al,
197632
Yerokhin, 197961
Berger,
198062
DOttavio, 198163
Total
Age Range
(yr)
Frequency
(%)
1211
11-16
15.9
837
10-19
16.2
407
12-25
14.7
10,000
10-17
12.4
586
10-17
9.0
5177
11-16
25.8
21,878
16.3
Retropubic
crossover vein
Superior
inguinal ring
Pampiniform
plexus
Internal spermatic
vein
Hypogastric vein
Deferential vein
Deep inguinal ring
Cremasteric vein
Superficial external
pudendal vein
Anterior scrotal vein
Figure 45-1 Venous drainage of the left testis. (From Levitt SB, Gill B,
Katlowitz N, et al. Routine intraoperative post-ligation venography in
the treatment of the pediatric varicocele. J Urol. 1987;137:716-718.)
chapter
587
Description
DIAGNOSIS
0 (subclinical)
The majority of pediatric varicoceles are asymptomatic, manifesting as a scrotal swelling discovered during routine physical
examination. A minority are discovered by the patient in the
same manner or because of a dull, nagging ache in the scrotum.
It is imperative that the examination to detect a varicocele be
done with the patient in an upright standing position, because
the dilated veins will collapse when the patient lies down and
even a large varicocele will remain undetected if the patient is
not upright. A Valsalva maneuver should be requested (cough
or abdominal straining or both); this will produce a tapping
sensation, representing transmission of increased abdominal
pressure in the scrotally palpated dilated veins.
Varicoceles are traditionally graded I through III (Table
45-2). Subclinical varicoceles (grade 0) are not recognized in
general in adolescence, because there is no reason to consider
their presence unless an otherwise unexplained small testis
is present. Observations indicate that varicocele frequency
and varicocele grade increase with progression of puberty.
A larger percentage of higher-grade varicoceles occurs during
later pubertal stages. When a varicocele is detected, the testis
size (volume) and consistency should be noted. Orchidometry
using the Prader or Takihara models should be performed, or
ultrasonography may be used to more precisely define differences in size.10 Orchidometry has been shown to provide
reliable reproducibility between observers, although its sensitivity in determining testis volume differentials was found to
be limited compared with ultrasound.27,28 Testis volume may
be compared with measurements in normal boys, but a more
practical and useful comparison is to note size differences
between the patients own two testes (except, of course, when
the contralateral testis is diseased or absent). Although minimal differences in size between the left and the right testes
occur in normal individuals, data indicate that a size difference greater than 2 cm3 should be regarded as significant and
abnormal.29 This measurement is obviously age- and pubertalstage dependent, a 2-cm3 size difference in an adult being less
significant than the same difference noted in a prepubertal or
peripubertal adolescent.
Even small varicoceles may be associated with a subfertility
effect. Doppler ultrasonography is useful to detect retrograde
venous reflux with a Valsalva maneuver and should be performed along with conventional morphologic imaging if there
is suspicion about the diagnosis and the varicocele is difficult
to feel. Ultrasonography may also prove useful occasionally in
diagnosing a subclinical varicocele in a boy with an unexplained
small testis and an impalpable varicocele. In these circum
stances, the subclinical varicocele should be corrected because
of its presumed effect on testicular growth. The significance of
a subclinical varicocele detected in the absence of ipsilateral testicular growth arrest in adolescence is unclear at this time.
Other techniques for diagnosing varicocele, such as preoperative internal spermatic vein venography and scrotal
thermography, have been utilized in adults. These have limited usefulness in adolescence and are not routinely utilized.
Similarly, semen analysis is an integral component of varicocele evaluation in adults but is seldom utilized in adolescents
because of associated anxiety regarding fertility-related issues
and masturbation and because decisions regarding treatment
are usually based on physical findings alone. Furthermore,
normative values for semen parameters during early puberty
have not been defined.
II
III
TREATMENT
Operative versus Nonoperative Treatment
When considering the varicocele effect, it is reasonable to
weigh the risks and benefits of operative versus nonoperative
treatment.
Nonoperative Treatment
Data indicate that nonoperative (observant) treatment is associated with a progressive number of smaller than normal testes
as puberty progresses. Testes initially determined to be equal
or slightly different in size sometimes demonstrate progressive
growth arrest with time. Puberty progression is also associated
with an increased percentage of higher-grade varicoceles, so a
direct relation exists between patient age, pubertal stage, and
varicocele size, and an inverse relation occurs between varicocele size and testis size.32 Selected studies in adolescents have
also indicated that observant therapy is associated with deterioration of semen parameters in some adolescent boys with
varicocele.13,15,29,33
These findings demonstrating progressive deterioration in
semen parameters are not limited to adolescence. At least two
studies in adults have demonstrated that some men with varicocele develop progressive loss of fertility with time despite
normal initial fertility. In one report, 98 of 1099 subfertile men
had secondary subfertility (i.e., they were fertile initially).34
588
part
VI: Genitalia
Complication Rate
Failure Rate
Comments
Conventional inguinal
3-8.6% Hydrocele
Cost*
$
Easiest technique
Microscopic inguinal
0% Hydrocele
$$
0.6% Recurrence
Microscopic subinguinal
0.8% Hydrocele
2.1% Recurrence
Retroperitoneal
7.2% Hydrocele
Laparoscopic
Similar to retroperitoneal
$$$
15% Recurrence
Embolization
$$$
Fast recovery
*Relative
costs estimated on necessity for anesthesia, time in operating room, and equipment.
relatively minor, including extravasation, contrast reactions, pain, puncture of femoral artery, testicular thrombophlebitis.
From Skoog SJ, Roberts KP, Goldstein M, Pryor JL. The adolescent varicocele: whats new with an old problem in young patients? Pediatrics. 1997;100:112-121.
Used with permission of the American Academy of Pediatrics.
Most
Operative Treatment
The risks and benefits of operative treatment need to be
considered as well. Varicocelectomy in childhood may, in
general, be performed with minimal morbidity; however,
the procedure is not without potential complications regardless of the surgical technique utilized. Hydrocele formation
despite varicocele cure and varicocele persistence are the
two most common complications (Table 45-3). Other complications, such as funiculitis, transient epididymitis, and
testis atrophy, are exceedingly rare. Hydroceles occur as a
result of lymphatic disruption at the time of venous ligation.
Lymphatic-sparing techniques minimize but do not fully
eliminate this risk. Hydroceles occurring in this context will
eventually require repair if they undergo progressive continued enlargement.
chapter
Absolute
Relative
Minor
Surgical Techniques
Multiple techniques for treating varicoceles in adults have been
described, and all are frequently used for pediatric varicoceles
as well. Retrograde femoral vein catheterization with embolization or sclerotherapy has found only limited appeal among
pediatric urologists. Until recently, conventional treatment
consisting of transinguinal or suprainguinal open surgical
589
repair was used exclusively. With the popularization of microsurgical varicocelectomy and laparoscopic varicocelectomy in
adults, these techniques have also been used in adolescents.
590
part
VI: Genitalia
Angiographic Repair
Angiographic varicocelectomy has a limited usefulness in
children. General anesthesia is invariably needed. These procedures are usually performed by interventional radiologists
and involve the injection of various sclerosing agents or placement of occluding detachable angiographic coils or balloons
to obliterate the internal spermatic veins. The occlusive agent
is usually delivered by first obtaining venous access via the
femoral or jugular approach. Complications in childhood
include difficulty catheterizing the internal spermatic vein,
extravasation of contrast material, coil migration, and a significant rate of varicocele persistence (see Table 45-3). As a result,
these procedures are seldom used as primary procedures in
children, but they may have a secondary role in treatment of
the recalcitrant persisting varicocele, because persisting veins
can be accurately studied and defined radiologically and then
obliterated in the same procedure.8,41
Microsurgical Repair
Microsurgical varicocelectomy has distinct advantages over
the other routes and has been widely adapted for adolescent
varicocele repair.42,43 A subinguinal or low transverse inguinal incision is made with isolation of the spermatic cord. The
external oblique aponeurosis is opened in prepubertal boys
and the cord is isolated higher up, which aids in identification
of the very small testicular artery. The testis is delivered out of
the scrotum, and all external spermatic veins and scrotal veins
are divided. The testis is then returned to the scrotum. Under
increased (6 to 25) magnification provided by the operating
microscope, all internal spermatic veins are clipped or tied and
divided. The vas deferens and its vessels and the arteries and
lymphatics are identified and preserved. Although this procedure may be done in adults under local anesthesia and sedation, general anesthesia is usually required in adolescents.
It has been argued that the use of approaches other than the
microsurgical approach is illogical because most adult infertility surgeons are gravitating to the latter technique because
of the benefits provided by significant magnification. The
testicular artery diameter ranges between 0.3 mm in the peripubertal boy and approximately 1.0 mm in the adult, so the
chapter
Management
591
592
part
VI: Genitalia
Role of Venography
In an effort to minimize the risk of varicocele persistence or
recurrence after open surgical varicocelectomy, the technique
of intraoperative internal spermatic postligation venography
(ISPLV) was developed.8 Internal spermatic vein venography
had previously been used preoperatively or intraoperatively
to define venous anatomy, but its intraoperative use after the
varicocele was ligated represented a new application.
After the varicocelectomy is completed, a single vein is
cannulated with a large-bore angiocatheter or a 5F (1.69-mm)
or 8F (2.64-mm) pediatric feeding tube placed retrograde
toward the testis, which is secured in place with a silk suture
(Fig. 45-6). A 30% intravenous contrast solution (1 mL contrast
agent per kilogram of body weight) is rapidly injected, and
C-arm angiographic films are exposed. The system is then
flushed with intravenous 0.9% normal saline solution.
Performance of the venogram in this fashion after varicocelectomy is completed demonstrates residual bypass collaterals predisposing to varicocele recurrence that may not be
visually recognized (see Fig. 45-5). Personal experience with
this technique in two separate studies with children indicated
that collaterals exist and fill the internal spermatic system
with surprising frequency, despite the impression that the
varicocelectomy was complete. Proximal bypass collaterals
were noted in one third and pelvic venous collaterals were
noted in about one half of the patients.8,50 These latter pelvic
collaterals filled, in diminishing order of frequency, the ipsilateral external iliac vein, hypogastric vein, external pudendal
vein, deferential veins, suprapubic and retropubic crossover
veins, the contralateral external and internal iliac veins, and
the contralateral lumbosacral crossover veins. These veins
were found to be unimportant clinically, because follow-up in
virtually all instances did not demonstrate varicocele recurrence despite their presence and preservation. Varicocelectomy
performed by the inguinal route was associated with a higher
frequency of proximal collaterals than was varicocelectomy by
the suprainguinal retroperitoneal route.
Occult veins existing within the testicular periarterial
sheath, which subsequently hypertrophied after varicocele
Frequency of Bilaterality
Controversy exists regarding the frequency of unrecognized
bilateral varicoceles and their potential significance. A growing
body of evidence suggests that many (if not most) varicoceles
are bilateral, with the right varicocele often undetected by
physical examination. Twenty-eight adolescent boys with suspected or confirmed varicoceles were evaluated by scrotal thermography and bilateral spermatic vein venography; in 87.5%,
the varicocele on the right side was not detected by physical
examination alone but only by thermography and subsequent
venographic confirmation.51 This study was important in
that venographic confirmation was used to confirm the finding. Other studies have demonstrated the high prevalence
of bilateral varicoceles in infertile men (77%)52 and the fact
chapter
593
Figure 45-7 Duplex sonographic demonstration of an enlarging hydrocele and persisting varicocele in a 12-year-old boy 2 years after left inguinal varicocelectomy. A, Large scrotal hydrocele. B, Retrograde enlargement of varicosities demonstrated on sonography with the Valsalva maneuver with the patient in the upright position. C, Intraoperative scrotal venogram demonstrates persistent filling of the internal spermatic vein
at and above the level of the internal inguinal ring (arrow). Scrotal hydrocelectomy and open high suprainguinal retroperitoneal varicocelectomy
resolved each problem.
that bilateral varicocelectomy leads to significantly greater
improvement in postoperative semen parameters in men with
repaired large left varicoceles and grade 1 right varicoceles,
compared to unilateral left varicocelectomy alone.53 Although
pediatric varicocele repair usually focuses only on short-term
outcomes, these findings indicate that a strong suspicion should
be maintained in these patients regarding diagnosis of occult
right-sided varicocele and the long-term fertility implications.
scrotal incision is closed with absorbable sutures. If the original procedure was performed transinguinally, a suprainguinal
open or laparoscopic reexploration is done. If it was initially
done retroperitoneally, a laparoscopic higher reexploration is
appropriate. Early data indicate that microsurgical repair is
effective for recurrences resulting from initial varicocelectomy
performed by either route.54
Treatment of Recurrences
RESULTS OF TREATMENT
Comparison of the various approaches to treatment of adolescent varicoceles is difficult, because published results diverge
widely. Initial evaluation outcomes consist of varicocele cure,
absence of hydrocele, observation of satisfactory testicular
catch-up growth, and, if available, assessment of hormonal
and semen parameters. One series contrasting four different methods of treatment (high mass ligation of vessels, high
ligation with artery sparing, artery-sparing inguinal, and
laparoscopic) indicated a clear advantage for the open high
retroperitoneal approach with artery preservation, including the least risk of hydrocele or persisting varicocele.55
Other series had divergent results, with varied frequencies
of hydrocele occurrence and varicocele persistence, although
catch-up growth was described in most. Sperm concentration
appears to improve in patients treated successfully by any
approach.
The late important outcome parameter of significance,
paternity, cannot yet be significantly evaluated, because
most boys treated in adolescence are just becoming of age.
One study demonstrated a 100% paternity rate in a cohort of
18men who had undergone adolescent varicocelectomy.56
VARICOCELECTOMY IN ADOLESCENTS
WITH PREVIOUS TESTICULAR CONDITIONS
POTENTIALLY AFFECTING FERTILITY
Boys with previous testicular pathology are at increased risk
for infertility when a varicocele appears. Examples of such
previous pathology include right or left cryptorchidism,
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part
VI: Genitalia
Table 45-5 Results of Semen Analysis Before and After Left Varicocelectomy
Volume
(mL)
Time
Sperm Concentration
(/mL)
Motility
(%)
Morphology
(%)
pH
Fructose
Preoperative
1.3
8.2
6 mo
2.2
>2 106
>50
>30
8.6
43
22
8.1
40
30
8.5
6 mo
2.6
12 mo
1.5
106
0.4
106
Figure 45-8 Duplex sonogram in a 15-year-old pubertal boy with absent right testicle from perinatal torsion and left varicocele. The solitary left
testicle is markedly hypertrophied, measuring 50 mL in volume. A, Large varicosities are noted in the spermatic cord. B, Retrograde venous filling
is noted during the Valsalva maneuver.
CONCLUSIONS
Significant evolution in the treatment of adolescent varicoceles
has occurred since 1970. These varicoceles are now recognized
as being the source of those varicoceles seen in men presenting
later with small testes and infertility. Varicocelectomy in
adolescence is a highly successful undertaking, resulting in
resolution of the varicocele and catch-up growth of the testis
in most instances. As the surgical approaches are further
refined, additional improved results of treatment are expected,
minimizing the frequency of postoperative hydrocele and varicocele persistence. Recognition of the contributory role of the
adolescent varicocele to male infertility and the importance of
treating adolescent varicoceles should significantly reduce the
number of subfertile adults in the future.
REFERENCES
For complete list of references log onto www.expertconsult.com
P A RT
VII
NEPHROUROLOGY
c h ap t e r
46
596
part
VII: Nephrourology
P
rerenal Failur
e
Decreased t
rue intravascular volume
Decreased effective intravascular volume
Intrinsic Renal Disease
which is associated with low inducibility of heat shock protein 72.18 Given the important role of heat shock proteins in
ischemic renal injury, this finding suggests that some neonates
are more susceptible to ischemic injury.19 Future studies of the
genetic background of the child at risk for AKI due to medication exposure, toxin exposure, ischemic hypoxic insults, or
other insults are likely to affect management in the child who
has or is at risk for AKI.
Hemoly
tic
-uremic syndrome
Hypopl
asia
/dysplasia with or without obstructive uropathy
Idio
pa
thic
Exposu
re
to nephrotoxic drugs in utero
Hereditary renal disease
Autosomal dominant polycystic kidney disease
Autosomal recessive polycystic kidney disease
Alport syndrome
Sickle cell nephropathy
Juvenile nephronophthisis
Obstructive Uropathy
Obstruction in a solitary kidney
Bilateral
ure
teral obstruction
Urethral obstruction
AKI and those without AKI, but the TNF-/IL6 AG/GC haplotype was present in 26% of newborns who developed AKI
compared to 6% of newborns who did not develop AKI. The
investigators suggested that the combination of these polymorphisms might lead to a greater inflammatory response
and the development of AKI in neonates with infection.16 As
described later, future therapies for AKI might involve strategies to interrupt the inflammatory response.
In other studies, the incidence of ACE I/D allele genotypes
or variants of the angiotensin I receptor gene did not differ
in neonates with AKI compared to neonates without AKI,
but they may be associated with patent ductus arteriosus
and heart failure and indirectly contribute to CKD.15,17 AKI
occurred more commonly in very-low-birth-weight neonates
carrying the heat shock protein 72 (1267)GG genetic variation,
Prerenal Failure
Prerenal failure occurs when blood flow to the kidney is
reduced as a result of true intravascular volume contraction or
a decreased effective blood volume, as described later. Because
the kidneys are intrinsically normal, prerenal failure is reversible once the blood volume and hemodynamic conditions are
restored to normal. Prolonged prerenal failure can result in
intrinsic AKI due to hypoxic/ischemic ATN. The evolution
of prerenal failure to intrinsic renal failure is not sudden, and
several compensatory mechanisms maintain renal perfusion
when renal hemodynamics is not optimal.
When renal perfusion is compromised, the afferent arteriole relaxes its vascular tone to decrease renal vascular
resistance and maintain renal blood flow. During renal
hypoperfusion, the intrarenal generation of vasodilatory
prostaglandins including prostacyclin mediates vasodilation
of the renal microvasculature to maintain renal perfusion.25,26
Administration of cyclooxygenase inhibitors such as aspirin
or NSAIDs can inhibit this compensatory mechanism and
precipitate acute renal insufficiency.26,27 Similarly, when renal
perfusion pressure is low, as in renal artery stenosis, the intraglomerular pressure necessary to drive filtration is in part
mediated by increased intrarenal generation of angiotensin II
to increase efferent arteriolar resistance.28-30 Administration of
ACE inhibitors in these conditions can eliminate the pressure
gradient needed to drive filtration and precipitate AKI.28-30
Therefore, administration of medications that can interfere
with compensatory mechanisms to maintain renal perfusion
may precipitate AKI in certain clinical circumstances.
Prerenal failure caused by true volume contraction can
result from hemorrhage, dehydration due to gastrointestinal losses, salt-wasting renal or adrenal diseases, central or
chapter
597
In hypoxic/ischemic ATN, the urinalysis may be unremarkable or may demonstrate low-grade proteinuria and
granular casts; urine indices of tubular function demonstrate
an inability to conserve sodium and water, as described previously. The creatinine concentration typically increases by
about 0.5 to 1.0 mg/dL per day. Radiographic studies demonstrate kidneys of normal size with loss of corticomedullary differentiation, whereas a radionuclide renal scan with
technetium 99mlabeled mercaptoacetyltriglycerine (Tc99mMAG3) or diethylenetriamine penta-acetic acid (Tc99m-DTPA)
demonstrates normal or slightly decreased renal blood flow
with poor function, delayed accumulation of the radioisotope
in the renal parenchyma, and no excretion of the isotope in the
collecting system (Fig. 46-1A).
Except in very severe insults in which microthrombi formation leads to the development of cortical necrosis, the prognosis of ATN is good and depends on the underlying events
that precipitated the ischemic/hypoxic insult. Mortality and
morbidity from AKI are much worse in children and neonates
with multiorgan failure; the child does not die of renal failure
but rather with renal failure and the associated conditions.1-5,40
In children who recover from ATN, the renal function returns
to normal but the time to recovery is quite variable. Some
children begin to recover renal function within days after the
onset of renal failure, whereas recovery may not occur for several weeks in other children. Recovery of renal function may
be accompanied by a diuretic phase with voluminous urine
output at a time when the tubules are beginning to recover but
have not recovered sufficiently to reabsorb solute and water
appropriately. If such a diuretic phase occurs, close attention
to fluid and electrolyte balance is essential.
598
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VII: Nephrourology
Figure 46-1 Tc99m-MAG3 renal scan in a 1-year-old with acute tubular necrosis (ATN) (A) and in a newborn with cortical necrosis (B). Each scan
was taken 4 hours after injection of the isotope. A, In the child with ATN, there is delayed uptake of isotope with parenchymal accumulation of
isotope and little to no excretion of isotope into the collecting system. B, In contrast, no renal parenchymal uptake of isotope is demonstrated in
a neonate with cortical necrosis. (A and B, From Andreoli SP. Clinical aspects and management of acute renal failure in children. In: Barratt TM,
Avner ED, Harmon WE, eds. Pediatric Nephrology. Baltimore: Williams & Wilkins; 1998:1119-1124.)
Vascular Insults
Large-vessel insults such as renal artery thrombosis and
renal vein thrombosis produce AKI only if they are bilateral
or if occur in a solitary kidney. Microvascular insults occur
chapter
in cortical necrosis, in typical (diarrhea-positive) and atypical (diarrhea-negative) HUS, and in HUS after bone marrow
transplantation.
and
Cortical Necrosis
Cortical necrosis as a cause of AKI is much more common in
younger children, particularly in neonates. Cortical necrosis
is associated with hypoxic/ischemic insults resulting from
perinatal anoxia, placenta abruption, and twin-twin or twinmaternal transfusions with resultant activation of the coagulation cascade. Children and newborns with cortical necrosis
usually have gross or microscopic hematuria and oliguria and
may have hypertension as well.56 In addition to laboratory features of elevated BUN and creatinine concentrations, thrombocytopenia may be present as a result of the microvascular
injury. Radiographic features include a normal renal ultrasound study in the early phase; in later phases, ultrasonography may show that the kidney has undergone atrophy and
substantially decreased in size. A radionucleotide renal scan
shows decreased to no perfusion with delayed or no function (see Fig. 46-1B), in contrast to the delayed function that is
observed in ATN (see Fig. 46-1A).
The prognosis for cortical necrosis is much worse than that
for ATN. Children with cortical necrosis may have partial
recovery or no recovery at all. Typically, children with cortical
necrosis need short-term or long-term dialysis therapy, but
those who do recover sufficient renal function are at risk for
the late development of CKD.
Hemolytic-Uremic Syndrome
HUS is a common cause of AKI in children and leads to substantial morbidity and mortality as well as long-term complications that may not become apparent until adulthood.57.58
Typical HUS usually follows a gastrointestinal illness characterized by hemorrhagic colitis associated with infection by
Shiga-like toxinproducing Escherichia coli, of which O157:H7
is the most common serotype. Approximately 10% of children
with hemorrhagic colitis associated with Shiga-like toxin
producing E. coli develop HUS.58,59 At the time the diarrhea
is subsiding, the child appears pale and lethargic due to the
hemolytic anemia. Oliguria and anuria occur in about 30%
to 50% of affected children, and about 40% to 75% will need
dialysis therapy.
HUS is a systemic disease in which the kidney and gastrointestinal tract are the organs most commonly affected;
however, evidence of central nervous system, pancreatic,
skeletal, and myocardial involvement may also be present.59-63
Gastrointestinal involvement may lead to rectal prolapse,
ischemic colitis, and transmural colonic necrosis. Pancreatic
involvement manifested as elevated pancreatic enzymes
599
occurs in 10% to 20% of affected children, and glucose intolerance due to pancreatic islet cell involvement occurs in fewer
than 10%.63 Central nervous system disease may manifest as
seizures, coma, lethargy, and irritability.
Laboratory studies usually demonstrate the characteristic
triad of HUS: microangiopathic hemolytic anemia, thrombocytopenia, and renal disease. Renal disease is manifested
as hematuria or proteinuria or both, with elevated BUN and
creatinine in most patients. However, epidemiologic studies
performed during epidemics of HUS clearly show that some
children have incomplete forms of HUS without the classic
triad.64 A high polymorphonuclear leukocyte (PMN) count
with a prominent left shift is typical of the disease, and a high
white blood cell (WBC) count is associated with more severe
disease and a worse outcome.65 Stool cultures usually yield
Shiga-like toxinproducing E. coli, but the incidence of positive cultures decreases as the diarrhea subsides.59 The yield
of positive cultures is greatest in stool cultures obtained soon
after the onset of the diarrhea.
During the acute phase of HUS, pathologic specimens
of the kidney reveal microvascular injury characterized by
microthrombi deposition in association with swollen and
detached glomerular endothelial cells and infiltration of
inflammatory cells.66 Similar pathologic changes have been
described in other organs, including the colon, central nervous
system, pancreas, and skeletal and myocardial muscle.67 The
mechanisms of this microvascular injury are unknown, but
evidence points to a role for Shiga-like toxins in mediating
endothelial cell injury with a resultant change in the normal
anticoagulant profile of the endothelial cell to a procoagulant
state. Shiga-like toxins have direct effects on endothelial cells,
and it is likely that inflammatory mediators are important in
the pathogenesis of endothelial cell injury as well.68-70 The
PMN count is usually elevated and correlates with a poor
outcome, and increased levels of IL8 and TNF- have been
described in children with HUS, suggesting that the inflammatory response, and PMNs in particular, are very important
in mediating microvascular injury in HUS.65-69
Some studies have shown that administration of antibiotics
to children with hemorrhagic colitis associated with Shigalike toxinproducing E. coli significantly increased the odds
of the childs developing HUS.71 However, a meta-analysis
did not demonstrate that antibiotic therapy was harmful.72
Antibiotic therapy has the theoretical potential to alter the
bacterial production of toxin, resulting in increased release of
the toxin. Similarly, antimotility agents are also not indicated,
because they may increase the systemic absorption of toxin as
a result of the slower gastrointestinal transit time. Therapy for
HUS is only supportive. In a multicenter, placebo-controlled
clinical trial, the administration of a toxin-binding compound,
8-methoxycarbonyloctyl oligosaccharides (Synsorb-Pk), at the
onset of HUS to diminish the severity of HUS and decrease
the incidence of extrarenal complications was found to be
ineffective.73
Renal Hypoplasia/Dysplasia
Renal dysplasia is frequently associated with obstructive uropathy including posterior urethral valves, ureteropelvic junction
obstruction, prune-belly syndrome, megacystis-megaureter,
and ureteroceles, which are each discussed in detail in other
chapters. In the absence of obstruction, cystic renal dysplasia can be associated with a number of syndromes, including
Meckel-Gruber syndrome and Zellweger syndrome.74
Renal hypoplasia/dysplasia may be isolated, or it may be
associated with numerous syndromes including the Noonan,
Denys-Drash, Turner, and Beckwith-Wiedemann.74 Depending
600
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VII: Nephrourology
chapter
601
602
part
VII: Nephrourology
Mechanism
K+
into cells
Dose
Onset
Complications
1 mEq/kg IV over
10-30 min
15-30 min
Hypernatremia, change in
i onized calcium
Sodium bicarbonate
Shifts
Albuterol
400 g by nebulizer
30 min
Tachycardia, hypertension
30-120 min
Hypoglycemia
Stabilizes membrane
potential
Immediate
Bradycardia, arrhythmias,
ypercalcemia
h
Kayexalate
1 g/kg PO or PR in
sorbitol
30-60 min
Hypernatremia, constipation,
c olonic membrane irritation if
given PR
Modified from Andreoli SP. Clinical aspects and management of acute renal failure in children. In: Barratt TM, Avner ED, Harmon WE, eds. Pediatric Nephrology.
Baltimore: Williams & Wilkins; 1998:1119-1124.
Anemia
Anemia in AKI may be related to hemolysis (e.g., in HUS),
whereas anemia in CKD is a result of deficiency of erythropoietin, which is produced by the kidney. Iron-deficiency anemia and decreased red blood cell survival may also play a role
in the anemia of CKD. Human recombinant erythropoietin
has been available since the late 1980s and has dramatically
changed the care of patients with CKD and end-stage renal
disease. Symptoms of anemia can be avoided, exposure to
blood-borne pathogens reduced, and sensitization to human
leukocyte antigens minimized by therapy with erythropoietin. Therapy is started when the hematocrit is approximately
30%, or earlier if the patient is symptomatic. The starting
dose is approximately 50 U/kg per dose, administered one to
three times a week. The dose can be incrementally increased
to achieve the target hemoglobin concentration. Erythropoietin may be given intravenously or subcutaneously, but the
subcutaneous route may be more effective because it allows
prolonged absorption and slower clearance of the hormone.112
The child usually requires concomitant iron therapy so that
the erythropoietin therapy will be effective.
Growth Failure
Growth failure is a very common complication of CKD and
is the presenting symptom in some cases. Among a large
cohort of children with CKD who had a mean creatinine concentration of 2.4 mg/dL, the average height was 1.5 standard
deviations (SD) below age- and gender-specific norms.113 The
mechanisms of growth failure are complex and multifactorial;
poorly controlled renal osteodystrophy, inadequate nutrition,
chronic acidosis, and abnormalities of the growth hormone
axis are major contributors to poor growth in the child with
CKD.107 Despite adequate nutrition and good control of bone
disease and acid-base balance, many children remain substantially growth retarded.
chapter
603
Hypertension
ic renal failure due to a neurogenic bladder. The radiograph demonstrates a coarse trabecular pattern of all bones, with acrosteolysis of
the distal phalanges and subperiosteal resorption of the phalanges.
There is severe fraying of the distal radial and ulnar metaphysis
(smaller arrows), and a cystic lesion is present in the first metacarpal
(large arrow), suggestive of a brown tumor resulting from severe
hyperparathyroidism.
Medications
Pharmacotherapy in AKI and CKD requires careful attention
to the metabolic elimination of the drug and adjustments for
the degree of renal failure. Many drug adjustment tables are
based on the glomerular filtration rate (GFR) (i.e., for patients
with >50, 20 to 50, or <20 mL/min/1.73 m2 GFR). It is important
Nutritional Therapy
AKI and CKD can be associated with severe anorexia, and
malnutrition can develop rapidly. Proper nutrition is essential
in the management of AKI and CKD. If the gastrointestinal
tract is intact and functional, enteral feedings with formula
(PM 60/40 for newborns and infants) should be instituted as
soon as possible. In older children, a diet of foods with highbiologic-value protein, low phosphorus, and low potassium
can be used. Infants should receive maintenance calories
(120kcal/kg/day), and older children should receive appropriate maintenance calories or higher if needed because of
the catabolic state and malnutrition. If the child is oliguric or
anuric and sufficient calories cannot be achieved while maintaining appropriate fluid balance and growth, earlier initiation
of dialysis should be considered.
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VII: Nephrourology
Peritoneal Dialysis
PD has been a major modality of therapy for AKI and CKD, particularly in neonates and small children.107,123-125 It is frequently
used in such patients when vascular access is difficult to maintain. Advantages of PD are that it is relatively easy to perform,
it does not require heparinization, and the child does not need
to be hemodynamically stable. The disadvantages include a
slower correction of metabolic parameters and the potential for
peritonitis. To increase the efficiency of PD, frequent exchanges
(as often as every hour) and use of dialysates with higher
glucose concentrations are used to remove more solute and
more water, respectively. Relative contraindications include
recent abdominal surgery and massive organomegaly or intraabdominal masses as well as ostomies, which may increase the
Hemodialysis
HD has also been used in the treatment of AKI and CKD during
childhood.127-129 HD has the advantage that metabolic abnormalities can be corrected rather quickly and hypervolemia
Peritoneal Dialysis
Hemodialysis
CVVHD
Solute removal
Good
Excellent
Fair (excellent)
Fluid removal
Good
Excellent
Excellent (excellent)
No
Yes
No (no)
Hyperkalemia treatment
Fair
Excellent
Ease of access
Not difficult
Difficult
Difficult (difficult)
Continuous treatment
Yes
No
Yes (yes)
No
Usually
Variable (variable)
Moderate
Low
Low (low)
High
No
No (no)
Precipitation of hypotension
Low
High
Moderate (moderate)
Disequilibrium
No
High
Low (moderate)
Moderate
High
High (high)
chapter
can be corrected by rapid ultrafiltration as well. The disadvantages of HD include the requirement for heparinization,
the need for maximally purified water supplied by a reverse
osmosis system, and the need for skilled nursing personnel.
Relative contraindications include hemodynamic instability or severe hemorrhage. If HD is needed in a child who has
active hemorrhage or is at high risk of hemorrhage, regional
heparinization, citrate anticoagulation, heparin-free dialysis,
or some combination of these can be used to minimize the risk
of hemorrhage.
During HD, rapid ultrafiltration may also lead to hypoten
sion, which has been shown to result in additional renal
ischemia and to potentially prolong an episode of AKI.130
Rapid removal of BUN and other uremic products can result
in dialysis disequilibrium, particularly if the child begins HD
with a high level of BUN (>120 to 150 mg/dL). The pathogen
esis of this syndrome is complex and multifactorial but may
be related to rapid removal of urea from the blood while
brain levels decline more slowly, resulting in disequilibrium.
Symptoms include restlessness, fatigue, headache, nausea,
vomiting leading to confusion, seizures, and coma.131 Mannitol
can be used during HD to offset the alteration in osmolality
that results from lowering the BUN.
Vascular catheters can be placed in the internal or external
jugular veins or in the femoral vein. To avoid hypotension, the
total volume of the dialysate circuit, including the dialyzer and
tubing, should not exceed 10% of the childs blood volume.
Another important consideration in HD treatment of a child
with AKI or CKD is the choice of a dialysis membrane. Several
studies in adults have shown that cuprophane membranes
are bioincompatible and activate complement and PMNs to
degranulate, produce reactive oxygen molecules, and initiate
the generation of proinflammatory cytokines.132-134 The generation of these toxic products results in additional systemic
and renal injury, potentially prolonging the course of AKI and
605
Hemofiltration
Renal replacement therapy for AKI with hemofiltration
including continuous venovenous hemofiltration (CVVH), or
with the addition of a dialysis circuit to the hemofilter, known
as continuous venovenous hemodiafiltration (CVVHD),
has become increasingly popular for the treatment of AKI
during childhood.107,135-139 Hemofiltration without dialysis
(CVVH) follows the principle of removal of large quantities
of ultrafiltrate from plasma and their replacement with an
isosmotic electrolyte solution; hemofiltration with dialysis
(CVVHD) also results in solute removal via the added dialysis
circuit.
The advantages of hemofiltration (with or without a dialysis circuit) are that it can result in rapid fluid removal, that
it does not require the patient to be hemodynamically stable
when a pump is inserted into the circuit, and that it is continuous, avoiding the rapid solute and fluid shifts that occur in
hemodialysis. The disadvantages are that hemofiltration may
require constant heparinization and that there is a potential
for severe fluid and electrolyte abnormalities owing to the
large volume of fluid removed and subsequently replaced.
Hemofiltration is typically used in children who are hemodynamically unstable, have multiorgan dysfunction, and require
pressor support; therefore, it is not surprising that the survival
of children with AKI treated with hemofiltration is less than
with other modalities.135-142
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
47
chapter
607
Malignancy
Adults
Children
Indication
Indication
Diabetes
27.1
Agenesis/dysplasia
15.9
Glomerular disease
21.5
Obstructive uropathy
15.8
Hypertension
21.4
Focal segmental
sclerosis
11.7
11.4
9.3
Adapted from the 2005 Annual Report of the OPTN and the 2006 Annual
Report of NAPRTCS.
Table 47-3 Chronic Kidney Disease (CKD) Stages and Glomerular Filtration Rate (GFR) in Children
Panel A: National Kidney Foundation Kidney Disease Outcome Quality Initiative Classification of the Stages of CKD
GFR (mL/min/1.73 m2)
Stage
Description
Action Plan*
90
60-89
30-59
15-29
Kidney failure
*The
actions that are listed in the more severe stages of CKD also include actions from less severe stages.
41 15
66 25
96 22
133 27
13-21 yr (boys)
140 30
13-21 yr (girls)
126 22
Equation
CCr (mL/min/1.73m2) =
CCr, creatinine clearance; SCr, serum creatinine. In the Schwartz equation, the constant to be used in young children (<1 year old) is 0.45; in adolescent boys, the
value of the constant changes to 0.7. To convert serum creatinine in mol/L to mg/dL, the value in mol/L is multiplied by 0.0113.
Adapted from Hogg RJ, Furth S, Lemley KV, et al. National Kidney Foundations Kidney Disease Outcomes Quality Initiative. National Kidney Foundations
Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and
stratification. Pediatrics. 2003;111(6Pt 1):1416-1421.
608
part
VII: Nephrourology
Urologic Aspects
The potentially devastating adverse influences of uremia on
the developing child have important implications for the pediatric urologist, who is often the first specialist involved in the
management of young children with severe renal injury. Early
intervention is essential to maximize the outcomes. Delays and
errors in early management are particularly detrimental. The
pediatric urologist should vigilantly monitor patients at risk
for ESRD for evidence of deterioration of renal function and for
growth retardation, developmental delay, anemia, acidosis, and
hypertension. Early recognition of the onset of significant renal
insufficiency is essential, with prompt involvement of the pediatric nephrologist and attention directed at nutrition, correction
of acidosis, maintenance of red blood cell mass (erythropoietin), stabilization of bone density (vitamin D), maximization of
growth (rhGH), control of hypertension and proteinuria, and
application of dialysis when indicated. Additionally, aggressive urologic intervention is indicated to maximize the extent
and duration of the contribution of native renal function. Interventions should be designed to minimize adverse affects on
subsequent dialysis and transplantation management.
Perhaps the greatest impediment to the development of
organized pediatric ESRD care and particularly to pediatric
renal transplantation has been the reluctance to recognize
the tremendous differences between children and adults.12,13
In addition to the relative urgency of attaining an allograft
with respect to such considerations as growth and neurologic
development, the etiology of ESRD is dramatically different in
that approximately 30% of pediatric patients have significant
urologic concerns (see Table 47-2).33 Also, many children with
such entities as renal dysplasia have significant underlying
bladder dysfunction pertinent to the pediatric urologist.
There has been a tendency to take a fatalistic view of urologic
intervention in children whose primary urologic disease is complicated by renal insufficiency. Although it is true that the ultimate incidence of ESRD may not be altered, early intervention
may enable the adverse effects of uremia on growth and
development to be positively affected, allowing the onset
of dialysis and transplantation to be delayed. This delay is
important because these modalities may be applied more
safely and successfully in older children.
Elevated bladder pressures have an adverse impact on
upper urinary tract integrity.11 Detrusor instability and detrusor-sphincter dyssynergy increase the risk of UTI, vesicoureteral reflux (VUR),34 and failure of antireflux surgery.35
Conversely, treatment with oxybutynin to decrease intravesical pressure has the potential to reduce the incidence of
UTI and VUR.36 Upper tract deterioration in children with
neurogenic bladder has been shown to be correlated with
intravesical pressures exceeding 40 cm H2O.37,38 In the setting of chronic retention, renal pelvic and bladder pressures
closely correspond even in the absence of VUR,39 and the
critical pressure of 40 cm H2O correlates the onset of renal
papillary morphologic distortion with the onset of intrarenal
reflux of urine.40 Additionally, an association between infravesical obstruction, intravesical pressure, and renal injury
may be inferred from the protective influences of pop-off
mechanisms occasionally encountered in infants with posterior urethral valves.41
Some series have documented diminished survival and
function of renal allografts after transplantation into the valve
bladder.42,43 That this association is not simply due to the presence of an irregular distorted bladder with stasis is suggested
by the observation that kidneys transplanted into EagleBarrett (prune-belly) syndrome bladders did not experience a
similar reduction in allograft survival or function.44 Our renal
allograft survival data are comparable between patients with
a valve bladder and a control group of ESRD patients with no
voiding dysfunction.45
The critical pathophysiologic interrelationship between the
dysfunctional bladder and the sequelae of renal deterioration
is perhaps best illustrated by the management of an infant
with posterior urethral valves. Although this interrelationship
is postulated, it has been difficult to accumulate data that
show an influence of bladder management on subsequent
growth and development. This is due primarily to the length
of follow-up required and the absence of controlled series. It
is possible, however, to infer an influence based on urinary
chapter
609
1.0
1.25
1.5
Height delta Z
Height Z score
1.00
2.0
0.75
01
25
6 12
12
0.50
0.25
0.00
2.5
1987
1990
1993
1996
1999
2002
2005
0.25
0
1
2
3
4
5
Years
Year
B
Figure 47-1 Height z score of children at the time of transplantation by transplant year (A) and change in z score after transplantation by age
group (B). Height z scores are calculated by dividing the difference between the patients height and the 50th height percentile for the patients
age by the standard deviation of height for the patients age. (From the 2006 NAPRTCS Annual Report.)
18 Patients
Dx 1 year
p 0.012
All 25
patients
p 0.004
SD) (%)
75
50
25
17 n
No diversion
12 n
Diversion
These data do not show that urinary diversion is superior to management methods that do not include diversion
because huge advances in infant valve bladder management
have developed since the 1970s. Although the number of
patients is small, these data strongly suggest that an ultimate improvement in clinical outcome may be attained by
early, aggressive attention to maintaining safe intravesical
pressureseven in patients whose renal injury is sufficient
ultimately to result in ESRD. Such patients must be conceptualized and managed according to established urodynamic
principles. Critical parameters include compliance (pressure
and volume), postvoid residual (PVR), voiding pressure, and
leak point pressure. An important clinical urodynamic parameter is urinary output volume. This factor is often overlooked,
but can become crucial in an azotemic child with a high urine
volume owing to a concentrating defect.
Another consideration favoring aggressive urologic management of the valve bladder is the maturation of bladder
function that may spontaneously occur with age. Figure 47-3
shows the effect of age on bladder compliance in the ESRD
valve bladder. It is evident that the valve bladder in a young
child is generally operating at high pressure and low compliance. In contrast, an older child tends to have a larger capacity,
low-pressure bladder that may require intermittent catheterization to empty. As the patient develops from a high pressure
bladder to myogenic failure, a period of balanced voiding
may be achieved. Urinary diversion by cutaneous vesicostomy or cutaneous ureterostomy or pyelostomy has no effect
on this maturation process, having no discernible negative
impact on the ultimate capacity or compliance. Consequently,
it is unusual to encounter an ESRD valve patient older than
5 years who has required augmentation. Younger valve
patients have occasionally required pretransplantation augmentation. The ability to defer transplantation by maintaining
native renal function can simplify care significantly, and avoid
the potential complications of augmentation in this challenging setting.
Figure 47-4 illustrates a physiologic approach to a patient
with threatened or injured upper tracts and a dysfunctional
bladder, such as is seen with the posterior urethral valve bladdereven after effective fulguration of valve tissue. A typical
pressure-volume relationship is shown (curve a). The exact
portion of the curve at which the patient is operative depends
610
part
3.0
VII: Nephrourology
7.8
PVR
155
(mL)
Previously diverted
Never diverted
Serum
creat.
(mg/dL)
2.9
3.2
2.0
Clinical
events
1.0
40 cm H2O/exp. cap. for age
Dialysis
0.8
14
1.1
1.4
L. nephrectomy
Mitrofanoff closure
of vesicostomy
Bilateral
hydronephr.
polyuria
vesicostomy
20
Diverted
R. nephrectomy
LRD transplant
CAPD
Mitrofanoff
excised
Time (years)
5
10
15
20
80
i.v.v.
PVR
i.v.v.
PVR
40
a.
b.
i.v.v.
c.
Bladder volume (mL)
functional bladder associated with renal injury (see text). i.v.v., incremental voided volume; PVR, postvoid residual.
on the PVR, the urinary output (mL/hr), and the elapsed time
between voids. During the filling phase, pressure increases
with volume until a threshold pressure is attained that risks
renal injury (shaded area). Voiding results in an abrupt and detrimental increase in pressure. The incremental voided volume
(i.v.v.) is indicated by the horizontal double arrow, which for purposes of illustration is held constant. The incremental voided
volume is determined by the elapsed time between voiding
(or catheterization) and by the urine output. The effective PVR
is determined by the bladders ability to empty and by reflux,
which displaces bladder volume (during filling and voiding)
into the upper tracts. On completion of voiding, this urine
immediately returns to the bladder.
The compliance curve may be altered medically by the
administration of oxybutynin chloride or surgically by bladder augmentation (curve b). The detrusor pressure may be
dramatically reduced for a given intravesical volume. This
intervention may also result in an increase in the PVR, however. Consequently, although the working pressure range is
improved, it is still deleterious. Voiding results in a further
increase in detrusor pressure. The pressure characteristics
can be dramatically improved by the addition of intermittent
catheterization (curve c). Here, the PVR is eliminated, as is the
incremental voiding pressure. The risk of infection is lessened,
and the pressure curve is entirely within the safe range. In an
older and compliant child, a less dramatic but often totally
satisfactory improvement can be obtained by frequent timed
double voiding. Approximating a satisfactory working pressure range (curve c) allows a maximal duration of significant
native renal function, delays ESRD, potentially reduces the
developmental sequelae of uremia, and ensures a safe receptacle for the allograft ureter when transplantation is needed.
A fixed, high urine output from a concentrating defect can
have an extremely detrimental effect on the bladder. Figure 47-5
illustrates the clinical course of a boy with ESRD from cystinosis. His bladder was gradually distorted because he could not
empty his bladder frequently enough to compensate for his
polyuria, resulting in progressive enlargement and ultimate
decompensation of his bladder and, subsequently, hydronephrosis. Ultimately, he could not empty his large, flaccid
bladder. Intermittent catheterization was initiated, which he
did not tolerate, and a vesicostomy was performed. He was
referred for transplantation, at which point the vesicostomy
was closed, the left kidney was removed, and the ureter was
employed to create a Mitrofanoff neourethra. He subsequently
underwent native nephrectomy and renal transplantation.
His bladder function progressively normalized, intermittent
catheterization was discontinued, and his Mitrofanoff neourethra was removed. This pathophysiology is operative to some
extent in a significant percentage of pediatric ESRD patients.
In addition to maintaining as much native renal function
as possible, modern bladder management has the potential to
delay the need for dialysis and transplantation. This delay may
significantly improve the success of both of these treatment
modalities. It is imperative from the inception of urologic care
that management be tailored to minimize any potential detrimental influence on subsequent dialysis and transplantation.
chapter
Ureteral
Mitrofanoff
stoma
Figure 47-6 Retroperitoneal creation of a ureteral Mitrofanoff conduit. A, Ureter is mobilized with preservation of the adjacent vascular
supply. Nephrectomy is performed (dorsal lumbotomy or flank incision). B, Detrusor incision is made, and a mucosal trough is developed. C, Detrusor flaps are approximated over the ureter. D, Final
position of the Mitrofanoff stoma does not interfere with subsequent
transplantation.
A key element in surgical care is preservation of the peritoneal cavity to allow effective peritoneal dialysis. An effort
should be made to avoid transperitoneal surgery, which may
prevent effective exchange of dialysate secondary to adhesions. In some instances, serosal changes can prevent effective ultrafiltration and obviate peritoneal dialysis even in the
face of what would seem to be adequate volume exchanges.
Consequently, an attempt is made to stabilize the urinary tract
through pharmacotherapy, intermittent catheterization, and, if
necessary, extraperitoneal surgery.
In selected circumstances, bladder augmentation in the
form of autoaugmentation or ureterocystoplasty can be performed extraperitoneally, as can the creation of a ureteral
Mitrofanoff neourethra (Fig. 47-6). These options should
always be considered. If transperitoneal reconstruction is
required before transplantation, this should be done when
the patient is otherwise ready for wait-listing or 6 to 12 weeks
before scheduled living donor transplantation.47 The patient
is maintained on hemodialysis in the interval. In exceptional
instances, in which sufficient recoverable renal function seems
to be present to defer dialysis, medical management fails, and
extraperitoneal reconstructive options are unavailable, extraperitoneal urinary diversion (e.g., cutaneous ureterostomy
or cutaneous pyelostomy) should be strongly considered.
Additionally, nephrectomy can readily be performed extraperitoneally through a flank or dorsal lumbotomy approach
when indicated. The extent of surgical rehabilitation feasible
before transplantation is exemplified in Figure 47-7.
Another important consideration regarding augmentation relates to solute transfer and acid-base abnormalities.
The metabolic effects of augmentation have been previously
reviewed in detail.11 These effects may be particularly problematic in ESRD when the kidneys are incapable of compensating for solute absorption or loss across the augmenting
segment. The resultant abnormalities include acidosis and
611
612
part
VII: Nephrourology
End-stage
hydronephrotic
kidneys
Gastrostomy
Ureterostomy
Colostomy
Mucous fistula
Vesicostomy
Rectourethral
fistula
Neurogenic bladder
B
Bilateral native
nephroureterectomy
Gastric closure
Colostomy closure
Mitrofanoff
neourethra
Renal allograft
Gastrocystoplasty
PSARP
chapter
613
Urologic Aspects
As outlined in Figure 47-9, the transplantation process is almost
overwhelmingly complex and potentially error-prone. In addition to care provided by the transplantation surgeon and the
nephrologist, the process is heavily influenced by the involvement of primary care physicians and urologic surgeons, and
by the organ procurement agency and laboratory personnel.
The transplantation physician may be placed at a tremendous
disadvantage as a consequence of previous suboptimal recipient care or as a result of problems created by physicians caring
for the donor before death and organ procurement surgeons
and registry or laboratory personnel. When complications are
averted or managed successfully, however, good long-term
patient and allograft survival are achievable (see later).
In some instances, a preemptive, as opposed to interventional, approach may be considered. The advantages to
preemptive transplantation, in which the patient receives a
transplant before the institution of dialysis, are the avoidance of the morbidity and psychological impact of profound
renal insufficiency, dialysis access surgery, and dialysis itself.
Although the concern that avoidance of the dialysis experience may adversely affect the childs motivation to care for the
allograft has been raised in the past, more recent NAPRTCS
data show a significant allograft survival advantage with preemptive transplantation.64 There are probably several reasons
for the better outcomes of preemptive kidney transplantation
compared with transplantation after initiation of long-term
dialysis.65
When accepted as a transplantation candidate, the recipient
undergoes careful preparation. The critical concerns regarding
the maximization of growth; nutrition; red blood cell mass;
acid-base, electrolyte, cardiovascular, and volume parameters;
and immunization status66 have been previously discussed.
Optimization of the urinary tract, which serves as the receptacle for the future allograft, is equally important. Table 47-4
outlines the basic evaluation of the recipient; Figure 47-10
depicts the pretransplantation recipient evaluation from a
urologic perspective. Basic to this process is the understanding that the adverse effect of a dysfunctional bladder on
an allograft can be overwhelming, that surgical correction
614
part
VII: Nephrourology
Antenatal
renal/bladder
injury
Pre-procurement
injury
Bladder
injury
FT
GRA
ALLO
ESRDspecific
injury
NT
PATIE
Postnatal
compromise
Organ
procurement
injury
Systemic
disease
Organ
preservation
injury
Injury at
transplantation
TRANSPLANTATION
Immunosuppressive
injury
Nonimmune
injury
Infection
Malignancy
PATIENT
Rejection
ALLOGRAFT
Renal
insufficiency
Acute
tubular
necrosis
Drug
toxicity
Disability
Urodynamic injury
Death
Allograft loss
chapter
615
Varicella-zoster virus
Immunization status
Epstein-Barr virus
HIV test
Laboratory tests
Immunologic tests
HLA-A, HLA-B, and HLA-C typing
HLA-DR typing
Interval screening
Uric acid
Radiologic examination
Renal ultrasonography
Crossmatching
Chest radiography
Microbiologic tests
Urine culture
Rapid plasma reagin test
Mantoux test
Virology titers
Cytomegalovirus
Herpes simplex virus
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part
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PEDIATRIC
TRANSPLANT CANDIDATE
Pre-oliguria/polyuria
voiding history
Physical exam
Routine
screening
antegrade continence enema; CMG, cystometrography; EMG, electromyography; FUD, formal urodynamic testing; LPP, leak point pressure; PVR, postvoid residual; SLPP, stress leak point pressure; UA,
urinalysis; UC, urine culture; VCUGR, radiographic voiding cystoure
thrography.
Native Nephrectomy
Urinary undiversion
Selective
investigation
Trial of medical
therapy
Pretransplant
urinary reconstruction
Continent, compliant,
sterile, evacuatable
reservoir
chapter
617
Gastrocystoplasty has proved highly applicable to the transplantation setting, avoids the risk of acidosis and calculi, and
markedly reduces the incidence of significant bacteriuria
and mucus production. Ureteral and Mitrofanoff neourethral
implantation are readily performed. The hematuria-dysuria
complex is occasionally encountered, particularly during
highly oliguric or anuric periods while the patient awaits
transplantation. It is generally readily controlled by bladder
cycling, histamine blockade, or proton-pump inhibition.
Whenever possible, allograft ureteral implantation should
be accomplished into the native component of the augmented
bladder97 or into a gastrocystoplasty segment to reduce the
risk of ureteral complications. If a nonreconstructable bladder
is encountered, an intestinal conduit or continent diversion
may be applicable.98 The risks of technical and infectious
complications are sufficiently high, however, to obviate their
use unless native bladder rehabilitation is impossible.97,99 An
isotopic neourethra and bladder, when applicable, provide an
excellent alternative (Fig. 47-12).100
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part
VII: Nephrourology
60
40
Percentage
Percentage
30
20
40
20
10
15
50
20
LRD
CAD
Donor source
60
Percentage
30
20
Follow-up
Range: 2151 months
Mean: 42.3 months
40
20
10
Yes
No
DFG
Graft functioning at report
40
1 Ureterocystoplasty performed
at the time of transplantation.
2 Gastrocystoplasties and
3 ileocystoplasties performed
after transplantation.
30
Percentage
80
40
Percentage
6 10 1115 16 20
Age of patient (years)
20
10
G
C
IC
U
Type of augmentation
SM
The preservation fluid constituents are designed to minimize the injury associated with hypothermia and hypoxia,
and represent some of the most pivotal work in transplantation science. The principal active ingredients of the two
most prevalent solutions are outlined in Table 47-8.103,104 A
significant benefit in delayed graft function and 1-year graft
survival favoring University of Wisconsin solution over
EuroCollins solution has been shown.106 The osmotic swelling and sodium pump paralysis associated with hypothermia
are compensated by the elimination or reduction of chloride,
whose intracellular shift facilitates osmotic edema, in favor
of impermeable ionic agents such as phosphate, sulfate, and
lactobionate. Osmotic impermeants, such as lactobionate,
chapter
619
Advantages
Disadvantages
Applications
None
Whenever possible
Autoaugmentation
No metabolic consequences
May be performed
extraperitoneally
Risk of perforation
No metabolic consequences
May be performed
extraperitoneally
Seromuscular augmentation
No metabolic consequences
Ileocystoplasty
Technically simple
Stomach unavailable
Stomach unavailable
Hematuria or dysuria
Wide application
Ureteral or MNU
implantation readily
performed
Rare alkalosis
Colocystoplasty
Technically simple
Ureteral or MNU
implantation possible
Gastrocystoplasty
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part
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Gastric closure
Donor Candidate
Right gastroepiploic
vascular pedicle
Gastric
neobladder
Respiratory tests
Graft
Appendiceal or
ureteral blood supply
Appendix or
ureter
Figure 47-12 Total anatomic urinary replacement with renal transplantation. An isotopic neobladder is constructed from a segment of
stomach or a composite of stomach and small bowel. An isotopic neourethra is constructed from appendix, ureter, or tubularized ilium and
implanted into the neobladder. After a period of healing and recovery,
a renal transplantation is performed with the ureter implanted into the
gastric component of the neobladder. (From Sheldon CA, Welch TR.
Total anatomic urinary tract replacement and renal transplantation:
a surgical strategy to correct severe genitourinary anomalies. J Pediatr
Surg. 1998;33:635.)
The long-term outcome of transplantation favors living donors (even unrelated) over well-matched grafts from
deceased donors, underscoring the critical impact of minimal
cold ischemia time and the absence of preharvesting renal
injury or disease.108 The virtual absence of delayed graft function, fewer episodes of rejection, and less accumulated exposure to immunosuppressant agents are other advantages that
are particularly important in children because survival of the
graft, level of graft function, and intensity of immunosuppression are important determinants of morbidity and mortality in
this population.111
Generally, the morbidity associated with living related donor
nephrectomy is small. Elevated systolic pressure, proteinuria,
and a reduced glomerular filtration rate have been documented decades after donation.109 Progression to significant
hypertension or symptomatic renal disease after nephrectomy
has proved to be rare, however.109,112 Table 47-9 outlines the
clinical evaluation and selection criteria for the proposed living
renal donor. This evaluation or parts of it should be repeated
as needed if the intended transplant is postponed significantly.
Donor nephrectomy is performed simultaneously with
the surgical exposure of the recipient. Historically, live donor
nephrectomy has been performed through an extended flank
incision, which enables excellent retroperitoneal exposure of
the renal hilar vessels and the ureter. In the last few years, the
popularity of laparoscopic donor nephrectomy has increased
EuroCollins
NA+
9.3
K+
107
Cl
14
HCO3
9.3
PO42
93
K+
University
of Wisconsin
lactobionate
100
KH2PO4
25
MgSO4
Glucose
182
Raffinose
30
50
Glutathione
Adenosine
Insulin (mg/L)
40
Dexamethasone (mg/L)
pH
7.0
7.4
Osmolarity (mOsm/L)
325
320
Modified from Ryckman FC. Organ donation, procurement and preservation. In: Oldham KT, Colombani PM, Foglia RP, eds. Surgery of Infants and
Children: Scientific Principles and Practice. Philadelphia: Lippincott-Raven;
1997:701.
100
100
90
90
80
80
chapter
70
60
50
0 1
25
612
12
40
30
70
60
50
0 1
25
612
12
40
3
Years
30
621
3
Years
Figure 47-13 Current deceased (A) and living donor (B) 6-year graft survival rates by recipient age groups. Note the inferior early outcomes in
infants receiving a transplant from a deceased donor, and the attenuated long-term success rates in teenage recipients. (From the 2006 NAPRTCS
Annual Report.)
Table 47-9 Evaluation of Living Donor Candidate
Evaluation
Exclusion Criteria
Initial Screening
Histocompatibility: ABO typing; crossmatching; tissue typing
Psychosocial evaluation
Positive test
Secondary Screening
Laboratory studies: complete blood cell count; prothrombin time;
partial thromboplastin time; fasting glucose level; electrolyte, liver
enzyme, fasting cholesterol, calcium, phosphorus, albumin, total
protein, uric acid levels
Chest radiograph
Malignancy
Malignancy
Tertiary Screening
Family history of diabetes or borderline fasting glucose level; 2-hr
postprandial glucose level; glycosylated hemoglobin level; oral
glucose tolerance test
Diabetes mellitus
622
part
VII: Nephrourology
considerably. This enthusiasm is fed by the safety and efficacy of the procedure comparable to the open technique with
attractive benefits for the patient during convalescence. The
less morbid approach leads to less postoperative pain and a
quicker return to normal activities, and has been reported to
increase the number of donations.113,114 More recent data suggest, however, that small pediatric recipients of adult kidneys
removed laparoscopically may be at risk for inferior outcomes
(i.e., delayed graft function and early rejection).115 A relatively
low threshold for open donor nephrectomy in these situations
seems advisable until more data are available.116
The laparoscopic donor nephrectomy procedure has been
well described because laparoscopic techniques are commonplace in surgical practice. Antiembolism sequential
compression stockings are placed, and the patient is placed
in a modified flank position. The abdomen is insufflated
with carbon dioxide, and four transperitoneal laparoscopic
ports are placed. Access to the retroperitoneum is obtained
by reflecting the colon after incising the line of Toldt. The left
kidney is gently mobilized, taking care to avoid excessive dissection of the lower pole, which could interfere with ureteral
blood supply, and the hilar vessels are dissected to their junction with the aorta or vena cava. The ureter is mobilized with
a generous cuff of retroperitoneal adipose tissue to maximize
its vascularity.
When the recipient room is ready, the ureter is clipped and
divided at the level of the iliac vessels, leaving the proximal
end open. Good urine output is documented from the divided
ureter and the indwelling urethral catheter. The renal artery
and vein are sequentially ligated with a stapler, the vessels
are divided, and the kidney is extracted from the Pfannenstiel
incision. The kidney is immediately flushed with cold preservation solution, placed in saline ice slush, and delivered to the
adjacent recipient room. Hand-assisted laparoscopy also has
been described for donor nephrectomy with similarly successful outcomes.114
RENAL TRANSPLANTATION
Establishment of Compatibility
The first consideration regarding compatibility concerns the
blood group antigen (ABO) system.117 The blood group polysaccharides are expressed on the endothelium of the allograft,
and the presence of preformed antibodies results in hyperacute
rejection when incompatibility is present in a fashion analogous to that of hemolytic blood transfusion reactions. These
antigens are not genetically linked to HLA, and even in the
presence of HLA identity, ABO incompatibility may be encountered. To avoid further disadvantaging group O recipients,
who tend to have a long wait for deceased donor allografts,118
organ procurement agencies have generally restricted the use
of organs from deceased donors with blood group O to group
O recipients. Living donor compatibility is managed in a fashion analogous to that of blood transfusion as regards the ABO
blood group antigens. Blood group D (Rh) has traditionally
not been considered to be a clinically relevant histocompatibility barrier in renal transplantation.117 Studies published in
1998 have shown on multivariate analysis an adverse impact
of Rh incompatibility, however, on long-term graft survival.119
Occasionally, the urgency of attaining a graft may influence
such evaluation. This is particularly true in a patient with
compromised dialysis access potential, which, as previously
noted, may be particularly problematic in a young child with
ESRD who has received urinary reconstruction. Attention has
been directed at transplantation across the group Aantigen
barrier in the specific setting of the group A2antigen subset,
chapter
623
Transplantation Process
As mentioned previously, recipients entering the operating
room for a kidney transplant should be in their best possible
medical condition. Children on dialysis may undergo hemodialysis on the day or peritoneal dialysis the night before their
transplant for metabolic control (e.g., to reduce serum concentrations of potassium or blood urea nitrogen), but they should
be relatively volume-loaded to facilitate adequate perfusion of
the new allograft.138 Dialysis immediately before transplantation should be performed with an adjusted ultrafiltration
goal, possibly requiring an increase in antihypertensive drug
therapy to compensate for this adjustment. If hemodialysis is
required on the day of transplantation, anticoagulation should
also be used sparingly, or not at all, to avoid an increased risk
of bleeding during surgery.
The transplantation process begins with the induction of
general endotracheal anesthesia. The patient is positioned
supine, a catheter is positioned in the bladder, and the bladder
is inflated under gravity flow with an antibacterial solution.
Central venous access is obtained for purposes of fluid monitoring and medication administration. Rarely, a pulmonary
arterial catheter is placed if indicated by primary pulmonary
or cardiac disease. A second-generation cephalosporin is
administered, and intravenous hydration is undertaken. Red
blood cell mass is expanded if indicated by a severely low
hemoglobin level.
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part
VII: Nephrourology
a natomy (see text). (Adapted from Sheldon CA, Martin LW, Churchill
BM. Surgical perspectives in pediatric renal transplantation. In: Gillenwater JY, Grayhack JT, Howards SS, Duckett JW, eds. Adult and
Pediatric Urology. Chicago: Year Book Medical Publishers; 1995.)
Postoperative Care
In addition to general perioperative care, which may require
efforts at circulatory, respiratory, and nutritional support,
postoperative care of the transplant recipient includes
chapter
625
Bladder neck
Caudal
Cephalad
Spatulated
donor ureter
Detrusor
Uroepithelium
B
D
immunosuppression
protocol of the Childrens Hospital/Medical Center of
Cincinnati. Generally, immunosuppressive therapy is in
constant evolution to achieve the best possible antirejection prophylaxis without an unacceptably high incidence of
overimmunosuppression or other drug-related toxicities.142
In this context, immunosuppressive protocols cannot be
administered in a one-size-fits-all fashion: First-time white
recipients of a living donor kidney who have no evidence of
presensitization seem to require less powerful antirejection
prophylaxis than recipients of a repeat transplant, especially one from a deceased donor recipient with evidence of
presensitization or recipients who are African-American.143
Additionally, the more recent discovery of genetic polymorphisms and related phenomena affecting drug metabolism
and exposure,144,145 and immunologic responsiveness146 further undermines the concept of a unified immunosuppressive approach.
It likely behooves transplant programs to adapt flexible
immunosuppression protocols that can be tailored to each
recipients perceived risk profile. Theoretically, the development of such protocols is augmented by sufficiently powered multicenter studies, but in view of the small number of
pediatric kidney transplants performed at any given time,
and given the increasing number of drugs and drug combinations available, such studies are difficult to set up and
perform. Additional guidance in the selection of pediatric
626
part
VII: Nephrourology
Induction*
Maintenance
Tapered steroids
Calcineurin inhibitor
(tacrolimus)
Mycophenolate mofetil
*Weeks/months
post-transplant.
An inhibitor of the mammalian target of rapamycin, such as sirolimus
(rapamycin) or everolimus, can be added or substituted for any one of the
three maintenance agents based on center practice.
the transplant is to be salvaged. Many centers perform a Doppler ultrasound evaluation or a nuclear scan of the transplant
immediately after skin closure or on arrival in the postoperative care unit, at least if there is no sufficient urine output
attributable to the transplant. Along these lines, many recipients still have their native, often urine-producing, kidneys at
the time of transplantation, making interpretation of urine
output immediately after transplantation sometimes challenging. If blood flow to the transplant is adequate, acute tubular
necrosis should be suspected as an alternative cause of initial
nonfunction, especially in deceased donor transplants. In
recipients who are not at particularly increased immunologic
risk, hyperacute rejection is unlikely. Lastly, the possibility of
complete urinary tract obstruction needs to be excluded by
ultrasound in this scenario.
In grafts with initially acceptable urine production, but a
subsequent decrease in output, additional possibilities need
to be considered, including low intravascular volume, rejection, and acute calcineurin inhibitor toxicity. Low intravascular volume can be diagnosed if a fluid challenge sufficient
to increase central venous pressure results in restitution of
adequate diuresis, and acute calcineurin inhibitor toxicity is
indicated by elevated trough levels (e.g., tacrolimus concentrations >15 to 20 ng/mL). Early rejection can be difficult to
diagnose because its recognition usually requires a kidney
biopsy, which may be risky in a fresh transplant. Different
types of rejection may need to be distinguished because they
require different therapeutic responses. Especially in presensitized recipients, acute rejection not only can be cellular
but also antibody-mediated (i.e., humoral), necessitating
the initiation of plasmapheresis and potentially other specific therapeutic measures instead of treatment for cellular
rejection, which consists of steroid pulses or the application
of depleting antiT cell antibody products. Cellular and
humoral rejection can coexist, and the recognition of humoral
rejection requires special studies on the biopsy material (i.e.,
staining for C4d) and the blood (i.e., identification of antidonor antibody).154
Additional complications resulting in early impairment of
graft function are thrombosis of the renal vein or one of its
major branches, obstruction of urine flow (e.g., by a blood
clot), and urinary leakage (e.g., from an unsatisfactory ureteral
anastomosis). Ultrasound and nuclear scan are useful tools to
identify these problems.
chapter
627
LIVING DONOR
100
19871990
19911994
19951998
19992002
20032005
100
80
60
Percentage rejection
Percentage rejection
80
DECEASED DONOR
40
20
60
40
1987 1990
1991 1994
1995 1998
1999 2002
2003 2005
20
12
24
36
48
12
24
36
48
B
Months
Months
Figure 47-17 Time to first rejection by transplant era and allograft source (A, living donor; B, deceased donor). Note that most rejection episodes
occur in the first post-transplant year. (From the 2006 NAPRTCS Annual Report.)
SURGICAL COMPLICATIONS
OF TRANSPLANTATION
The incidence of surgically significant renal transplantation
complications, as encountered in four large pediatric series,
is diagrammed in Figure 47-18.164-167 Technical complications occurred in 13% of transplantation procedures, of which
628
part
VII: Nephrourology
Table 47-11 One-Year Graft Survival and Acute Rejection Rate by Graft Source and Transplant Era
Panel A: Percent 1-Year Graft Survival by Donor Source and Annual Cohort Groups
Transplant Year
1987-1990
89.4
75.2
1991-1994
91.7
85.2
1995-1998
94
90.5
1999-2005
95.4
93.7
Deceased Donor
Transplant Year
SE
SE
1987-1990
54.2
1.7
69.1
1.5
1991-1994
44.8
1.5
60.6
1.6
1995-1998
33.4
1.4
40.8
1.7
1999-2002
22.6
1.3
26.8
1.9
2003-2005
13.2
1.9
15.8
2.3
Extracorporeal shock wave lithotripsy has been used effectively in the allograft,175 and endourologic approaches have
proved useful for urolithiasis and other upper tract urologic
complications.176
The significance of VUR has been controversial. When
VUR was detected by routine post-transplantation screening, no statistical significance in the survival of patients
or grafts was shown for adults177 or children.178 The adult
series had no patients with greater than grade III reflux,
however, and all patients with greater than grade III reflux
in the pediatric series received antireflux reconstruction. In
most cases, reflux is detected because of a clinical event.
Decreasing allograft function may prompt an ultrasound
examination that shows hydronephrosis, suggesting the possibility of reflux. Alternatively, pyelonephritis or recurrent
UTI prompts a study. It would seem reasonable that dilating reflux into a previously nondilated collecting system,
when ureterovesical junction obstruction has been excluded,
should be considered clinically significant. Most often, the
underlying problem is occult or incompletely managed bladder dysfunction, and the reflux is controllable by management directed at the bladder. Dilating reflux associated with
nonimmune allograft injury or infection (particularly pyelonephritis) in the absence of a dysfunctional bladder should
be considered for correction. Dilating reflux in young recipients is associated with a definite risk of pyelonephritis and
subsequent allograft injury.179 VUR also has been implicated
as a significant etiologic factor for hypertension on long-term
follow-up.180
chapter
Total
Total
Series
Total
Percentage
4
Extrav.
Technical
Stenosis
U. Obstr.
U. Necr.
Sign.
VUR
Urologic
No. Pts.
Kalicinski (1994)
Tanabe (1998)
Sheldon (1992)
Zaontz (1988)
107
120
303
166
Total
696
Lymphocele
629
Rupture
Hemorrhage
RAT
RVT
Infection
Renovascular
Wound
Other
Rupture
Other
100
100
90
90
80
LD 1987 1994
LD 1995 2005
DD 1987 1994
DD 1995 2005
80
70
60
50
40
30
0
1
2
3
4
5
6
24
36
48
60
Years
Months
A
B
Figure 47-19 Five-year patient (A) and kidney graft (B) survival by transplant era and graft source. DD, deceased donor; LD, living donor. (From
the 2006 NAPRTCS Annual Report.)
70
12
risk factors to add up to a tremendous odds ratio for cardiovascular morbidity and mortality in children with ESRD.184,185
Malignancies currently cause slightly more than 10% of all
deaths in pediatric kidney transplant recipients (NAPRTCS
2006 Annual Report), and more than half of these malignancies are some form of PTLD.186 Many of these cases of PTLD
are driven by EBV,187 which in many cases is introduced via
an EBV-positive transplant from an adult donor into an EBVnaive immunosuppressed pediatric recipient.
Although more recently half-lives of more than 35 years
for renal allografts from living donors have been predicted
by some,188 the challenge for the future is to develop better
long-term care regimens for kidney transplant recipients with
special emphasis on the avoidance of CAN and cardiovascular disease142 and PTLD. Such optimistic half-life predictions
630
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a meaningful transition from teenage to adulthood, including transfer of transplant-related care to providers for adults.
Teenage and the transition phase into adulthood are associated with an increased incidence of adverse outcomes, at least
partly as a result of more frequent noncompliance (see Fig.
47-13).55 Better strategies to enhance compliance during these
critical stages in the life of pediatric transplant recipients are
urgently needed.
Lastly, adequate living kidney donor follow-up is required
because of their increased risk of hypertension and proteinuria several decades after donation.109 Along these lines,
efforts to standardize this follow-up and to create a donor registry are under way in the United States. Some former donors
have even lost function of their remaining kidney because of
trauma, malignancy, or kidney disease that was not apparent
at the time they donated, and these individuals are given very
high priority in the organ allocation algorithm currently in
place via the United Network for Organ Sharing.
CONCLUSION
Renal transplantation is the treatment of choice for pediatric
patients with ESRD, and is associated with excellent shortterm and medium-term outcomes, at least in recipients without
extraordinary immunologic or other risk factors. In many children receiving a kidney allograft, urologic issues are of special
importance before, during, and after transplantation because
of the comparably high incidence of urologic disease in this
age group. Important current challenges revolve around optimal long-term outcome, specifically CAN and long-term calcineurin inhibitor nephrotoxicity and other complications of
prolonged administration of immunosuppressive agents, and
compliance.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
48
UROLITHIASIS IN CHILDREN
Henri Lottmann, M. F. Gagnadoux, and M. Daudon
EPIDEMIOLOGY
Urolithiasis in children is considered uncommon in Western
countries. No recent data have assessed possible changes in
the epidemiology. The overall incidence of stones in children
was reported to be less than 2 per 1 million total populations
in Great Britain.1 In Spain, Camacho Diaz and colleagues2
observed 1 case of urolithiasis among 4500 children admitted to their pediatric hospital. Edvardsson and coworkers3
reported an annual incidence of kidney stones equal to 5.6
per 100,000 Icelandic children for the period 1995-2000. In the
United States, stone disease accounted for 1 in 7600 to 1000
hospital admissions4,5 in children. More recent reports suggest that urinary calculi are being recognized with increasing
frequency.6-9
PATHOPHYSIOLOGY
Stone Location
Stones in children are essentially located in the upper urinary
tract. Kidney stones represented 61.1% of stones in the series
reported by Gearhart and colleagues,4 61.6% of stones in a
Spanish study,2 and 58.8% of stones in our 1091 cases. Bladder
stones are currently found in only 5% to 10% of cases. Spontaneous passage of calculi, in most cases coming from the upper
urinary tract, seems to be frequent (35% to 50%), although less
than observed in adults (70% to 75%).
Stone Composition
Figure 48-1 illustrates typical calculi found in children. Differences in stone composition are noted according to the published
series. Calcium oxalate was found as the main component in
65% of cases in Germany,10 39% in Spain,2 and 26% to 65% in
the United States.4,11,12 Among 1091 pediatric stones, we found
calcium oxalate as the main component in 34.7%. Calcium
and magnesium phosphates represented 43.5% of stones in
Spain,2 whereas calcium phosphate stones represented 40.1%
of stones in our series, in which struvite was present in 287
calculi (26.3%).
Stone composition differed according to sex and age of
patients (Table 48-1). In children younger than 5 years, carbapatite was the main component, predominantly in boys.
Struvite was present in 40.8% of stones in boys and in 27.6%
in girls, but it was the main component in only 6.4% of all calculi. Calcium oxalate was significantly less frequent in boys
Infection-Induced Lithogenesis
The most common lithogenic process resulting from urinary
tract infection (UTI) involves urease-producing microorganisms. Gram-negative bacteria, such as Proteus species, are able
to hydrolyze urea, producing ammonium and carbon dioxide
and increasing urine pH and bicarbonate content.19 The main
biochemical effect is alkalinization of urine and high levels
of struvite and calcium phosphate supersaturation, which
frequently induce the crystallization of several compounds,
including struvite, carbapatite, and ammonium urate when
hyperuricosuria is present. Another consequence is the high
carbonate content of carbapatite, which is highly suggestive
of such a lithogenic process, even if struvite is not present in
631
632
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VII: Nephrourology
Figure 48-1 Typical aspect of some urinary stones found in children. Stone fragility: + (resistant) to ++++ (easy to fragment with extracorporeal shock
wave lithotripsy). A, Very large bladder endemic stone surgically removed in Laos. The stone came from a 20-year-old man. It contained ammonium
urate, calcium phosphates, and struvite. Fragility: ++++. B, Section of an endemic bladder stone surgically removed from a 7-year-old Tunisian boy. The
stone was composed of calcium oxalate monohydrate surrounding a core made of ammonium hydrogen urate. Fragility: +. C, Another section of an
endemic bladder stone from Thailand. The stone was made of a mixture of uric acid, ammonium hydrogen urate, and calcium oxalate. Fragility: +++.
D, Renal infection stones from an infant with an ureteropelvic junction stenosis. The stone composition was carbapatite mixed with struvite and amorphous carbonated calcium phosphate. Fragility: ++++. E, Pure cystine bladder stone discovered in a 3-year-old girl. Fragility: + to ++. F, Pure dihydroxyadenine stone secondary to a complete adenine phosphoribosyltransferase deficiency in a 9-year-old boy. Fragility: +++. G, Pure calcium oxalate
monohydrate from a 13-year-old child presenting with very low diuresis (0.5 L/day) and imbalanced diet including high animal protein and chocolate
intake and low dairy products. The stone morphology is Ia. Note the dark color, resulting from mainly the slow growth of the stone and fixation of urinary pigments. Fragility: +. H, Pure calcium oxalate dihydrate in a 10-year-old boy with hypercalciuria. The morphology is typical of type II, which is
the main morphologic type found in hypercalciuria. Fragility: ++++. I, Pure calcium oxalate monohydrate spontaneously passed in a 9-year-old girl with
primary hyperoxaluria type I. Note the budding surface and the very light color of the stone, which is typical of type Ic, found in heavy hyperoxaluria.
Fragility: ++.
chapter
633
Table 48-1 Main Components of Urolith According to the Sex and Age of the Patients (N = 1091)
Boys
<2 yr
(n = 241)
Ratio M/F
Phosphates
Carbapatite
4.73
2-5 yr
(n = 154)
2.85
5-10 yr
(n = 131)
Girls
10 yr
(n = 204)
<2 yr
(n = 51)
2-5 yr
(n = 54)
5-10 yr
(n = 94)
10 yr
(n = 162)
1.39
1.26
21.6a,b
60.8
31.5c
23.4a
18.5a
77.2
50.7
22.1a,b
71.8
39
15.3
14.2a
47.1f
25.9
16
14.8a
7.5
3.7d
Other calcium
phosphates
5.4
11.7
6.9
7.4
13.7
5.6
Struvite
4.2
9.1
16.8
10.3e
5.9
9.3
2.1f
4.9
27.5
27.8
9.6f
10.5d,g
41.5
39.6
30.5
15.2a,b
3.7
25.3
42.8
50a,b
9.8
37f
48.9
62.4a,g
Whewellite
(COM)
1.2
11
17.6
26.5a,h
20.4d
19.1
37.7a
Weddellite (COD)
2.5
14.3
25.2
23.5a,i
7.8
16.7
29.8d
24.7d
5.8
10.3
5.3
5.5
9.8
9.3
7.5
0.6d
Ammonium urate
3.3
8.4
2i
5.9
5.6
5.3
0.6e
Uric acid
2.5
1.3
1.5
2.5
3.9
3.7
1.1
0e
Other purines
0.6
0.8
1.1
Proteins
3.3
7.6
6.4
5.9
3.7
6.4
5.6
Cystine
1.2
1.3
1.5
3.9
9.3j
4.3
5.6
Drugs
2.1
1.5
3.2
0.6
Miscellaneous
0.8
0.8
3.9
4.3
1.9
(Presence of
struvite)
Calcium oxalates
Purines
Endemic Urolithiasis
In developing countries, pediatric urinary stone disease
occurs more commonly than in industrialized nations, with
particular patterns including bladder location, high male
preponderance, and frequency of ammonium hydrogen urate
in stones.22,23 Stones from the bladder have been reported in
Occurrence of Strains
Producing Urease (%)
90-100
32
90-100
63
Other microorganisms
Serratia marcescens
29
Staphylococcus aureus
80
Staphylococcus epidermidis
88
Corynebacterium urealyticum
100
Ureaplasma urealyticum
100
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VII: Nephrourology
100%
Other
80%
Pain
Hematuria
60%
Stone passed
40%
Proteinuria
Pyuria
20%
0
<2 yr
2 5 yr
5 17 yr
n = 33
23
35
Figure 48-2 Presenting symptoms of urolithiasis in childhood according to patient age.
endemic calculi. Phosphate supplementation and consumption of dairy products correct crystalluria and prevent stone
formation in most patients.
DIAGNOSIS
Clinical Presentation
The symptoms of urolithiasis in children differ from the symptoms observed in adults; in particular, children with stones
rarely present with typical renal colic. The presenting symptoms
vary according to the childs age.11 In infants, UTI (usually with
Proteus) and passing of stones in diapers are the usual manifestations. In young children, hematuria and pyuria are the main
symptoms, whereas in older children, abdominal pain (of various localization) and hematuria are the most frequent presenting
signs (Fig. 48-2). Urolithiasis in children is commonly discovered
by microscopic or macroscopic hematuria, and the presence of
stones must be sought in any child with isolated hematuria.
Imaging
Imaging is essential at all steps of the management of urolithiasis: diagnosis, treatment, and follow-up. The principles are
the same as in adults; however, external radiation delivered to
children should be a constant concern and limited to the strict
minimum necessary, considering that patients with urolithiasis are subject to repeated imaging procedures during treatment and follow-up.
radiograph.
chapter
635
Figure 48-4 Ultrasound shows a stone as a typical bright hyperechoic structure with an echo-free shadow behind it.
A KUB film and urinary tract ultrasound together allow an
accurate diagnosis of around 90% of urinary calculi.4,29 These
modalities also provide information about the stone (size and
number) and its composition according to its degree of opacity.
Ultrasound also provides information about the renal parenchyma and the eventual dilation of the collecting system.
An intravenous pyelogram (IVP) is the study of choice
for the very rare calculi not seen on the KUB film or
ultrasound, particularly ureteral calculi. 30 An IVP provides morphologic and functional information (Fig. 48-5).
Noncontrast-enhanced computed tomography (CT) also
can be used to diagnose renal calculi; all stones are much
more dense than any other lesion within the collecting
system,31 and each type of stone has its own density (e.g.,
cystine 100 to 300 Hounsfield units, calcium salts 400 to 600
Hounsfield units) (Fig. 48-6).32 A subsequent injection of
contrast medium can provide functional information and
allow additional IVP films to be performed to appreciate
the morphology of the collecting system.
CT scan is probably the most sensitive way to detect urinary tract calculi. Use of CT should be limited in children to
difficult cases, however, such as small and faintly opaque ureteral stones, because CT delivers significant irradiation.
At the diagnosis phase, imaging is also essential for the
pretreatment evaluation. Various parameters influence the
choice of treatment, including the characteristics of the stone,
its exact location, and underlying abnormalities of the collecting system. Functional information concerning the affected
kidney and contralateral kidney may prove to be important
for the final treatment decision.
Figure 48-5 IVP of a kidney transplant shows a stone at the ureterovesical junction.
636
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VII: Nephrourology
Figure 48-7 A, IVP shows multiple uric acid stones in the left kidney in a 6-month-old boy. B, Multiple cystine stones in a 13-year-old girl (obstructed
lower moiety on the left side). C, Struvite left pelvic stone in an 18-month-old boy. D, Calcium oxalate staghorn calculus in an 8-year-old boy.
abnormality that may require specific treatment to prevent recurrences must be recognized. It is not always easy, however, to
determine if a pelvicalyceal or ureteropyelocalyceal dilation was
primary or occurred secondary to an obstructive stone.
Functional information about the affected kidney and
contralateral kidney may also be essential in the pretreatment evaluation when the function seems so poor on IVP
that a nephrectomy is considered,33 or when evaluating the
parenchymal consequences of a treatment (e.g., ESWL or
nephrolithotomy). Radionuclide studies are the most appropriate in such situations.34
EVALUATION
The finding or the suspicion of urolithiasis in a child necessitates a comprehensive evaluation to define the causes and
consequences of renal stones.
History
In addition to preexisting diseases, all possible causative factors in the childs history must be sought, such as previous
treatment with furosemide in early life or with corticosteroids,
or prolonged immobilization or malnutrition. Familial history
is also important, as is a history of other stone formers, renal
failure, or parental consanguinity suggestive of an inherited
metabolic disorder (Table 48-3).
Dietary Information
In children, as in adults, a low urinary volume is a crucial factor
for stone development. Normal children, especially young children, rarely feel thirsty, and they often have concentrated urine.
If their diet is rich in animal proteins and salt, or if they have
a mild metabolic disorder, they may have excessive urinary
concentration of stone-promoting substances, such as calcium,
chapter
Laboratory Evaluation
Bacteriology
Urine cytobacteriology is the first step of the laboratory investigation in cases of lithiasis. Because many stones in children
are discovered secondary to UTI or hematuria, the diagnosis
of infected or infectious stones is rarely missed.
637
Crystalluria
Stone Analysis
Stone analysis is an important step in the etiologic investigation,
and is mandatory if a stone is available. The analysis should
include morphologic examination and separate identification
Table 48-3 Data Suggestive of Hereditary Disorder
Biochemical Analysis
Associated nephrocalcinosis
Associated renal symptomspolyuria, acidosis, growth
retardation, renal failure
Associated extrarenal symptoms
Frequent pH Range
<5.3
Acidic urine
5.3
Hyperuricosuria
Amorphous urates
5.2-6.0
Hyperuricosuria
Weddellite (dodecahedrons)
5-7
Hypercalciuria
Whewellite
5-7
Hyperoxaluria
Brushite
<7
Hypercalciuria hyperphosphaturia
Alkalinizing UTI
6.5
Hypercalciuria
>6.5
Struvite
6.8
6.2-6.8
>6.8
Cystine
5-7.5
Genetic cystinuria
Xanthine
5-7
2,8-Dihydroxyadenine
5-8.5
Variable
Carbapatite, ACCP
ACCP, amorphous carbonated calcium phosphate; APRT, adenine phosphoribosyltransferase; UTI, urinary tract infection.
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in Childhood
Calcium
Oxalate
Cystine
anomalies are found in 15% to 33% of children with urolithiasis.2,5,52 UPJ obstruction, megaureter, and vesicoureteral reflux
(because of secondary UTI) are the three most frequently
encountered anomalies associated with stone disease in children.11,52 As emphasized by several authors, however, anatomic anomalies are associated in 70% to 80% of cases with
metabolic disorders that are the main factors involved in stone
formation in these patients.1,5,53
Urine stasis in a neurogenic bladder or in urinary diversion is also a frequent cause of stone formation.11,54 In urinary
diversions or bladder augmentations with sigmoid colon or,
more frequently, ileal conduit, acidosis induced by bicarbonate secretion from intestinal mucosa is a factor favoring stone
formation through hypercalciuria. Other renal structural
abnormalities leading to some degree of stasis, such as medullary sponge kidney, dominant polycystic kidney disease, or
horseshoe kidney, may also be complicated by urolithiasis.
Infection-Related Stones
Infection-related stones are frequently seen in children, particularly in infants and children younger than 5 years. Among
1091 children with urolithiasis, we found that 90% of either
boys or girls younger than 5 years presented with UTI or had
a past history of UTI. In patients older than 5 years, the incidence of UTI decreased to 42% in boys and 50% in girls.
As described earlier, the role of urease-forming bacteria,
mostly Proteus, in the development of many stones is clear,
particularly as regards phosphate stones; however, it is often
difficult to determine whether a bacterial infection is the primary cause or complicates a preexisting stone, particularly
in cases of obstructive uropathy. If a stone is available, its
sequential analysis by physical methods is especially useful
in such cases. Based on stone analysis, the presence of struvite
is not the only criterion for asserting that an infection process
caused the stone. Other criteria should be considered, such
as the carbonate rate of carbapatite, the protein content, and
some other characteristics of the stone.40
Metabolic Lithiasis
Hypercalciuric Lithiasis
Urate
Citrate
Magnesium
Phosphate
Variable
Hypercalciuria is present in a child if at least two or three measures of 24-hour calcium excretion, at intervals of some weeks,
exceed 4 mg/kg (>0.1 mmol/kg). When timed urine samples
are not possible, the calcium-to-creatinine ratio may be used.
The normal limit of this ratio is much higher in infants than
in older children and adults (see Table 48-6).44-47 In addition,
Oxalate (mmol/mmol)
(mean/95th percentile)
<6 mo
0.7/2.4 (0.25/0.86)
0.14/0.36
7-12 mo
0.5/1.7 (0.2/0.6)
0.11/0.23
1-5 yr
0.4/1.1 (0.14/0.4)
0.08/0.18 (1 yr)
5-12 yr
0.35/0.7 (0.12/0.25)
chapter
639
Secondary Hypercalciuria
Hyperoxaluric Lithiasis
Among iatrogenic causes for hypercalciuria, some (e.g., vitamin D excess, high-dose steroid therapy) have almost disappeared because of better knowledge of this complication and
adequate prevention, whereas new causes have appeared.
Currently, the most frequent cause of drug-induced hypercalciuric urolithiasis in children is the prolonged use of furosemide, theophylline, or corticosteroid therapy in premature
infants.56-58 Prematurity also seems to be a risk factor for urolithiasis.58-60
Hypercalciuria may also result from nutritional causes,
such as excessive intake of calcium, or more often of proteins
and sodium, with a diet poor in potassium and phosphate.
An example of a nutritional cause of lithiasis is the ketogenic diet (high proteins/low carbohydrates) increasingly
used in refractory pediatric epilepsy, which induces hypercalciuria and hypocitraturia through acidosis.61 In cases of
long-term immobilization, hypercalciuria resulting from
excess bone resorption may cause stone formation, particularly in cases of insufficient hydration in mentally disabled
children.
Primary hyperparathyroidism is very rare in children, but
may be observed in adolescents.62 The parathyroid hormone
concentration must be checked if calcemia is increased.
Genetic Hypercalciurias
Genetic diseases that alter renal tubular reabsorption of calcium are numerous.63 The most frequent one in childhood
used to be distal tubular acidosis (Albright acidosis), in all its
genetic varieties. In this disorder of urine acidification, hypercalciuria and hypocitraturia are the consequence of blood
acidosis; in the absence of alkalizing treatment, it leads to medullary nephrocalcinosis and nephrolithiasis originating from
the papilla. Owing to earlier diagnosis and better management
of these children, the incidence of lithiasis in this disease has
decreased considerably in the last decades.
Hypercalciuria is also a major symptom of the two main
forms of neonatal Bartter syndrome, but associated polyuria
reduces the stone risk. In X-linked nephrolithiasis, or Dent
syndrome, renal stones are a major symptom in adults, but
are rarely observed in childhood. Stones may also develop
in rare diseases, such as familial hypomagnesemia with
hypercalciuria, autosomal dominant hypocalcemia, familial isolated hypoparathyroidism, Lowe syndrome, Wilson
disease, glycogen storage type I, and tyrosinemia type I.63
Among genetic diseases increasing calcium intestinal absorption, stones have been observed in hypophosphatemia due to
NPT2a gene mutation and in glucose-galactose malabsorption.63
Primary Hyperoxaluria
Primary hyperoxaluria type I (PH1), the most frequent and
most severe form of inherited hyperoxaluria,65 is an autosomal
recessive disorder of glyoxylate metabolism in the liver that
is caused by a defect in the enzyme aniline/glyoxylate aminotransferase (AGT).66 The first manifestations of the disease
usually occur in infancy or childhood as a recurrent whewellite urolithiasis or nephrocalcinosis or both.39,67 In the absence
of adequate management, end-stage renal failure ultimately
develops. Oxaluria, in children with PH1 without advanced
renal failure, frequently reaches values greater than 1 mmol/24
hours. Associated hyperglycolaturia (normal value <80 mg or
900 mol/1.73 m2/day) is present in two thirds of cases. Direct
measurement of the defective enzyme AGT through liver
biopsy or molecular diagnosis of AGTX gene mutations is possible in a few laboratories in the world.68
Primary hyperoxaluria type II, which is rarer than PH1,
results from the absence of glyoxylate reductase, which has
also a d-glycerate dehydrogenase activity. Hyperoxaluria is
associated with excessive urinary excretion of l-glyceric acid.
Diagnosis can be confirmed by measurement of glyoxylate
reductase activity in a liver biopsy specimen.69
Secondary Hyperoxaluria
The main cause of secondary hyperoxaluria in children is
enteric hyperoxaluria, which results from intestinal malabsorption of fats and bile acids that, by binding calcium, result in
increased oxalate absorption.70 This complication, which has
been described in inflammatory bowel diseases, ileal resection, and cystic fibrosis, can be avoided by adequate dietary
prescriptions. Absence of the anaerobic intestinal oxalatedegrading bacterium Oxalobacter formigenes may also play a
role in some cases of secondary hyperoxaluria, as has been
shown in cystic fibrosis patients, in whom the development of
renal stones is common.71,72
Idiopathic Hypercalciuria
When no etiology or genetic disease is found, and hypercalciuria persists despite adequate diet, hypercalciuria is
considered idiopathic. The proportion of idiopathic hypercalciurias among childhood lithiasis series decreased as several
640
part
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Cystine Lithiasis
Cystinuria is a hereditary disorder involving the transport
of cystine and other dibasic amino acids (lysine, arginine,
ornithine) through the renal proximal tubular and intestinal
epithelium. Because of the low solubility of cystine in urine,
its increased excretion results in recurrent urolithiasis, often
beginning in childhood. Type I cystinuria, caused by mutations
in the SLC3A1 gene on chromosome 2, is a recessive disease in
which the parent carriers show a normal cystine excretion. In
the nontype I form, caused by mutations in the SLC7A9 gene
on chromosome 19, heterozygotes are usually (but not always)
mildly cystinuric.74 Cystinuria accounts for 5% to 10% of cases
of pediatric urolithiasis,5,11,50,51,75 and it frequently is revealed
during infancy by pyuria, hematuria, or stone passing. Cystine stones are usually faintly radiopaque. Cystinuria must be
suspected in any child with lithiasis; before the availability of
stone analysis or crystalluria study, the diagnosis could be suspected from urinalysis indicating a positive sodium nitroprusside test (red color of sulfhydryl compounds) and had to be
confirmed by urinary amino acid chromatography and cystine
dosage (>200 mg or 0.8 mmol/1.73 m2/day, or >0.1 mmol/g
creatinine, usually approximately 1 mmol/g).
Purine Stones
Uric Acid Stones
Uric acid stones depend on acidic urine pH and hyperurico
suria. The fractional excretion of uric acid is high in newborns
and regularly declines from birth to puberty, in parallel with
a linear increase in plasma urate,76 explaining the possible
risk of uric acid stones in infants who present with tubular
immaturity or with a risk of low diuresis and acidic urine
because of diarrhea. Uric acid stones, still observed in developing countries,48,49 are currently rare in children in Western
countries.50
In acute acquired hyperuricemia secondary to cellular
lysis in myeloproliferative or lymphoproliferative syndromes,
uric acid stones may develop if adequate preventive measures of hyperhydration and alkalinization are not applied.
Among genetic disorders, hereditary renal hypouricemia, an
isolated defect of urate tubular handling owing to mutation
in the gene of tubular exchanger URAT1, may induce stones
through increased urate clearance.77 Several inborn errors
of purine metabolism result in hyperuricemia and hyperuricosuria. Hypoxanthine guanine phosphoribosyltransferase
deficiency, an X-linked disorder, is an infrequent cause of uric
acid nephropathy and stone disease in boys.78 The deficiency
may be complete (Lesch-Nyhan syndrome), or incomplete
with only gross uric acid overproduction and excretion.
Purine phosphoribosylpyrophosphate synthetase superactivity is another infrequent X-linked inherited cause of uric acid
overproduction.78
Drug-Induced Lithiasis
In children, stones made of crystallized drugs are rare because
the main drugs responsible for this complication, triamterene
and sulfadiazine, have little use at this age.79 Stones made of
ceftriaxone are common in the gallbladder, but are uncommon
in the urinary tract.80 Amorphous silica has been found in the
core of stones in some infants who received formula-thickening
powders containing silica.81 Stones made of antiproteases
(e.g., indinavir), which are frequent in adults with human
immunodeficiency virus infection,82 are very rarely observed
in children.
Idiopathic Urolithiasis
In some children, the etiologic investigation remains negative,
and stone does not recur; in these patients, stone formation was
probably caused by transitory urologic, metabolic, or dietary
factors that had already disappeared by the time of stone discovery. In such cases, stone analysis by physical methods may
be useful to identify the risk factors that were involved in stone
formation. In children with recurrent stones, it is exceptional
not to find a cause, and the diagnosis of pediatric idiopathic
lithiasis should not be accepted before a comprehensive evaluation, including stone analysis, has been made.
Nonspecific Measures
Pain Alleviation
Not all children with stones complain of pain, particularly
younger children, and when pain is present, it more frequently has an abdominal localization than typical renal colic
symptoms. Pain treatment should be adapted to the degree and
type of pain, and the use of nonsteroidal anti-inflammatory
drugs may be necessary in case of renal colic.
Anti-Infectious Treatment
Antibiotic treatment is mandatory in case of infected urine;
however, urine sterilization is often difficult to obtain as
long as numerous stones fill the urinary tract, and becomes
chapter
Etiology-Specific Measures
In many cases, treatment of the causative disease is sufficient
to prevent stone recurrence. This includes treatment of recurrent infection or of urologic abnormalities, and adequate management of acquired or genetic metabolic disorders.
Metabolic Causes
Primary Metabolic Urolithiasis
Hypercalciuria. Dietary measures should be prescribed
first. A low-calcium diet is never advisable in children. A low
calcium intake (<700 mg/1.73 m2/day) seems to increase the
risk of stone formation.83 Milk product intake that is clearly
excessive for the childs age must be reduced to a normal
amount. The reduction of sodium intake is much more efficient to decrease urinary calcium excretion, and a moderate
restriction should be prescribed, and a moderate protein restriction in children with a high appetite for meat.84 In contrast, increased potassium intake has been shown to reduce
calciuria by increasing the urinary sodium-to-potassium ratio
in hypercalciuric children.85 Dietary potassium supplementation is easy to prescribe to children.
When dietary measures fail to decrease urinary calcium to
a normal range, hydrochlorothiazide (0.5 to 1 mg/kg/day),
generally efficient in reducing calciuria, may be prescribed
with caution (regular plasma ionogram checking is needed) in
children with renal tubular leak. An advantage of hydrochlorothiazide is it increases diuresis and fluid intake.
Primary Hyperoxaluria. In primary hyperoxaluria, the
prevention of nephrocalcinosis and iterative nephrolithiasis is
crucial because it may prevent the eventual development of
end-stage renal failure.86 This prevention must be initiated as
soon as possible after birth to preclude any calcium oxalate
deposits within the kidneys.
The first measure consists of massive hyperhydration
(>3 L/m2/day); infants and young children require fluid
administration through a nasogastric tube, at least during the
night. When children with PH1 are submitted to surgical procedures or to ESWL, it is crucial to continue massive hydration
intravenously during anesthesia to avoid intrarenal oxalate
precipitation induced by dehydration.
The second treatment is pyridoxine, which is a cofactor
of glyoxylate metabolism. About 20% of patients with PH1
have a pyridoxine-sensitive enzymatic defect and experience
641
Cystinuria
The prevention of stone recurrence in children with homozygous cystinuria is a particular challenge for the pediatric
nephrologist or urologist because of the tendency toward high
recurrence and the difficulty for children to comply endlessly
with preventive treatment.90 The basic preventive measures
are simple: high fluid intake (>2 L/m2/day) throughout the
day and night and permanent urine alkalinization with potassium citrate or bicarbonate (1 to 3 g three to four times a day),
with regular urinary pH checking at home aiming to maintain pH at 7.5. Excessive protein and sodium intake should
be avoided, particularly at the evening meal. Children rarely
consume methionine-rich food (e.g., stockfish, horsemeat, fish
eggs); a moderate consumption of eggs should be advised.
If these preventive measures are appropriately followed, it
is possible to avoid stone formation in most children with
homozygous cystinuria before lithiasis development and, in
most compliant children, to avoid stone recurrence after stone
removal.
In the case of stone appearance or recurrence, sulfhydryl
compounds must be added to try to dissolve small stones and
to avoid recurrence, by decreasing free cystine via the formation of more soluble complexes with cysteine.90 Penicillamine
(20 to 40 mg/kg) is the most effective, but its side effects
(ageusia, cutaneous rash, leukopenia, and proteinuria) limit
its use and necessitate close surveillance; -mercaptopropionyl-glycine or tiopronin (20 to 30 mg/kg) is better tolerated,
but seems slightly less effective. Dosage of sulfhydryl compounds must be gradually increased and given in divided
doses, with half of the daily dose taken at bedtime because
the cystine urinary concentration is maximal during the night.
The efficacy of treatment must be monitored at regular intervals by checking the disappearance of cystine crystalluria,91
urine volume (>1.5 L/m2/day), urine pH (>7), and free cystine urine concentration (<250 mg/L).
Purine Stones
General advice in addition to the treatment of all purine disorders is hyperdiuresis and restriction of purine intake because
high purine consumption may worsen the clinical symptoms
and stone formation.
Uric Acid Stones. Allopurinol is appropriate in all cases
of overproduction of uric acid, as in myeloproliferative disorders and their chemotherapy, and in cases of genetic disorders.
Allopurinol dosage must not exceed 4 mg/kg to avoid xanthine accumulation and xanthine stones.
Other Purine Stones. In homozygous APRT deficiency,
allopurinol is an effective drug to reduce DHA production.
Medical management of homozygous xanthine dehydrogenase deficiencies mainly includes high fluid intake (>2 L/day),
642
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VII: Nephrourology
Medical Follow-up
Children with stones require close follow-up from the pediatric nephrologist or urologist, with frequent outpatient visits
(every 3 or 4 months) because they are unable to adhere continuously to the preventive measures without strict surveillance and emotional support from parents and the physician.
Compliance to preventive and therapeutic measures must be
assessed at each visit through biochemical urinary monitoring, including, if possible, crystalluria on fresh urine.43
Imaging
During conservative treatment or medical management,
repeated KUB studies and urinary tract ultrasound examinations generally provide sufficient information for patient follow-up. They must be performed at various intervals according
to the causal disease, the clinical symptoms, and the presence
or absence of a significant crystalluria. In the absence of symptoms or crystalluria, one imaging examination per year seems
sufficient. IVP and CT scan also can be useful to detect residual
fragments when necessary.
SURGICAL MANAGEMENT
Rarely, a child with a calculus presents in an emergency situation, such as severe sepsis, colic resistant to medical therapy,
anuria, or acute urinary retentionall consequences of the
obstruction of the upper or lower urinary tract. In all these
conditions, urine drainage above the obstruction level must be
obtained by straightforward stone extraction or destruction,
or, particularly in case of infection, by the endoscopic or percutaneous insertion of a catheter.
Most of the time, the surgical management of urolithiasis in children is discussed out of a context of emergency.
Because of its efficiency and its low morbidity, ESWL should
always be considered as the first treatment option; other treatment modalities (i.e., PCNL, ureteroscopy, or open surgery)
generally are discussed when ESWL is a poor choice or has
failed, or as a combined approach.
Ultrasound
probe
The computer integrates the position of the stone in the three dimensions of the space, and subsequently moves the generator
into the proper position. The shock wave is conducted through
the water medium, then through the body, and converges on
the stone.
Generator
Computer
chapter
Nature
of the
Shock Wave
Targeting Mode
Lithotripters have targeting systems that use fluoroscopy,
ultrasonography, or both modalities combined. Fluoroscopy
allows the treatment of every stone, either renal or ureteral;
however, an IVP or an opacification through a nephrostomy
tube or ureteral catheter may be necessary for the treatment
of radiolucent stones. Bush and coworkers99 showed that the
estimated radiation exposure during ESWL is less than that
643
of diagnostic radiographic procedures (e.g., voiding cystourethrogram) or of percutaneous stone manipulation,99 although
this claim has yet to be documented in young children. Ultrasonography does not deliver x-rays, and no opacification is
required for visualization of radiolucent calculi; however, ureteral stones (except the most proximal and most distal ones)
cannot be localized.
B
A
644
part
VII: Nephrourology
of the
Patient
Renal and upper ureter stones are treated with the patient in
supine position, and lower ureter stones are treated with the
patient in prone position (see Fig. 48-9B and C). The exact positioning of the patient is an important step. Bones and gas interposition on the track of the shock wave, and fragile organs such
as spleen, liver, or lung should be avoided. In small children,
particularly in infants, the lung area should be protected by
application on the skin above the level of the 12th rib of a thick
colloidal foam. In a particular situation, such as spinal deformity, the possibilities of positioning the patient adequately for
treatment should be checked before anesthesia is instituted.
Pretreatment insertion of a ureteral catheter may be necessary when the calculus creates an acute obstruction with
intractable pain or pyelonephritis. The insertion of a ureteral
catheter to prevent obstruction by the fragments after ESWL is
more debated, particularly in young patients and infants; the
ureter is more compliant than that in adults, and symptomatic
Steinstrasse is unusual. Even authors who have used ureteral
stenting in their preliminary experience do not routinely use
stenting before ESWL, even for staghorn calculi.100-103 We no
longer use ureteral stenting, even for the treatment of large
stones, in children younger than 5 years; we inform the parents that insertion of a ureteral stent or nephrostomy drain
may be necessary after the session in case of symptomatic
obstruction. Similar to Myers and colleagues,103 we recommend insertion of a double-J stent in older children with large
calcified stones (>25 mm in diameter) when several ESWL
sessions are anticipated.
Targeting
of the
Stone
Anesthesia
General anesthesia is still required in most cases for ESWL
in children, at least for infants and patients younger than
6 years old, who are generally uncooperative and are upset
by the atmosphere of an operating room.100,101,103,104 At the
Puigvert Foundation in Barcelona, a painless method of treatment was developed in 1987 with the Lithostar electromagnetic lithotripter (Siemens Medical). The principle is to start
at low power (11 kV) and increase the power progressively
so that the initial shocks desensitize the skin nerve receptors
with a transcutaneous electrical nerve stimulatorlike effect.105
This method was successfully applied by Myers and others in a series of 446 pediatric patients and by several other
authors.101,103,106 There is a trend toward development of anesthesia-free ESWL with the use of piezoelectric and electromagnetic lithotripters in pediatric patients.
Stone Fragmentation
No scientific data clearly define the upper limit of power and
number of shocks during an ESWL session in children. With the
spark gap lithotripters, it seems that the power should be kept
to less than 20 kV, and the number of shocks to a maximum
Follow-up
after
Treatment
KUB and ultrasound studies of the urinary tract and abdominal cavity are performed before the patient leaves the hospital,
mainly to detect covert complications, such as upper tract dilation or damage to the renal parenchyma and adjacent organs.
This evaluation is repeated after 1 month, together with a urine
culture and, if necessary, an IVP or a CT scan. At this point,
a decision is reached regarding retreatment, in case of large
fragments, or follow-up, in case of small fragments or stonefree status. After the treatment has been completed, patients
should be monitored on a yearly basis with physical examination including measurement of blood pressure, urinary tract
ultrasonography, and eventual KUB films.
chapter
PAL... 24 months
DMSA 1: 10/20/98
pre treatment
DMSA2 : 02/22/98
6 months post treatment
L
LK : 45 %
RK : 55 %
645
e xperience.119,120 The possibility of development of hypertension after ESWL has been evoked through clinical and
experimental studies with contradictory conclusions.11,121,122
No study to date has proved, however, that the incidence of
hypertension after ESWL related to age was higher than in the
general population.
Damage induced by ESWL to adjacent organs includes
hemoptysis secondary to lung contusion, which has been
reported in the literature always without any serious consequences.123,124 Thick colloidal foam is applied over the
pulmonary area to prevent hemoptysis, particularly when
treating upper calyx stones and in infants. Pancreatitis has
been reported in adults,125 but not in children. Hematemesis
has also been observed in adults,126 and Traxer and associates127 reported a single episode in an 11-year-old child, with
no further consequences. Mobley and colleagues98 reported
one case of small bowel perforation at the site of an adhesion
from a previous appendicectomy and adjacent to a ureteral
calculus. Also, thrombosis of the iliac vessels has occurred in
adults after ESWL for ureteral calculi.128,129
These complications are described in case reports among
several thousands of ESWL treatments in adults since the
1980s and have not been reported so far in pediatric patients.
Although no adverse effect on audition was noted by Stoller
and colleagues,130 it is wise to shield the ears of patients
(particularly infants) with a headset during treatment.
Kroovand6 documented that experimental animals exhibited
no adverse effect on epiphyseal growth plates or nearby reproductive organs after ESWL, and no bone growth abnormality
has been reported so far. During ESWL of distal ureteral calculi, potential damage to ovaries has been evoked. Vieweg and
associates131 specifically studied female fertility after ESWL
of distal ureteral calculi and found no case of infertility. After
more than 20 years of clinical applications of ESWL in children,
and despite extensive clinical studies of potential side effects
with careful follow-up, no serious renal or extrarenal damage
imputable to extracorporeal shock waves has been observed.
Also, most experimental studies in animals that have shown
deleterious effects of ESWL cannot be extrapolated to clinical
situations because they involved extreme parameters and conditions of treatment, far from the human practice.
KIS... 8 months
DMSA : 10/14/97
pre treatment
LK : 48 %
RK : 52 %
DMSA 2: 04/28/99
6 months post treatment
R
LK : 38 %
LK : 36 %
RK : 62 %
RK : 64 %
1 session treatment on the left kidney: 2500 shocks
Figure 48-10 A, Normal pretreatment and 6-month post-treatment technetium 99m dimercaptosuccinic acid (Tc99m-DMSA). B, Postinfectious
lesions on pretreatment Tc99m-DMSA; they are unchanged after extracorporeal shock wave lithotripsy.
646
part
VII: Nephrourology
Table 48-7 Results of Renal and Ureteral Extracorporeal Shock Wave Lithotripsy (ESWL)
Author
Lithotripter
Newman et al93
Dornier HM3
50
% Stone-free
% Retreatment
79
11
al132
Dornier HM3
71
70
13
Nijman et al133
Dornier HM3
124
15
69
32
Lithostar
238
208
78
9.2
Sigman et
Myers et
al103
Lottmann et
al144
Sonolith Nova
78
30
79
19
Muslumanoglu et al134
Lithostar Plus
224
168
80
54
al135
Lithostar Plus
Netto et
al137
Landau et al138
Delakas et
al139
Tan et al140
Aksoy et
al141
Dornier MPL9000
EDAP LT02
68
18
98
28
95
55
177
37
84
30
Dornier HM3
38
97
18
25
84
25
Lithostar
41
82
30
20
75
50
Ureteroscopy
The principle of ureteroscopy is the retrograde introduction
of an endoscope through the ureterovesical junction (UVJ)
into the ureter (anterograde ureteroscopy is also feasible during a percutaneous nephroscopy, using a flexible endoscope
introduced into the ureter through the UPJ). The first routine
clinical applications were developed in the late 1970s by Goodmann146 and Lyon and coworkers.147 The first two pediatric
cases were reported in 1988 by Shepherd148 and Ritchey149
and their colleagues in patients 4 and 7 years old. In 1997,
Minevich and coworkers150 collected 50 additional pediatric
ureteroscopies from the literature. This technique is gaining
popularity because most series show its efficacy and innocuousness in children. Most authors consider ureteroscopy as
their first-line treatment for the management of lower ureter
calculi. The limitations of this technique related to the small
size of the anatomic structures have been reduced with miniaturization of the instruments. Two difficulties persist: first, to
achieve adequate experience, considering the limited number
of indications (two to five patients treated per year in most
series), and second, the availability of the equipment.
Technique
Most ureteroscopies in children are performed with the patient
under general anesthesia. Urine must be sterile at the time of
the procedure, and perioperative antibiotic prophylaxis is
a safe option because extravasation of urine may occur. The
patient is placed in the lithotomy position, and the stone is
located with fluoroscopy. It is crucial that all of the potentially
chapter
Ureteroscopes
Rigid and flexible ureteroscopes are available. Technologic
improvements in rigid ureteroscopes have led to progressive
reduction in caliber of the sheath size, while maintaining a
working channel as large as possible to allow the introduction
of forceps, stents, baskets, and lithotripsy probes. The Circon
6.9 ACMI rigid miniscope (Circon Corp, Portland, OR) has a
5F working channel. The 4.8F Wolf ureteroscope has a working channel that can accommodate only electrohydraulic lithotripsy (EHL) or laser lithotripsy probes. Flexible ureteroscopes
are also available, although the size of the working channel is
small and cannot accommodate rigid tools.
of the
Ureterovesical Junction
647
Placement
of a
Guidewire
Introduction
of the
Ureteroscope
Figure 48-11 A, Staghorn calculus of the left kidney in a 20-month-old boy. B, Small fragments are visible 48 hours after extracorporeal shock
wave lithotripsy (ESWL). The patient was stone-free 1 month after a single treatment session.
648
part
VII: Nephrourology
C
E
maneuver. Fluoroscopy may be useful to monitor the progression of the instrument, eventually associated with the injection of diluted contrast medium (Fig. 48-12B). As soon as the
stone is reached, the progression stops, and the management
of the calculus per se can begin. The progression of a flexible
ureteroscope is conducted either under direct vision or, preferably, with the use of a guidewire previously introduced into
the working channel. The progression of the instrument is
monitored under fluoroscopy with or without the use of contrast medium.
chapter
649
must be performed under vision control: The catheter is introduced into the working channel of the ureteroscope until the
tip becomes visible close to the stone level; the assistant then
opens the basket, and the operator, with a rotation of the catheter, introduces the stone into the basket. The assistant then
closes the basket sufficiently to trap the stone within it. The
operator checks that the basket is free in the ureteral lumen,
and in particular that no ureteral mucosa has been trapped
within the branches of the basket. The withdrawal of the ureteroscope and the basket can then start safely.
The basket with the stone in it must be kept under vision
control until the extraction out of the urinary tract is completed. A critical phase is the extraction of the basket out of the
is stone-free after a third treatment session and removal of the doubleJ stent. H, No residual fragments or dilation of the renal cavities on
post-treatment ultrasound.
UVJ; at this level, a stone that is too large for direct extraction
can be stopped in its progression. The traction exerted on the
basket catheter must always be gentle. If the stone is encrusted
in the ureteral mucosa or is too large to be extracted directly
through the UVJ, a lithotripsy is required. Excessive traction
on the basket catheter can lead to a ureteral avulsion, which is
a major complication.
Lithotripsy
Fragmentation can be performed by several means: ultrasonic lithotripsy, EHL, laser lithotripsy, and ballistic lithotripsy. Ultrasonic lithotripsy consists of the transmission of
high-frequency vibrations along a rigid metal probe from the
650
part
VII: Nephrourology
Complications
Ancillary Procedures
Afshar et al142
No. Patients
83
Renal colic: 6
Double-J stent: 2
Gross hematuria: 3
Ureteroscopy: 3
Muslumanoglu et al134
344
Steinstrasse: 13 (7.8%)
In situ ESWL: 8
Hydronephrosis: 14 (4%)
Double-J stent: 14
UTI: 4 (1.2%)
Renal colic: 10 (2.9%)
Al-Busaidi et al143
42
Steinstrasse + sepsis: 2
Nephrostomy +
ureteroscopy
10
Partial obstruction: 2
Ureteroscopy: 1
86
Renal colic: 8
None
10
105
EHL/holmium:YAG
laser/basket
None
19
Fever: 15 (8.5%)
None
Steinstrasse: 2 (1.1%)
Nephrostomy: 2
Steinstrasse: 7 (7.8%)
Ureteroscopy: 2
In situ ESWL: 1
Netto et al135
Ather and
Noor136
Steinstrasse: 2 (2%)
Febrile UTI: 3 (3%)
Rizvi et
al137
177
Aksoy et al141
Lottmann et
al144
Orsola et al106
129
UTI: 10 (7.75%)
None
Subcapsular hematoma: 1
None
23 staghorn
Upper ureteral: 1
obstruction
Pyelotomy: 1
15 staghorn
Febrile UTI: 1
None
14
4
6.6
EHL, electrohydraulic lithotripsy; ESWL, extracorporeal shock wave lithotripsy; UTI, urinary tract infection.
No. Patients
al139
Landau et al138
Delakas et
Tan et
al140
Gofrit et al145
Complications
Ancillary Procedures
25
None
24
38
None
None
41
None
7.9
38
UTI: 1
None
7.8
Renal colic: 1
Laryngospasm: 1
UTI, urinary tract infection.
chapter
651
C
Figure 48-12 A, Ureteroscopy in a 3-year-old girl shows insertion of the guidewire. B, Insertion of an 8F ureteroscope up to the lumbar ureter.
C, Ballistic lithotripsy with a 3F probe of the Swiss Lithoclast.
652
part
Extraction
VII: Nephrourology
of the
Fragments
Complications of Ureteroscopy
During the various steps of the procedure, complications
of various degrees of severity may occur. The first may be
the impossibility of inserting a guidewire above the level of
an impacted calculus; performing a ureteroscopy without a
guidewire is hazardous and probably should not be attempted
if the operator is not well experienced. If the procedure is pursued, a guidewire should be inserted whenever possible. The
second potential complication is the impossibility of introducing the ureteroscope through the UVJ despite an acute
dilation because a perforation has occurred in the intramural ureter during the preliminary maneuvers. Several options
can be discussed in this situation depending on the context:
a straightforward open ureterolithotomy; ESWL; or leaving a
double-J stent in place for a few days to provide a subacute
dilation of the UVJ, with a second attempt performed after
this delay.
During the preliminary maneuvers, during the progression of the ureteroscope under hydrodilation, or during the
lithotripsy, the calculus can be dislodged from its position
and flushed upward. The new position of the stone can be
assessed with fluoroscopy and eventual injection of contrast
medium. In some instances, it is possible to progress further
upward, catch the stone in a basket, and proceed to lithotripsy.
In other cases, it becomes impossible to progress further with
the ureteroscope without significant risk for the urethra (in
boys), the UVJ, or the ureter in general; it is then safer to flush
the stone back to the kidney if it is not already there, leave a
catheter large enough to prevent secondary migration back
down the ureter, and perform in a second step an ESWL or a
percutaneous stone extraction. During the basket maneuvers,
the basket can get blocked with ureteral folds trapped within
the wires; if the basket cannot be reopened, the procedure
must be converted to open surgery.
A perforation of the ureteral wall may occur during lithotripsy, with encrusted stones when using EHL; the stone can
eventually be expulsed outside the ureteral lumen. Injection of
contrast medium confirms the diagnosis. These perforations
are usually without consequences, provided that a guidewire
has been inserted at the initial phase of the procedure, allowing the safe insertion of a ureteral catheter, which is left in
place for a few days until the retroperitoneal urinoma has
been reabsorbed, and the ureteral perforation has healed.
A calculus expulsed in the retroperitoneal space can be
ignored without further consequences; the patient or parents
should be informed that the stone, which may still be seen on
Percutaneous Nephrolithotripsy
The principle of PCNL is the percutaneous introduction of an
endoscope into the pelvicalyceal cavities; through this access,
the stone is reached, identified, and fragmented when necessary, and then the stone or its fragments are extracted through
the same percutaneous channel. Feinstrm and Johannson in
1976165 were the first to report a percutaneous stone extraction.
After the first description of the concept in adult patients, it
took almost 10 years before the first reports concerning pediatric PCNL were published, by Woodside and associates in
1985166 and Papanicolaou and colleagues in 1986.167 The advent
of ESWL during the same period has limited the expansion of
this more invasive technique of stone removal. PCNL has its
place for the treatment of renal stones in children, however,
mainly when ESWL is contraindicated or has failed.
chapter
653
Patient Age
Procedure
Ureteroscope
Procedure Lithotripsy
Thomas et al204
16
16 mo15 yr
7.5F/8.5F/11.5F
EHL
100
Scarpa et al152
3.5-10 yr
4.8F/7F
100
Author
al205
17
Minevich et al150
Kurzrock et
Jayanthi et
al157
Stone-free
Rate (%)
10 mo16 yr
6.9F/7F
100
7-16 yr
6.9F/7F/9.5F
EHL
85
12
2-14 yr
7.5F/8F/9.5F
EHL/holmium:YAG laser
92
Bassiri et al159
66
2-15 yr
8F/11.5F
EHL or pneumatic/basket
88
Al-Busaidi et al160
26
2-12 yr
8F
Holmium:YAG
92
Holman et
al161
30
8 mo14 yr
9.5F
Not mentioned
90
Dogan et al162
33
1-14 yr
7.5F/8F/10F
Holmium:YAG or pneumatic/
grasper
82
Tan et al163
21
2-14 yr
7.5F/8F/9.5F
EHL/holmium:YAG laser/
basket
95
Satar et al164
33
9 mo15 yr
6.9F/10F
Pneumatic lithotripsy/
forceps
94
Creation
of the
Nephrostomy Tract
A needle (usually 18 to 22 gauge) is introduced along the posterior axillary line (a line is drawn from the external extremity
of the acromion to the posterior superior iliac spine) into the
appropriate calyx (Fig. 48-13). This introduction can be done
under fluoroscopic control or under ultrasound guidance (Fig.
48-14A-D); the latter is more appropriate to aim the calculus
and enter the kidney along a posterolateral axis in a relatively
avascular area of the kidney where the parenchyma is thin.
The appropriate calyx is penetrated through the papilla. Ultrasound guidance also reduces the irradiation of the patient.
When the renal cavities are not dilated, it is useful to insert a
ureteral catheter and inject either saline or contrast medium
to dilate the cavities and improve their visualization. As soon
as the needle has been inserted in the pelvicalyceal system, an
injection of contrast medium and fluoroscopic control allow
the physician to check its appropriate position. If the needle is
in a calyx adjacent to the one containing the stone, it should be
removed, and a new puncture should be performed.
Dilation
of the
Nephrostomy Tract
Figure 48-13 Puncture of the calyx along the posterior axillary line.
(From Le Duc A, Teillac P, Cussenot O, et al. Chirurgie percutane du
rein pour lithiase. Paris: Techniques Chirurgicales Urologie; 1994:No.
41090 B. Editions Scientifiques et Medicales Elsevier SAS. Tout droits
reservs.)
it seemed advantageous to limit dilation to the minimum
size necessary for efficient stone removal.
The less invasive percutaneous access to the pelvicalyceal cavities is described by Jackman and coworkers169 as the
mini-perc technique: a 0.035-inch floppy-tipped guidewire
is inserted through the access needle and kept as a safety wire;
a stiffer working wire is then introduced. The fascia is incised,
and an 11F peel-away vascular access sheath with its trocar is
introduced along the guidewire into the pelvicalyceal system
under fluoroscopic control. No dilation is needed before this
maneuver. The trocar is removed, and a 7F rigid pediatric
cystoscope or a 9.5F flexible ureteroscope is inserted through
the peel-away sheath. Among the advantages listed by the
authors of this mini-perc method are the universal availability of the introducer sets and the avoidance of excessive
654
part
VII: Nephrourology
Introduction
of the Instrument
E
Figure 48-14 A, Noncontrast-enhanced CT scan of a cystine staghorn calculus in a 12-year-old boy. B, Posterior axillary line. C, Puncture of the
cavities under ultrasound guidance. D, Puncture assisted with fluoroscopic guidance. E, Dilation of the puncture tract.
chapter
655
Figure 48-14, contd F, Insertion of the nephroscope. G, Ballistic lithotripsy using the Swiss Lithoclast. H, Insertion of a nephrostomy tube at
the end of the procedure.
Stone Destruction
and
Extraction
Postoperative Drainage
The pelvicalyceal system is controlled under fluoroscopy with
eventual injection of contrast medium to check the patency of
the ureter and to rule out a perforation of the pelvis. A nephrostomy tube is left in the tract. A radiologic study is usually
performed after 48 hours, and if the patient is stone-free, and
the urinary tract is intact and patent down to the bladder, the
nephrostomy tube is removed. If residual fragments are still
present (sometimes the procedure has to be interrupted before
complete stone extraction because of excessive bleeding or
excessive duration), in the pelvicalyceal system or in the ureter,
a second session is performed, or, if the fragments are small, the
nephrostomy tube is kept in place until they are eliminated.
656
part
VII: Nephrourology
Renal Calculi
An anterior approach, such as that described by Duckett and
colleagues,186 usually provides a satisfactory exposure of the
entire kidney in children. In adolescents or obese children,
a flank incision may be a better option, particularly when
access to the upper pole is needed; 12th rib resection usually is
unnecessary. The procedures are performed extraperitoneally.
In a reoperation, a transperitoneal approach may be preferable, however, to carry the dissection through unoperated
tissues and to avoid an inadvertent injury to intraperitoneal
structures.
When the calculus and associated obstruction and infection
have induced extensive parenchymal damage with a residual
function of the involved kidney less than 10% of the total renal
function, a nephrectomy is indicated. A partial nephrectomy is
indicated in children with impacted calculi and severe parenchymal atrophy.33 For calculus removal, a pyelotomy is the
least invasive route; the pelvic incision should have a U shape
distant to the UPJ and can be prolonged when needed along
the calyceal infundibula to remove branched calculi. A conventional resection of the UPJ is performed only in the case of an
associated UPJ stenosis with a need for pyeloplasty. Calyceal
stone fragments are removed with the use of an angulated
calculi forceps; residual fragments can be dislodged with a
pulsatile saline flow irrigation of the pelvicalyceal system.
To search for residual calculi and define their location, the
physician can use either operative ultrasonography or renoscopy with a flexible endoscope or intraoperative radiographs
using dental films as described by Braren.187 At the end of the
procedure, insertion of a nephrostomy tube or ureteral stent
is a safe, although not routine, option, and a watertight pelvic
closure is performed with fine absorbable suture. A Penrose
or suction drain is left in the renal fossa to collect any extravasated urine, and the wound is closed.
Pyelotomy may be associated with segmental nephrotomies
and is considered to be a safe and effective procedure with low
morbidity. Much more invasive is anatrophic nephrolithotomy
for the management of complete staghorn calculi with a large
stone burden or multiple calyceal calculi.6 The technique has
been extensively described by Smith and Boyce.188,189 The
kidney is exposed and completely mobilized. The principle is
to bivalve the kidney along an avascular plane between the
anterior and posterior renal segment. The posterior branch of
the renal artery is isolated and temporarily occluded with an
atraumatic clamp. Injection of indigo carmine or methylene
blue may serve to define the anatrophic line. The renal pedicle
is clamped, and an ice slush is placed around the kidney within a rubber dam to ensure cold ischemia during the procedure.
Careful monitoring of core body temperature is important to
prevent systemic hypothermia and acidosis. The nephrotomy
is performed along the anatrophic line, deep to the pelvicalyceal system. All the calculi are extracted with intraoperative renal radiographs. The pelvicalyceal system is then
reconstructed using absorbable thin suture material. Optical
magnification and microsurgical technique are necessary in
infants and young children to reconstruct the collecting system without creating areas of stenosis along the infundibula.
After careful progressive hemostasis of any bleeding point in
the renal parenchyma, the renal capsule is tightly closed with
a continuous locked suturing technique. Drainage of the renal
cavities is not routine, but a Penrose-type drain should always
be left in the renal fossa.
This procedure is associated with a high morbidity.
Specifically, significant blood loss requiring transfusion is
frequently encounteredin 6 of 11 patients reported by
Assimos and associates190 and in 3 of 9 patients more recently
described by Gough and Baillie.191 This heavy procedure does
not guarantee a stone-free status; 2 of the 11 patients described
by Assimos and associates and 1 of the 9 reported by Gough
and Baillie had residual calculi. Also, the long-term consequences of this technique with prolonged hypothermic renal
ischemia are still unclear because they have been studied in
only a few children. Cendron and colleagues192 reported on
a series of five patients with preoperative and postoperative
chapter
657
Patient Age
Procedure
Nephroscope
Procedure
Lithotripsy
Stone-free
Rate (%)
Boormans et al178
23
16 mo15 yr
16F
Ultrasonic/grasper
forceps
58 (1 session)
Dawaba et al179
65
9 mo16 yr
14F/30F
Ultrasonic/grasper
forceps
Salah et al180
135
8 mo14 yr
19F/26F
98.5
56 complex calculi
6 mo15 yr
20F/24F tract
Pneumatic/grasper
forceps
56 (1 session)
Author
81 (at discharge)
86 (1 session)
93 (at discharge)
Desai et
al181
14F scope
72 noncomplex
al182
14
8-17 yr
Zeren et al183
55
10 mo14 yr
Sahin et
24-30F tract
90 (at discharge)
EHL/holmium:YAG laser
97 (at discharge)
Ultrasonic/laser grasper
forceps
69 (at discharge)
Ultrasonic-pneumatic/
grasper forceps
87 (at discharge)
14-28F scope
18F-30F tract
10% retreatment
rate
Badawy et al184
60
3-13 yr
26F/28F tract
Ultrasonic/grasper
forceps
24F scope
Rizvi et
al137
62
4-14 yr
22F tract
90 (at discharge)
Ultrasonic/grasper
forceps
19.5F scope
Jackman et al169
11
29
2-6 yr
1.4-5 yr
11F
83 (1 session)
68 (1 session)
95 (after ESWL in
27%)
None
85 (at discharge)
Mini-perc
45% retreatment
rate
17F scope
60%
100% when
combined with
ESWL
renal scintiscans and observed no deterioration of renal function; however, more recently, Gough and Baillie191 observed a
significant decline (>5%) in differential function in five of nine
children after surgery.
For these reasons, the indications for anatrophic nephrolithotomy in pediatric patients should be limited to the strict
minimum. ESWL monotherapy or ESWL in association with
minimally invasive procedures or pyelotomy, even if several
treatment sessions are necessary, is probably a better option
in most situations in which anatrophic nephrolithotomy is
considered.
Ureteral Calculi
In view of the excellent results achieved with ESWL or ureteroscopy for the treatment of ureteral calculi in children,
indications for an open procedure are exceptional, primarily
when the calculus is associated with an obstructive uropathy
Laparoscopy
Most procedures performed by open surgical techniques
can now be performed using a transperitoneal or retroperitoneal laparoscopic approach, including total or partial
658
part
VII: Nephrourology
No. Patients
Boormans et
al178
Dawaba et al179
Salah et
al180
Desai et al181
Blood Transfusion
Urinary Leakage
Sepsis
Other
23
65
Pelvic perforation: 1
11 (8%)
Urinoma: 10 (7%)
5.4%
5%
135
10 (7%)
56 complex
14%
Total (%)
8.6
3
22
24.4
72 simple
5.4%
5.5%
10.9
Zeren et al183
55
24%
5%
29.5
Badawi et al184
60
Colonic perforation: 1
6.6
62
17 (25%)
4 (6.4%)
Hydrothorax: 1
35.5
29
2 (7%)
Retention: 1
Rizvi et
al137
Mahmud and
Zaidi185
10
chapter
659
660
part
VII: Nephrourology
Urethral Calculi
Figure 48-16 A, A 6-mm upper ureteral stone in a 2-year-old girl. B, On IVP, the stone is stopped in its migration at the level of a partially
obstructive ureteral loop. C, Under general anesthesia, the patient was placed in a left lumbotomy position, and using three 5-mm ports, the calculus and a vascular loop were identified. D, The calculus was extracted through a longitudinal ureterotomy.
chapter
661
Figure 48-16, contd E, The ureterotomy was closed with endocorporeal separate stitches, and the vascular loop was transected. F, Normal
postoperative IVP at 3 months.
Figure 48-17 A, Bladder stone after failed hypospadias repair. B, Voiding cystourethrography in the same patient.
REFERENCES
For complete list of references log onto www.expertconsult.com
PART
VIII
urogenital tumors
chapter
49
WILMS TUMOR
Initially described in seven children by Wilms in 1899, Wilms
tumor is an example of success in treatment and understanding of childhood cancer.3 Initial success through surgical treatment was followed by multimodality therapy, leading to an
approximately 90% overall survival. Recent decades have
seen a dramatic increase in understanding of the genetic and
molecular features of this cancer. Today, the focus of therapy
is on tailoring treatment without compromising survival and
expanding knowledge of the molecular biology of this cancer.
Molecular Biology
WT1
The clinical observation that patients with aniridia, genital
anomalies, and mental retardation developed Wilms tumor at
a higher rate than the general population led to the discovery
of a heterozygous deletion at 11p13 by cytogenetic analysis.3-6
Cloning techniques subsequently identified the WT1 gene. The
association with aniridia occurs because the PAX6 gene, which
is important to eye development, resides adjacent to WT1 and
is affected by the deletion abnormality.7
WT2
The identification of a second Wilms tumor locus at 11p15
occurred as a consequence of the association of Wilms tumor
and Beckwith-Wiedemann syndrome. The connection between
the two was initially identified by familial-linkage studies and
cytogenetic analyses.10 These studies pointed to inheritance
of two copies of paternal chromosome 11 or duplication of the
paternally derived 11p15 locus, resulting in germline mutations.
The specific gene responsible at 11p15 has not been identified, but several candidate genes have been suggested. One
of the most attractive candidates is IGF2 at 11p15. IGF2 is a
paternally expressed embryonic growth factor.11,12 Studies
in mice have shown that overexpression in transgenic mice
leads to overgrowth, consistent with Beckwith-Wiedemann
syndrome in humans.13 Other genes implicated in BeckwithWiedemann syndrome include H19 (fetal liver mRNA), p57
(a cyclin-dependent kinase inhibitor), and L1T1 (an untranslated RNA region adjacent to p57).14
664
part
Proportion relapse-free
1.0
TP53
More recent studies using microdissection techniques have
identified that TP53 mutations are commonly present in anaplastic areas of Wilms tumors. Alternatively, in tumors with
adjacent favorable-histology areas, TP53 mutations are rare.
These findings suggest that TP53 mutations may be required
for the development of anaplasia.19 The role of p53 in tumorigenesis is well established; p53 induces cell cycle arrest and
apoptosis in cells with DNA damage. Because of these findings, current COG protocols are evaluating the prognostic
value of TP53 mutations in patients with anaplasia.
0.9
0.8
No LOH
LOH 1p only
LOH 16q only
LOH both Ioci
0.7
WTX
0.6
0
ity (LOH) at chromosomes 1p and 16q for stage VII favorable istology Wilms tumor patients. (From Grundy PE, Breslow NE, Li S,
h
et al. Loss of heterozygosity for chromosomes 1p and 16q is an adverse
prognostic factor in favorable-histology Wilms tumor: a report from
the National Wilms Tumor Study Group. J Clin Oncol. 2005;23:73127321.)
-Catenins
-Catenins are multifunctional proteins, related to the E-cadherin
family, that are involved in the Wnt signal transduction pathway. Although not commonly known, activating mutations of
-catenins are among the most common somatic genetic lesions
identified in Wilms tumor.16 These mutations frequently coincide with WT1 mutations.17 In the absence of degradation,
-catenins cross into the nucleus, where they interact with
T cellspecific transcription factor and lymphoid enhancer
factor, forming a transcription complex.18 This complex activates factors that promote cell proliferation, survival, cellular
invasion, angiogenesis, and immune invasion. A partial list of
these downstream effectors includes c-myc, cyclin D, VEGF,
IL-8, PPARd, and COX-2. Initial studies suggest that 10% or
more of Wilms tumors may harbor abnormalities of -catenins.
Syndromes
Wilms tumor patients with germ cell mutations are characterized
by syndromic conditions, associated genitourinary anomalies, fami
lial tumors, and tumors that develop at an earlier age than in pati
ents with sporadic disease (Table 49-1). The association of Wilms
tumor with aniridia, genitourinary anomalies, and mental retar-
dation has been recognized as the WAGR syndrome. Characterized by germline WT1 mutations, WAGR syndrome also illustrates
the importance of WT1 for normal genitourinary development.
Patients with WAGR syndrome typically have defects such as
renal hypoplasia or ureteral, urethral, or gonadal abnormalities.
In contrast to WAGR syndrome, Denys-Drash syndrome,
which is also associated with WT1 abnormalities, is much
more severe. An arginine-to-tryptophan change in exon 2 is
the most common finding in patients with Denys-Drash syndrome.21 This abnormality may lead to a dominant negative
effect, whereby the mutated protein affects the function of the
remaining wild-type protein by dimerization.21
Simpson-Golabi-Behmel syndrome is a rare congenital overgrowth syndrome; features include macroglossia, macrosomia,
renal and skeletal anomalies, and an increased risk of cancer.
The syndrome is related to the loss of function of the glypican-3
gene (GPC3) at chromosome Xq26.22 The syndrome is complex
and significantly overlaps with other overgrowth syndromes.23
chapter
665
Table 49-1 Syndromes Associated with Wilms Tumor and Estimated Risk
Syndrome
Gene
Presenting Features
WAGR
11p13 (WT1)
30%
Denys-Drash
11p13 (WT1)
90%
Frasier
11p13 (WT1)
Rare
Beckwith-Wiedemann
11p15
Organomegaly, macroglossia,
hemihypertrophy
5%
Simpson-Golabi-Behmel
Xq26
7.5%
Prognostic Factors
Therapy for Wilms tumor is determined by stratifying the individual patients risk. Several clinical, pathologic, and biologic
factors have been identified to be prognostic in Wilms tumor
and are used to stratify patients. We briefly review the principal
risk factors before discussing principles of therapy. Chapter 50
provides details of surgical therapy and adjuvant treatment.
Tumor Stage
Stage is determined solely by the anatomic extent of the tumor.
Tumors that are locally advanced or metastatic carry a worse
prognosis than tumors that remain localized. The NWTS (now
known as the COG Renal Tumors Committee) and the International Society of Pediatric Oncology (SIOP) staging systems
have been shown to correlate well with outcomes. The principal difference is that the NWTS/COG system is a prechemotherapy, surgical based system, whereas the SIOP system
stages patients after they have received chemotherapy. This
fundamental difference precludes stage-by-stage comparisons
of patients enrolled in the two groups.29
Tumor Risk
Patient Age
Age younger than 2 years with small favorable-histology
tumors (<550 g) has been associated with an excellent prognosis.33,34 This observation led to the incorporation of a surgical treatmentonly arm in NWTS-5 for patients with stage I
tumors that met the above-mentioned criteria. After treating
75 patients, the study was closed because at 2 years 13.5% of
patients had relapsed. All of these patients were salvaged with
standard chemotherapy.34 Current plans call for revisiting this
strategy in future COG protocols.
Biologic Factors
As discussed previously, patients with LOH at chromosomes
1p and 16q have higher recurrence and mortality rates.
LOH at these sites may explain the poor outcomes of 5% of
favorable-histology patients. COG studies are expected to
stratify these patients to receive more aggressive therapy.
The presence or absence of WT-1 mutations does not significantly alter outcome. Patients with p53 abnormalities
seem to do poorly relative to patients without p53 abnormalities. p53 abnormalities are commonly associated with
anaplasia.35,36
Treatment Overview
Current treatment for children with Wilms tumor focuses on
limiting therapy for patients in low-risk groups and intensifying treatment for patients at risk for failure or relapse.
Histology
Histology remains the strongest predictor of outcome. In particular, anaplasia, defined by cells showing irregular mitosis, enlarged nuclei, and hyperchromasia, portends a poorer
666
part
High-Risk Patients
The presence of cellular anaplasia is the strongest predictor of
outcome for patients with Wilms tumor. Patients with focal
or diffuse anaplasia are enrolled in a separate high-risk protocol. Patients with high-risk non-Wilms tumors, such as clear
cell sarcoma, malignant rhabdoid tumor, and pediatric renal
cell carcinoma, are also addressed in this protocol. Relative
to Wilms tumor, primary study goals include the impact of
cyclophosphamide/carboplatin/etoposide alternating with
vincristine/doxorubicin/cyclophosphamide in patients with
diffuse anaplasia, and the role of vincristine in combination
with irinotecan for patients with metastatic anaplastic Wilms
tumor. This study also is expected to evaluate secondary questions, such as the outcomes of patients with focal anaplasia
treated with three-drug therapy and radiation, and molecular
questions regarding TP53 mutations.
Late Effects
The long-term deleterious effects of childhood cancer therapy are increasingly being recognized. An example of this is
a report from the Childhood Cancer Survivors Study, which
Secondary Cancer
A review of more than 5000 NWTS patients that were enrolled
between 1969-1991 identified 43 secondary cancers compared
with an expected number of 5.38,39 This evaluation suggests a
bona fide increased risk in patients treated for Wilms tumor.
Further analysis showed a significant positive correlation
between dose of radiation and risk of secondary cancer. The
addition of doxorubicin to radiation also seemed to increase
risk. Hematologic and solid tumors were identified.40 A significant concern was that the latency interval for solid tumor
occurrence was 16 years, without plateau, suggesting indefinite follow-up to be appropriate.
Cardiovascular Disease
Treatment with doxorubicin is a known risk factor for cardiovascular disease. Initial evaluation of risk in Wilms tumor
patients estimated that the cumulative risk at 20 years was
4.4%.41 Factors associated with increased risk included female
gender; total dose of doxorubicin; and radiation to left side of
heart, abdomen, or lung. More recently, the long-term cumulative risk has been recalculated to be 1.2%, with patients having
left-sided tumors at a considerably higher risk.42
Pulmonary Complications
Pulmonary complications have been primarily associated
with radiation exposure to the lungs. Of approximately 6500
patients treated in NWTS-1NWTS-4, 67 developed pulmonary fibrosis.43 In this study, patients were placed into four
groups for analysis. Group 1 consisted of patients who did not
receive radiation. Group 2 patients received radiation that did
not include the lungs. Group 3 patients received pulmonary
radiation. Group 4 comprised group 1 and 2 patients who went
on to receive pulmonary radiation therapy. The incidence of
pulmonary complications 15 years after treatment was 0.1%
for group 1, 0.3% for group 2, 4.4% for group 3, and 5.3% for
group 4.43 Cyclophosphamide treatment seemed to increase
risk among patients receiving radiation therapy.43
Renal Failure
The risk of renal failure in patients treated for Wilms tumor
has been studied extensively. Total incidence was reported to
be 17% among patients with bilateral disease and 1% among
patients with unilateral disease.44 A subsequent analysis
excluded patients developing renal failure as a result of bilateral nephrectomy. This analysis determined the rates of failure
for patients with Denys-Drash syndrome, patients with WAGR
syndrome, and male patients with genitourinary anomalies to
be 62.4%, 38.3%, and 10.9%.45 Patients with bilateral and unilateral disease had rates of 5.5% and 1%. Patients with WAGR
syndrome developed renal failure after puberty; patients with
Denys-Drash syndrome typically developed renal failure after
chapter
Growth
Children treated with flank radiation are at particular risk for
somatic growth problems because the radiation fields encompass the spine. Evaluation of patients treated during NWTS1NWTS4 showed the growth deficit in children treated with
10 Gy of radiation therapy before age 1 year to be 7.7 cm. For
children treated at age 4 with 10 Gy, the deficit was reduced to
1.1 cm. Younger patients are at greater risk.46
Fertility
Evaluation of male patients receiving radiation showed that
their offspring had no significantly greater incidence of prematurity or low birth weight. Conversely, radiation had clear
adverse effects on the offspring of mothers treated for Wilms
tumor. Duration of pregnancy and birth weights of newborns
were significantly negatively affected by a history of radiation exposure.47,48 Congenital malformations also were more
common in children of irradiated mothers: 12% versus 3.2%
(P = .03). Available data also suggest that female patients
undergoing abdominal/pelvic radiation have a poor outlook
for fertility.47,48
667
Molecular Biology
In 1986, it was shown that pediatric papillary renal cell carcinoma is associated with a translocation, or fusion of genes,
located on separate chromosomes. The translocation typically
affects genes located on chromosomes X and 1.61 In 1996, the
specific loci on chromosome X and 1 involved in this translocation were identified.62 The translocation results in a fusion of
the papillary renal cell carcinoma (PRCC) gene in the 1q21.2
region with the transcription factor E3 (TFE3) gene in the
Xp11.2 region. A PRCC-TFE3 fusion protein is produced, and
normal transcription is disrupted, leading to the development
of papillary renal cell carcinoma.62
The TFE3 gene product is a member of the MiT family
of basic helix-loop-helix transcription factors, which include
TFEB, TFEC, and MiTF.55,63 This family of transcription
factors has been implicated in various tumors, including
melanoma, alveolar soft part sarcoma, and renal cell carcinoma.62,64-67 It is hypothesized that the upregulation of any
of these genes leads to an unbalanced ratio of transcription
factors that may change downstream signaling mechanisms,
resulting in renal cell carcinoma, or other tumors.68 Multiple
fusion genes involving TFE3 have been associated with papillary renal cell carcinoma, including translocations with the
PSF (splicing factor) gene, ASPL (alveolar soft part sarcoma
locus) gene, and CLTC (clathrin heavy-chain) gene.69-74 These
translocations are extremely rare in adult renal cell carcinoma
(<1% of tumors harbor translocations). More typical in adults
is either VHL in conventional renal cell carcinoma or a duplication of the MET gene on chromosome 7 in papillary renal
cell carcinoma.75
Treatment
Chemotherapy, radiation, and immunotherapy all have been
used in pediatric renal cell carcinoma; however, none have
been studied in a prospective fashion. A review of various
series indicates that prognosis is not affected by adjuvant treatment.76-80 Although it has been suggested that the PRCC-TFE3
fusion may disrupt the mitotic checkpoint in the cell cycle,
making these cells sensitive to conventional microtubuletargeted chemotherapy agents, this has not been shown in any
trial so far.81
The relatively good survival for children with localized
renal cell carcinoma (including patients with local lymph
node involvement), combined with the relative inefficacy
of the best treatments for renal cell carcinoma, support
treating patients with localized disease without adjuvant
therapy. Patients with advanced renal cell carcinoma are
encouraged to seek treatment with immunotherapy or
phase I/II studies.
668
part
Rhabdomyosarcoma
Syndrome
Characteristics
Gene
Li-Fraumeni
TP53
Neurofibromatosis
NF1
Overgrowth, skeletal
abnormalities, benign
tumors, rhabdomyosarcoma, malignant tumors
PTC
RHABDOMYOSARCOMA
Rhabdomyosarcoma was first described in 1850 by Wiener.82
Subsequently in the 1950s, Horne and Enterline published a
histologic classification system that remains the basis for the
system that is used today.83,84 Since the 1950s, the outcomes
of children with bladder/prostate rhabdomyosarcoma have
improved significantly. Progress has largely been due to collaborative trials, such as those conducted by the Intergroup
Rhabdomyosarcoma Study (IRS).
Histology
Prognosis
Sarcoma botryoides,
spindle cell
Favorable
5-Year Survival
Embryonal, pleomorphic
Intermediate
65-75%
Alveolar, undifferentiated
Unfavorable
40-55%
90%
Prognosis
In addition to stage of disease and treatment risk groups, histologic classification continues to be one of the strongest predictors of outcome in rhabdomyosarcoma (Table 49-3).
chapter
Treatment
New protocols have been developed by the IRS/COG. A broad
overview highlighting principles of chemotherapy and radiation therapy follows.
Low-Risk Group
The low-risk group includes patients with localized embryonal tumors occurring at favorable sites (stage I), including botryoid rhabdomyosarcoma (groups I, II, and III), and patients
with embryonal tumors located at unfavorable sites who have
completely resected disease or only microscopic residual
disease. Current protocols attempt to reduce the cumulative
doses of cyclophosphamide in this population to limit toxicity.
The low-risk group would be divided into two subsets based
on stage, location, and clinical group. Patients treated in both
subsets would receive vincristine, actinomycin-D, and cyclophosphamide (VAC) for a total of four cycles with diminished
doses of cyclophosphamide. Patients in subset 1 would go on
to receive another four cycles of actinomycin-D and vincristine
(V), whereas patients in subset 2 would continue V for another
12 weeks. Radiation therapy would be given at week 13.
Timing of radiation continues to be a controversial subject in
patients with rhabdomyosarcoma.
Intermediate-Risk Group
The intermediate-risk group includes patients with embryonal
tumors occurring at unfavorable sites (i.e., bladder/prostate),
patients with gross residual disease (group III), patients with
metastatic embryonal rhabdomyosarcoma who are younger
than 10 years, and patients with nonmetastatic alveolar or
undifferentiated sarcoma. In this group, the likelihood of
bladder preservation decreases to 25% to 45% based on IRS II
and IRS III data. Complete resection at the initial procedure is
typically impossible.
In the current protocol, irinotecan is combined with vincristine in a randomization arm. Irinotecan belongs to a newer
class of chemotherapeutic agents (topoisomerase I inhibitors)
and has shown promise in phase I studies.105,106 Patients in
the intermediate-risk group would be randomly assigned to
receive VAC alone or VAC alternating with vincristine/irinotecan for 43 weeks of therapy. Local radiotherapy would be
669
High-Risk Group
The high-risk group consists primarily of patients with alveolar and undifferentiated rhabdomyosarcoma and patients
older than 10 years with embryonal tumors and metastatic
disease. Because of the historically poor response to chemotherapy by high-risk patients, the next protocol is expected
to combine VAC cycles with interval-compressed multiagent
chemotherapy. Specifically, patients would receive intervalcompressed cycles of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide. Patients
also would receive an up-front window of vincristine/irinotecan to assess further the response of this combination in previously untreated high-risk patients. Irinotecan also would be
used in conjunction with radiotherapy, as a radiosensitizer.
Tolerability and toxicity of this combination have not been
studied previously in children and would be assessed in this
study at weeks 19 to 23.
Late Effects
Patients treated for bladder prostate rhabdomyosarcoma,
similar to patients with Wilms tumor, are at risk for the systemic late effects associated with chemotherapy and radiation
therapy. The apparent preliminary success of bladder preservation has drawn particular attention to late effects related to
genitourinary tract function.
670
part
IRS IV (1993-1997). Eighty-eight patients with bladder preservation rhabdomyosarcoma were identified. Seventy percent of these tumors arose from the bladder. Overall 6-year
survival was 82%; however, event-free survival was 77% at
a mean of 6.1 years follow-up. Of 55 patients who retained
their bladders, only 36 (40%) had normal bladder function. Urodynamics and standardized questionnaires were not
used, suggesting that the true extent of dysfunction may be
greater.135
More recently, the International Workshop reported on
the late effects in 164 patients undergoing treatment for bladder/prostate rhabdomyosarcoma.136 After biopsy only, 48%
of patients had an intact bladder. Of patients 6 years old or
older, 31% had urinary incontinence; 27% of patients who
had undergone partial cystectomy had similar complaints.
Fifty-five percent of patients had recurrent urinary tract
infections, 40% had decreased renal function, and 25% had
hematuria.136
Soler and colleagues137 presented data on eight children
undergoing treatment. Three patients (37.5%) were asymptomatic and had normal urodynamic studies, and another
patient had dysuria (this patient went on to continent urinary
diversion with transverse colon). The other four patients had
urologic complaints, and their urodynamic findings included
reduced bladder capacity in four, overactivity in two, urgency
in three, and suprapubic pain during filling.
There is a paucity of objective data regarding bladder
function in patients treated for bladder/prostate rhabdomyosarcoma. Although many authors have reported reasonable
bladder function after therapy, objective analysis with urodynamics, standardized questionnaires, or imaging has not been
performed.138-140 This question is central to determining the
effectiveness of current treatment strategies.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
50
WILMS TUMOR
Mohan S. Gundeti
Wilms tumor (nephroblastoma) is the most common primary malignant solid renal tumor of the kidney in childhood.
The incidence rate in the United Kingdom is 7 per 1 million
children, accounting for approximately 80 to 90 cases each
year. In the United States, the incidence is similar with 8.1
cases per 1 million children accounting for 450 to 500 cases
each year.1
Since the first description of Wilms tumor by Wilms in the
18th century, the first nephrectomy by Jessop2 in 1877, and
the addition of radiotherapy in 1915, there have been many
advances in the treatment of this tumor, especially in the latter
part of the 20th century. The chemotherapeutic agent actinomycin was added in 1953 by Farber and colleagues,3 and vincristine was added in 1963 by Sutow and coworkers.4
Wilms tumor is an ideal example of the progress made by
a multidisciplinary team (i.e., surgeon, oncologist, geneticist,
and pathologist) working toward a single goalimproving
survival of these children. The introduction of trials by the
International Society of Pediatric Oncology in Europe (SIOP)
and the National Wilms Tumor Study (NWTS) in the United
States has been extremely beneficial in treatment guidelines and strategies. These trials have resulted in an overall
improved survival rate and reduced morbidity compared
with previous survivals rate of 15% with surgery alone5 and
40% with surgery and radiotherapy.6 Present and future
work is directed toward finding new therapeutic strategies
for high-risk patients, reducing the therapy for low-risk
patients, and studying the new biologic parameters of the
tumor.
EPIDEMIOLOGY
Tumor occurrence is almost equal in boys and girls, with a
slightly higher predominance in girls in the United States.7
The median age of presentation is 40 months (3.5 years), and
the tumor is seen until age 5 to 6 years. Most tumors at presentation are unilateral; about 5% to 6% are bilateral. Bilateral
tumors are especially common in girls with an earlier age of
presentation (28 months).8 There is some ethnic variation in
the incidence, with lower reported rates in east Asia compared
with the United States and Europe.7 Familial Wilms tumor
occurs in 1% to 2% of all cases.9
WT1 (11p13)
74 gene is usually expressed in the developing genitourinary tract and has been detected in the developing kidney at
20 weeks of gestation; it is rarely found in adults. This pattern
suggests its importance in the role of renal development and
differentiation. Abnormal expression, lack of expression, or
deletion usually leads to Wilms tumor. The exact location of
this gene is on short chromosome 11 at the p13 position. This
abnormality of 74 is associated with WAGR syndrome16 and
Denys-Drash syndrome.17
WT2 (11p15)
An excess of material on the chromosome as an extra band
at 11p15 in the 74 gene coding for insulin-like growth factor has been found. This excess material is responsible for
the overgrowth as seen in hemihypertrophy and BeckwithWiedemann syndrome.18
672
PART
VIII:
Urogenital Tumors
Overgrowth
Non-overgrowth
Beckwith-Wiedemann
Denys-Drash
Hemihypertrophy
WAGR
Perlman
Aniridia
Sotos
Depending on their location in the kidney, these nephrogenic rests are divided into intralobar rests (i.e., within the
lobe of the kidney) or perilobar rests (i.e., at the periphery of
the kidney). Perilobar nephrogenic rests are associated with
11p15 (74): Beckwith-Wiedemann syndrome and synchronous bilateral Wilms tumor. Intralobar nephrogenic rests
are associated with 11p13 (74): aniridia, Denys-Drash syndrome, and metachronous Wilms tumor (Fig. 50-2).24
Figure 50-1 A, Beckwith-Wiedemann syndrome in high-risk syndromes. B, Isolated hemihypertrophy in high-risk syndromes. (A, Courtesy of
Mr. D. T. Wilcox.)
CHAPTER
673
Intralobar
nephroblastomatosis
(ILNR)
Pelvis
Ureter
Calyces
PRESENTATION
674
PART
Table 50-2
VIII:
Urogenital Tumors
Benign
Malignant
Renal abscess
Nephroblastoma
Multicystic kidney
Neuroblastoma
Multilocular cyst
Xanthogranulomatous pyelonephritis
remnants into Wilms tumor during embryogenesis is considered the cause. These tumors are located in the retroperitoneum,32 in the uterus, in the cervix, in the pelvis, along the
line of spermatic cord testes, and in the thorax. The histologic
characteristics are the same.
Ultrasonography
Ultrasound scan is the initial fast noninvasive test to help
to distinguish between a cyst and tumor, and to detect
small tumor in the opposite kidney or liver and abdominal
metastasis. Ultrasound with Doppler also detects inferior
vena caval patency. The SIOP protocol places emphasis on
three-dimensional measurement of the tumor on ultrasound
scans. The challenge with ultrasound is differentiating the
nephrogenic rests from tumor. The nephrogenic rests are usually ovoid, static, supercial, and multiple compared with
tumor, which is rounded, expanding, deeply situated, and
solitary.
Echocardiography
Echocardiography is performed to detect the intra-atrial
extension of the tumor thrombus, which was found in 20% of
children with thrombus. Echocardiography is also mandatory
before starting doxorubicin (Adriamycin) as part of chemotherapy in high-risk children.
Chest Radiograph
Posteroanterior and lateral radiographic views to detect pulmonary metastasis are mandatory. The chest radiograph
has limitations in detecting micrometastasis, however. Most
centers prefer performing a CT scan of the chest at the same
time as the abdomen, which may be more convenient and specic for the detection of metastasis.
CHAPTER
675
B
Figure 50-7 A, CT scan showing inferior vena cava thrombus. B, MRI scan showing inferior vena cava thrombus with tumor.
Table 50-3
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
Surgery
Radical nephrectomy for removal of the primary tumor
with the kidney is the mainstay of treatment. This procedure
allows the removal of the primary tumor and accurate staging
of the tumor. The usual approach is transperitoneal through a
transverse abdominal incision, which gives good access to the
tumor and vasculature.
The principles of surgery are as follows:
1. Palpation of liver, abdomen, and para-aortic region for
regional spread of disease
2. Removal of intact specimen in total
3. Avoidance of local spillage because these children have a
sixfold increase in local abdominal relapse36
4. Nodal sampling rather than clearance because there is no
added advantage in the long-term survival37
5. Proper identication and avoidance of injury to
contralateral renal vessels, aorta, and iliac and superior
mesenteric arteries38
6. Palpation of the renal vein and inferior vena cava before
ligation to rule out thrombus
From Qualman SJ, Bowen J, Amin MB, et al. Protocol for the examination
of specimen from patients with Wilms tumor or other renal tumors of childhood. !RCH0ATHOL,AB-ED 2003;127:1280-1289.
676
PART
VIII:
Urogenital Tumors
Surgical Steps
After initial palpation of the abdomen, the colon is reected and
moved completely away from the kidney. Major vessels (i.e.,
aorta, inferior vena cava, renal artery and vein, superior mesenteric artery) are identied. Mobilization of the tumor toward
the surgeon helps in exposure of the renal hilum. Renal vessels
are ligated after conrmation. The ureter is divided, and the
specimen is removed in total. The adrenal may not need to be
removed if it is clearly away from the tumor (Fig. 50-8).
CHAPTER
Surgical Complications
677
NWTS-1 (1969-1973)
During NWTS-1, 606 patients were included in the study
group. The conclusion was that postoperative radiotherapy is
effective for selected patients. The combination of vincristine
and actinomycin D is more effective than either drug alone.
There is no evidence for a role for preoperative vincristine, but
numbers were too small to be conclusive.45
NWTS-2 (1975-1978)
Laparoscopic Approach
In a more recent report,42 the primary nephrectomy was performed by a transperitoneal approach after preoperative chemotherapy. There are no randomized control studies looking
at the benecial role of this approach.
NWTS Protocols
NWTS was established in 1969 to determine treatment protocols to improve the survival and reduce the toxicity of
adjuvant treatment. Over the last 40 years, the treatment has
NWTS-3 (1979-1985)
NWTS-4 (1986-1994)
In NWTS-4, 905 previously untreated children were randomly
assigned for duration of treatment or for single dose versus
divided dose of drug administration. The aim was to evaluate
the efcacy, toxicity, and costs of the administration of different
regimens for the treatment of Wilms tumor. The conclusion
was that 6-month treatment was more effective than 15-month
treatment with lower cost of treatment.48
NWTS-5
The aim of NWTS-5 is the evaluation of biologic prognostic
factors on tumor specimens to predict the risk of relapse (e.g.,
16q1p),20 which would allow a reduction in the amount of
therapy for low-risk patients, while maximizing therapy for
high-risk patients (Table 50-4).
678
PART
VIII:
Table 50-4
Urogenital Tumors
Postoperative Treatment Protocol (after Nephrectomy) According to National Wilms Tumor Study5
Radiotherapy
Chemotherapy
Stage 1, 2 FH
None
Stage 1 anaplasia
1080 cGY*
Yes
Yes
Stage 3, 4 FH
Stage 2-4 focal anaplasia
Stage 2-4 diffuse anaplasia
Stage 1-4 CCSK
Stage 1-4 RTK
*Stage
SIOP-1 (1971-1974)
In SIOP-1, 398 patients were studied, and the conclusion was
that prenephrectomy radiotherapy reduces the number of
tumor ruptures and produces a more favorable stage distribution after surgery. Postoperative prolonged administration
of actinomycin D does not contribute to better disease-free
survival.53
SIOP-2 (1974-1976)
In SIOP-2, 138 patients were studied to conrm the ndings of
SIOP-1 without randomization. The conclusion was that there
was no need for a two-drug combination (vincristine and actinomycin D) to be given for more than 9 months in the postoperative period.
SIOP-5 (1977-1979)
In SIOP-5, 433 patients were randomly assigned for preoperative chemotherapy with vincristine/actinomycin D and
radiotherapy. The conclusion was that chemotherapy is comparable to radiotherapy in regard to tumor rupture or stage
distribution during the nephrectomy.54
SIOP-6 (1980-1987)
In SIOP-6, 1095 patients were enrolled in this study, which
answered the following questions:
1. After preoperative chemotherapy and surgery, 17 weeks of
postoperative chemotherapy with vincristine and actinomycin D is as effective as 38 weeks in stage 1.
2. The arm looking at the need for postoperative
radiotherapy in stage 2 without nodal involvement was
prematurely withdrawn because of relapse in cases
without radiotherapy.
3. Stage 2 nodal involvement and stage 3 patients had
overall better disease-free survival with the addition of
doxorubicin.55
SIOP-9 (1987-1991)
Of 852 patients in SIOP-9, 382 had eligible localized tumors
and were randomly assigned for the duration of the preoperative chemotherapy. At the end of the study, it was shown that
4 weeks of chemotherapy is equivalent to 8 weeks in terms of
SIOP 2001
SIOP 2001 is the current ongoing study (Tables 50-5 and
50-6). On the basis of previous SIOP studies, the aims are as
follows:
1. Conrm continued use of preoperative chemotherapy for
4 weeks (vincristine and actinomycin D) in stage 1 patients;
patients with metastasis at diagnosis would continue
to receive chemotherapy for 6 weeks with addition of
doxorubicin
2. Perform a multicenter prospective study to nd out if
doxorubicin is necessary in intermediate-risk tumors and
local stage 2 and 3
3. Study specic histologic subtypes in relation to prognosis
(e.g., epithelial and stromal dominant are good prognostic
factors, blastemal is a poor prognostic factor), studying
signicance of necrosis in postchemotherapy specimens
4. Minimize acute and late toxicity of therapy without
affecting survival in focal anaplasia and intermediate-risk
tumors
5. Determine the relationship of tumor volume after
chemotherapy and histologic subtypes
6. Establish single-dose actinomycin D as opposed to a
fractionated schedule
7. Perform a biologic study to correlate allele loss at 16q1p
with relapse-free and overall survival
CHAPTER
Table 50-5
For Primary
Nephrectomy Cases
Low-risk tumors
Low-risk tumors
Mesoblastic nephroma
Mesoblastic nephroma
Cystic partially
differentiated
nephroblastoma
Completely necrotic
nephroblastoma
Intermediate-risk tumors
Intermediate-risk tumors
Nephroblastomaepithelial
type
Nonanaplastic
nephroblastoma
and its variant
Nephroblastomastromal type
Nephroblastoma
focal anaplasia
Nephroblastomamixed type
Nephroblastomaregressive type
Nephroblastomafocal anaplasia
High-risk tumors
High-risk tumors
Nephroblastomablastemal type
Nephroblastoma
diffuse anaplasia
Nephroblastomadiffuse
anaplasia
Rhabdoid tumor of
the kidney
Table 50-6
679
Stage 2
Stage 3
Low risk
No further treatment
AV-2
AV-2
Intermediate risk
AV-1*
High risk
AVD
High-risk + RT
High-risk + RT
*Regimen
680
PART
VIII:
Urogenital Tumors
Total nephrectomy
Excision biopsy
Partial nephrectomy
Figure 50-12 Surgical options for bilateral Wilms tumor depending
on the tumor volume. (Courtesy of Mr. P. G. Duffy.)
Stage 187%
Stage 285%
Stage 374%
Stage 460% to 70%
The favorable-histology tumors have good survival compared with the anaplastic variety. According to NWTS-3, in
patients of all stages randomized, the disease-free survival
was 86% for favorable-histology tumors and 64% for anaplastic tumors. Although age is not an independent prognostic
factor, it has significance in extremes of ages, such as in neonates and adults.
In regard to chromosomal abnormalities, patients with
tumor-specific loss of heterozygosity for chromosomes 1p
and 16q have a higher relapse rate than patients without loss
of heterozygosity.20 Expression of high levels of telomerase
(TERT mRNA, or telomerase RNA template) is associated
with a high recurrence rate.62 DNA flow cytometry, vascular
endothelial growth factor, hyaluronic acid, fibroblast growth
factor, and serum renin are under study to determine their
exact prognostic role and the potential ability to identify
recurrence early with these markers (Table 50-7).
The NWTS follow-up protocol is somewhat similar to
SIOP. The aim is to detect potential metastasis early and the
sequelae of therapy (i.e., radiotherapy and chemotherapy) on
various organs.
MANAGEMENT OF NEPHROBLASTOMATOSIS
The characteristic feature of nephroblastomatosis is nonenhancement (homogeneous) with contrast CT and MRI. Wilms tumor
is generally heterogeneous and enhances with contrast CT.
The management of nephroblastomatosis is controversial.
A more recent retrospective long-term study of the perilobar
hyperplastic variety of Wilms tumor showed that children who
were not treated all developed Wilms tumor compared with children treated with chemotherapy or surgery. The interval between
diagnosis and development of tumor was 13 to 116 months
(median 42 months).63 Children with multifocal nephroblastomatosis in a kidney removed for Wilms tumor are at an increased
risk for contralateral Wilms tumor and need ultrasound scans
every 3 months. If these contralateral tumors are increasing in size
during the follow-up period, a local excision (nephron-sparing
surgery) should be contemplated. Another report suggested that
chemotherapy or local excision (nephron-sparing surgery) for
multifocal enlarging nephroblastomatosis is effective.64
CHAPTER
Table 50-7
681
On Treatment
Chest x-ray
Abdominal ultrasound
Serum creatinine
Blood pressure
Echocardiography
At diagnosis
Before DOX
At end of therapy
GFR with 51Cr EDTA before and after every third course of carboplatin
End of treatment
In children with renal dysfunction
Off Treatment
Chest x-ray
Abdominal ultrasound
Every 3 mo to age 7 yr if patient was <12 mo old at initial diagnosis, nephrogenic rest on
nephrectomy specimen, initial bilateral tumors, partial nephrectomy
Blood pressure
Annually
Growth
Every 3 mo for 2 years or clinical examination in compliant patients for all other patients
51Cr
682
PART
VIII:
Urogenital Tumors
form of hematuria and abdominal mass is common. Radiologically, it may be difcult to differentiate renal cell carcinoma from Wilms tumor. The common histologic variety
is papillary cell carcinoma.79 Treatment is radical nephrectomy, although partial nephrectomy has been reported.78 The
overall survival is more than 80% with a mean follow-up of
4.9 years.78
CHAPTER
Cardiac Dysfunction
Doxorubicin is known for its cardiotoxicity. SIOP has shown
that post-treatment left ventricular fractional shortening was
reduced in 2.5% of patients. Abnormal electrocardiogram ndings that were not detectable before therapy were found in
5.6% of children. The median interval was 2.9 years from the
median post-treatment interval.91 This was very low, presumably secondary to the short post-treatment interval. In a large
single institutional study, 25% of the anthracycline-treated
group showed cardiac abnormalities. All but one of these
patients had increased left ventricular afterload. The median
interval for follow-up was 7.1 years. There was direct correlation with the dose and intensity.92
683
Reproductive System
The germ cells are more sensitive to radiation damage than
Leydig cells. In a long-term follow-up, survivors have shown
impaired spermatogenesis.96 Vincristine is also implicated as a
risk factor for spermatogenesis. Ovarian failure after abdominal radiation was about 68%,97 and there have been one or
two small or absent ovaries and a small uterus98 during the
follow-up. Fertility can be preserved if the pelvis is excluded
from the radiation eld; NWTS has reported pregnancy in
these patients.99 Women who received ank radiation therapy
as girls as part of their treatment for Wilms tumors are at
increased risk of fetal malposition and premature labor. The
offspring of these women are at risk for low birth weight, premature (<36 weeks gestation) birth, and occurrence of congenital malformations.100
Liver Dysfunction
Acute and chronic hepatitis is a sequela of radiation therapy.
Concurrent administration of actinomycin D and vincristine
causes severe toxicity and is dose-dependent.101
Renal Dysfunction
Chemotherapy or radiation eld covering the remaining kidney or hyperltration leads to temporary or chronic nephropathy. A single institutional study showed renal dysfunction
in 32%, including 19% with a low glomerular ltration rate
(<80 mL/min/1.73 m2), 11% with hypertension, and 9% with
increased urinary albumin excretion, over a 13-year follow-up
after treatment.102 In contrast, in another study with a median
follow-up of 8.8 years, there was an encouraging report that
the treatment for Wilms tumor rarely causes long-term renal
impairment.103 This change may be due to modied new protocols of treatment over last 15 years.
Pulmonary Dysfunction
The survivors of Wilms tumor who have received the either
whole-lung irradiation or abdominal radiation have abnormal pulmonary function in the form of reduced vital and total
lung capacity.93 Chemotherapeutic agents actinomycin D and
doxorubicin potentiate the pulmonary dysfunction. Interstitial
pneumonitis is also reported in the long-term follow-up.
Musculoskeletal System
Another consequence of radiotherapy with the addition of
chemotherapy is abnormal musculoskeletal development. In
a long-term review (median follow-up 15 years), the percentages of patients who developed muscular hypoplasia, limblength inequality, kyphosis, and iliac wing hypoplasia were
16.7%, 11.9%, 7.1%, and 7.1%. Scoliosis was seen in 42.9% and
was directly related to the duration of follow-up and radiation dose.86 The surviving children have stature loss, which is
FUTURE CHALLENGES
Work of NWTS and SIOP in relation to optimizing the management protocols for children with Wilms tumor and nding
the biologic parameters is ongoing and is expected to add to
improved survival and reduction of long-term therapy-related
toxicity. Immunotherapy105 is a potential challenge for the
future, with the hope that the current research will transpire
into future therapy, especially the characteristic expression of
74 gene peptides and recognition by cellular and humoral
immune responses, which acts as a potential target antigen in
immunotherapeutic trials.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
51
RHABDOMYOSARCOMA
ETIOLOGY
The cause of rhabdomyosarcoma is unknown, but is thought
to be multifactorial. Most tumors occur sporadically, with no
predisposing risk factors. Congenital and environmental factors have been shown to influence the incidence of rhabdomyosarcoma, however. In a large epidemiologic study, 5% of
affected children were found to have a strong family history.
Congenital Rhabdomyosarcoma
Rhabdomyosarcoma is associated with Li-Fraumeni syndrome, neurofibromatosis, Noonan syndrome, BeckwithWiedemann syndrome,10 Costello syndrome,11 fetal alcohol
syndrome, and basal cell nevus syndrome (Table 51-1).
Li-Fraumeni syndrome has an autosomal dominant inheritance.12-14 The diagnosis of Li-Fraumeni syndrome raises the
problem of preventive screening for mutation carriers who
have a high lifetime risk of malignancyestimated 73% for
male carriers and 100% for female carriers.15 These families
have various malignant conditions, including rhabdomyosarcoma, breast cancer, brain tumors, adrenal carcinoma, and
leukemia. Typically, families have a history of premenopausal
breast cancer, and the child is usually male and younger than
2 years.12 A diagnosis of Li-Fraumeni syndrome should be
considered in every child younger than 3 years diagnosed
with rhabdomyosarcoma.15 This syndrome has been linked
with abnormalities of the tumor-suppressor gene p53, which
is located on the short arm of chromosome 17.16 The gene
p53 controls cellular DNA damage during cell proliferation;
a defect in this function can lead to abnormal cell proliferation. Independent of Li-Fraumeni syndrome, mutations of the
p53 gene have been identified in 10% of children with rhabdomyosarcoma.17
Patients with neurofibromatosis 1 are at greater risk of several
malignancies. A study from IRS IV reported the prevalence of
neurofibromatosis 1 in children diagnosed with rhabdomyosarcoma as approximately 0.5%. Rhabdomyosarcoma of bladder
and prostate were more common in this group of patients and
did not seem to be different from other children with rhabdomyosarcoma in terms of prognosis.18 Patients who develop a second
malignancy after successful treatment of rhabdomyosarcoma
may have a genetic predisposition, with Li-Fraumeni syndrome,
neurofibromatosis, and chromosomal translocations occurring
with a greater than expected incidence in these patients.1
Costello syndrome is a rare congenital anomaly syndrome
associated with an increase in the number of solid tumors, the
most common being rhabdomyosarcoma followed by neuroblastoma and bladder carcinoma. The tumor frequency in these
patients is 17%. It may be classified as an overgrowth syndrome
because of slightly increased birth weight and relative macrocephaly; it is characterized by severe postnatal failure to thrive
and short stature.11 With a better understanding of the human
chapter
30
685
25
Million/year
51: Rhabdomyosarcoma
Congenital
Li-Fraumeni syndrome
20
Neurofibromatosis
15
10
p53 mutations
Noonan syndrome
C
e
sy ntr
st al
em ne
tu rvo
m us
or
s
Ly
m
ph
om
N
a
eu
ro
bl
as
to
m
a
W
ilm
s
R
ha
tu
m
bd
or
om
yo
sa
rc
om
a
Beckwith-Wiedemann syndrome
Costello syndrome
Acquired
Marijuana
Cocaine
Maternal exposure to radiation
Maternal history of stillbirths
Retroperitoneum
13%
Extremity
15%
Orbital
8%
Other
head and neck
7%
Miscellaneous
4%
Parameningeal
24%
Genitourinary
29%
Acquired Rhabdomyosarcoma
Many environmental factors have been implicated in rhabdomyosarcoma; these may work in conjunction with or independently of genetic risk factors. Chemical risk factors include
chlorinated phenoxy herbicides, parental use of marijuana,
parental use of cocaine, and maternal alcohol ingestion.19
Maternal exposure to radiation and a maternal history of stillbirths also increase the tumor risk to the fetus.20 Some animal
studies have suggested a link with viral illness, although this
has not been identified in humans.
PATHOLOGY
Anatomic Sites
Pediatric urologists see patients presenting with rhabdomyosarcoma arising from the urinary tract, genital tract, and other
nongenitourinary sites in the pelvis. The most common sites
Macroscopic Appearance
There are no specific gross features of rhabdomyosarcoma
except sarcoma botryoides. This is a tumor that arises from
a hollow organ, typically the vagina or bladder, and usually
manifests as a prolapsing tumor resembling a bunch of grapes
(Fig. 51-3). Children younger than 4 years typically present
with sarcoma botryoides. The remaining tumors are normally
firm and nodular; they appear to be well circumscribed when
they actually are often infiltrating surrounding tissues.
686
part
Histology
Incidence(%)*
Prognosis
Embryonal, botryoid
Favorable
95
Good
Favorable
88
Good
Embryonal, NOS
Favorable
49
66
Intermediate
Unfavorable
31
53
Poor
Anaplasia, diffuse
Unfavorable
45
Poor
Undifferentiated sarcoma
Unfavorable
44
Poor
*Total incidence is only 94%; approximately 6% of accepted cases fall into the sarcoma NOS category because of insufficient or inadequate tissue to make a more
specific diagnosis.
NOS, not otherwise specified.
Embryonal Rhabdomyosarcoma
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51: Rhabdomyosarcoma
687
Alveolar Rhabdomyosarcoma
Alveolar rhabdomyosarcoma is the next most common type; it
usually occurs in older children and in adults. It resembles 10to 21-week gestational striated muscle. The features are clusters of small round cells adherent to fibrous septa, giving the
appearance of well-defined alveolar spaces. Cross-striations
are uncommon (Fig. 51-5). Occasionally, there are clusters of
cells separated by fibrous septa, but the alveolar spaces are not
present. These are called solid alveolar rhabdomyosarcoma.21
There is no evidence of a different prognosis for solid versus
classic alveolar rhabdomyosarcoma, but both have a poor
prognosis.8 Some tumors can have features of embryonal and
alveolar types and are classified as mixed tumors.
Undifferentiated Rhabdomyosarcoma
Some tumors are so undifferentiated that it is difficult to classify them. They are composed of primitive, small round cells
that can often resemble Ewing sarcoma. The difference is
that they arise from soft tissue not bone. With an increasing
understanding of the immunohistochemistry of these tumors,
undifferentiated tumors now can frequently be identified as
rhabdomyosarcomas. Rhabdomyosarcoma tumors frequently
express the muscle proteins actin, myosin, and desmin.23,24 In
addition, with electron microscopy, the Z bands associated
with actin-myosin bundles can help to distinguish rhabdomyosarcoma from other small round cell tumors. Perhaps
the most sensitive and specific group of proteins useful in the
immunohistochemical diagnosis of rhabdomyosarcoma are
muscle transcription factors MyoD and myogenin. These proteins, which define the earliest events in molecular determination of myoblastic lineage, are paradoxically expressed at
With a better understanding of the human genome, chromosomal and gene anomalies are increasingly being identified
in patients and families with rhabdomyosarcoma. Embryonal
and alveolar tumors can now be identified by different structural chromosomal changes. Embryonal tumors have a loss of
heterozygosity on the long arm of chromosome 11. The paternal DNA appears duplicated, with the maternal DNA absent.
Although a single key genetic mutation cannot be identified
in embryonal rhabdomyosarcomas, aberrations affecting the
methylation status of key genes such as MyoD26 and p2127 have
been identified. These findings suggest embryonal rhabdomyosarcoma may be epigenetic rather than genetic.
In alveolar rhabdomyosarcoma, key genetic mutations
have been identified. Unique gene fusions of PAX3 or PAX7
(on chromosomes 1 and 2) and the FOXO1a (FKHR) gene
on chromosome 13 specifically identify alveolar rhabdomyosarcoma.28 Most alveolar tumors express PAX3-FKHR
or PAX7-FKHR gene fusions resulting from t(2;13) or t(1;13)
translocations. The PAX-3 gene, which is involved in transcription regulation, is moved to a site close to FKHR, which
is part of the forkhead family of transcription factors. Of the
alveolar rhabdomyosarcoma patients involved in IRS IV, 55%
had PAX3-FKHR and 22% had PAX7-FKHR fusion transcripts.
All other patients lacked these transcripts. In patients presenting with metastatic disease, the survival rate was significantly
higher in patients with PAX7-FKHR fusion transcripts (75%)
compared with patients who had PAX3-FKHR fusion (8%).
These patients have a significantly increased risk of failure
and death.29,30 Both translocations can now be identified by
polymerase chain reaction and can be used to diagnose alveolar rhabdomyosarcoma and may predict outcome.
Increased transcriptional levels of some growth factors or
receptors in rhabdomyosarcomas are found to be associated
with survival. Rhabdomyosarcomas with increased plateletderived growth factor receptors and insulin-like growth
factor (IGF) were associated with decreased survival.31 The
loss of heterozygosity in embryonal rhabdomyosarcomas is
closely approximated with the IGF-II gene, which can lead to
overexpression of IGF-II.32 Alveolar and embryonal tumors
produce excess IGF-II, and in experimental studies, blocking
IGF receptors resulted in an inhibition of tumor growth.33,34
Tumor Spread
Rhabdomyosarcoma can spread by local infiltration into surrounding tissues. This depends on the site of the primary
tumor, but it is unusual for tumors to spread into the rectum.
Pelvic tumors also can spread directly to the omentum. Spread
to local and regional lymph nodes is also a common feature,
occurring in approximately 20% at presentation.35 Distant
metastatic spread is present in nearly a quarter of patients, and
the most frequently affected sites are the lung (40% to 50%),
bone marrow (20%), and bone (10%); metastases to liver and
brain are rare.22,36,37
CLINICAL FEATURES
The presenting signs and symptoms of rhabdomyosarcoma
vary and depend on the site of the local disease and the presence or absence of metastatic spread.
688
part
of Rhabdomyosarcoma
Visible tumor
Abdominal mass
Prolapsing tumor (sarcoma
botryoides)
Strangury
Mucosal damage
Urinary infection
Urinary retention
Urinary incontinence
Hematuria
Vaginal discharge
Passing tumor fragments
Local Disease
The most common presenting feature of the primary tumor
site is the visible sign of the tumor. This can occur in two
wayseither as a prolapsing mass seen with sarcoma botryoides or as a large abdominal mass (Table 51-3). These tumors
often manifest as an abdominal mass because pelvic tumors
can grow very large before they impinge on the surrounding rectum or bladder sufficiently to cause symptoms. Other
presenting features are signs of bladder outlet obstruction or
mucosal damage or both.38,39
Distant Spread
Approximately 25% of patients have metastatic spread at the
time of presentation.37 A few patients present only with systemic signs associated with diffuse metastatic spread; these
include fever, weight loss, anorexia, and pain. In these patients,
the site of the primary tumor may become apparent only after
considerable investigation.
INVESTIGATIONS
Blood and Urine
Hematologic investigations should include hemoglobin
level, a white blood cell analysis, a platelet count, and clotting studies. Serum chemistry studies to evaluate renal
and liver function are required. In contrast to the situation
with neuroblastoma and liver tumors, no specific serum
or urine markers of rhabdomyosarcoma have been identified. In some patients, creatine kinase levels are increased,
which can give a clue to the underlying diagnosis. Standard
urinalysis is necessary to exclude concurrent urinary tract
infections.22
Imaging
Accurate reproducible imaging is vital to the successful management of children with rhabdomyosarcoma. Imaging is
required to identify the organ of origin and to assess the surgical management options. It is also used to identify local and
metastatic spread. In addition, after therapy is initiated, imaging is used to monitor tumor responses.40
the bladder.
Local Disease
The initial imaging is often performed using ultrasound (Fig.
51-6); however, once a tumor has been confirmed, crosssectional imaging of the primary site is required. Either computed tomography (CT) (Fig. 51-7) or magnetic resonance
imaging (MRI) can be used. Both should be performed using
intravenous contrast material, with care being taken to record
measurements of the tumor in at least two directions.40 In terms
of diagnostic accuracy, there is little difference between CT and
MRI, although CT may be superior in assessing abdominal
lymphadenopathy. Because of the lack of ionizing radiation
and multiplanar capabilities, MRI is recommended by many
radiologists.40 To ensure consistent imaging, the same modality should be used to follow the tumor response to therapy. In
addition to visualization of the primary tumor site, the local
and the regional lymph nodes must be identified.
Although MRI is recommended for all genitourinary tumors, it
has its problems. Edema after radiotherapy can be misinterpreted
as residual disease in 20% of cases, using cross-sectional imaging
techniques.41 On T2-weighted images, urine images brightly, and
this can obscure tumor in the bladder wall. Gadolinium enhancement is probably best avoided because it can lead to layered contrast material in the bladder, which can confuse interpretation.
chapter
51: Rhabdomyosarcoma
689
Figure 51-9 Intravenous urogram shows bladder rhabdomyosarcoma as a filling defect within the bladder.
Distant Spread
At the initial presentation, distant metastases are present in
25% of patients; consequently, the common sites for distant
metastases require imaging. Chest CT should be used to identify lung metastases even in the presence of a normal chest
radiograph. Where available, spiral CT should be used in preference to conventional CT because it is superior in detecting
lung lesions.40 Positron emission tomography has been used to
detect metastases, but it is not considered a standard staging
tool for rhabdomyosarcoma currently.7
Bone marrow aspiration is used to investigate marrow
invasion, and bone scintigraphy can record the presence of
skeletal metastases. Bone scintigraphy, similar to all investigations, has false-negatives and identifies lesions in only 4% of
patients.40 This situation has caused some investigators to recommend bone scans only for patients with bone symptoms or
patients whose tumor has an unfavorable histologic appearance. This approach is still controversial.
Endoscopy
Patients in whom tumor in the bladder or vagina and uterus
is suspected on clinical and radiologic investigations require
endoscopy (Fig. 51-10). Endoscopy can be used to delineate
further the extent of the tumor and obtain tissue biopsy specimens. The advantages of endoscopic biopsy are that the risk of
needle tract seeding is eliminated, and it is less invasive than
open biopsy. Technically, obtaining a satisfactory biopsy specimen for tissue diagnosis can be difficult. Care must be taken to
avoid destroying the histologic appearance of the tissue by the
690
part
Rhabdomyosarcoma
Neurofibroma
Lymphohemangioma
Leiomyosarcoma
Adenocarcinoma
Clear cell adenocarcinoma
Benign adenosis
Squamous cell carcinoma
Inflammatory pseudotumor
From Snyder H, DAngio G, Evans A, Raney R. Pediatric oncology. In:
Walsh P, Retik A, Vaughan E, Wein A, eds. Campbells Urology. 7th ed. Philadelphia: Saunders; 1998:2210-2256.
Differential Diagnosis
Although rare, numerous tumors can mimic pelvic rhabdomyosarcoma (Table 51-4). In patients who present with
a prolapsing tumor indicating sarcoma botryoides, vaginal
prolapse, urethral prolapse, prolapsing ureterocele, and rare
urethral polyps should be excluded.
Clinical Staging
The two main study groups, IRS and SIOP, have staged rhabdomyosarcoma using two different systems. SIOP uses a pretreatment TNM staging system.42-44 Since its inception, IRS
has devised and has continued to use a staging system that
classifies these tumors by IRS group, which is determined by
extent of the initial tumor resection (Table 51-5). One of the
difficulties inherent in this system is that the staging depends
on the surgical excision. This can lead to interpatient staging
variability, depending on the extent of surgical resection individual surgeons perform.
Since the early 1990s, IRS has also used a clinical staging
system, which is a modification of the TNM staging system
that is based on the pretreatment assessment of tumor site and
size and regional and systemic tumor spread (Table 51-6).45
This system depends on the tumor invasiveness (T1 means the
tumor is confined to the anatomic site; T2 means extension of
tumor); the tumor size (<5 cm [Ta] or >5 cm [Tb]); the clinical
presence (N1) or absence of nodes (N0); and the presence (M1)
or absence (M0) of distant metastases. This system has been
modified to take into account the different outcomes associated with sites.22 The disadvantage of the TNM system is that
it can be difficult to identify tumor-positive nodes accurately
on imaging, or to differentiate them from inflammatory nodes.
This difficulty can lead to errors in pretreatment staging; however, with improvements in imaging techniques, the incidence
of staging errors should be reduced.
TREATMENT
Initial Treatment
Initial management is the symptomatic treatment of the presenting symptoms and a prompt diagnosis. If bladder drainage is required, urethral catheterization is preferred because
suprapubic drainage has resulted in the seeding of malignant
cells along the tract, leading to local recurrence. A tissue diagnosis is required before adjuvant therapy is begun. If possible, the tissue specimen should be obtained endoscopically
to avoid tract seeding; if this is not possible, the approach to
biopsy requires careful consideration. Ideally, the site of the
Tru-Cut biopsy should be planned so that at excisional surgery the biopsy site can be incorporated in the surgical incision. Generally, an adequate biopsy specimen can be obtained
using a Tru-Cut needle; rarely, a surgical biopsy is required.
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691
Stage
Sites*
Size
Favorable
T1 or T2
a or b
N0 or N1
or Nx
M0
Unfavorable
T1 or T2
N0 or Nx
M0
Principles of Radiotherapy
Unfavorable
T1 or T2
N1
M0
N0 or N1
or Nx
M0
a or b
N0 or N1
M1
All
T1 or T2
*Favorable
Curative Treatment
All patients with rhabdomyosarcoma are presumed to have
micrometastatic disease at diagnosis. The current standard
treatment includes a combination of chemotherapy with or
without adjuvant radiotherapy and surgical excision as a specific treatment directed at control of primary site.7
Principles of Chemotherapy
Early clinical trials concentrated on examining the effect of
single-agent chemotherapy. From these studies, many agents,
such as actinomycin D, cyclophosphamide, vincristine,
and doxorubicin, were found to be effective, although few
patients were cured.46 Use of these agents in combination led
to an improvement in survival. In the early 1960s, Pinkel and
Pinkren5 described combining surgery and radiotherapy with
prophylactic chemotherapy. When chemotherapy was added
to the therapy, survival increased from 47% to 85%.47 After
these studies, Wilbur48 expanded this use of chemotherapy
and gave repeated doses of vincristine, actinomycin D, and
cyclophosphamide to children with inoperable or metastatic
disease. Using this approach, Wilbur was able to prolong
survival in these patients.48 These initial studies showed that
combination chemotherapy can downstage inoperable tumors
to operable, and can improve survival in children with rhabdomyosarcoma.
Since these pioneering studies, large collaborative study
groups have been set up to identify new drug regimens,
improve survival, and reduce therapy-induced morbidity.
The current standard treatment for rhabdomyosarcoma established by IRS studies includes vincristine and actinomycin D
(VA), and vincristine, actinomycin D, and cyclophosphamide
(VAC). For the more favorable subset of low-risk patients, IRS
studies showed a 95% overall survival rate by VA therapy.
In metastatic rhabdomyosarcoma, using an upfront window
design, IRS studies have established the activity of many
agents in newly diagnosed patients, including ifosfamidedoxorubicin, ifosfamide-etoposide, melphalan-vincristine,
topotecan (an inhibitor of the enzyme topoisomerase),
topotecan-cyclophosphamide, and irinotecan. The overall
survival in the high-risk metastatic group remained low.7
In this group of patients, consolidation using a high-dose
Principles of Surgery
For many years, complete primary surgical excision of the
tumor was the only hope of survival. Long-term survival varied from 40% for vaginal tumors to 70% for bladder tumors.42
Surgery often involved complete pelvic exenteration. This
form of radical surgery, even when successful, resulted in
enormous morbidity. With the advent of chemotherapy and
radiotherapy, it has become possible to perform less aggressive, organ-preserving therapy without altering survival. The
role of surgery is now restricted to initial biopsy and then reassessment after induction chemotherapy. If there is complete
response to chemotherapy on imaging, there is no need for an
operation and biopsy to confirm the absence of tumor. If there
has been a partial response to therapy, surgery can achieve
a complete remission in more than 50% of patients. Whenever possible, surgery should be restricted to wide local excision, with emphasis on preserving organ function. In the few
patients with unresponsive primary disease and in patients
with local recurrence, more radical organ-removing surgery is
required. In patients who require secondary radical surgery,
survival is still greater than 80%.
Current therapy relies on tissue biopsy followed by multi
agent chemotherapy; after this, repeat imaging is performed. If
there is complete remission, chemotherapy is continued alone.
If there is partial remission, a second operation to excise the
tumor is performed. Second-look surgery after therapy may
692
part
Dry
Complete
response
Partial
response
Chemotherapy
Local excision
Wet
Wet at night
Complete
excision
Incomplete
excision
Chemotherapy
Radiotherapy
Chemotherapy
Stable
Tumor growth
Further surgery
OUTCOME
Overall survival for patients with pelvic rhabdomyosarcoma
has increased from approximately 30% to 80% to 90%.9 This
improved survival has been due to the introduction of new
chemotherapeutic agents and the use of radiotherapy. As more
patients survive, long-term problems appear; these can be secondary to the treatment or to the underlying genetic makeup of
the patient. Survival with minimal morbidity is now the main
aim of the international rhabdomyosarcoma study groups.
Bladder
Chemotherapy, in particular, therapy with cyclophosphamide,
and radiotherapy can cause hemorrhagic cystitis in 30% of
patients.57 Prophylaxis with mesna should be used with cyclophosphamide therapy, but in some cases the acute problem
can be severe enough to warrant direct bladder instillation
Kidney
The kidneys can be damaged by all three therapeutic modalities.57,62 Chemotherapeutic agents such as ifosfamide are nephrotoxic.62 Radiation therapy can cause direct renal injury and
secondary fibrosis and indirect injuryhydronephrosis resulting from a ureteral stricture after treatment.57 Finally, surgical
reconstruction using bowel increases the frequency of urinary
tract infection, ureteric strictures, and stone formation, which
all can result in renal damage.
Nongenitourinary Complications
Respiratory and cardiac complications can occur with drugs
such as cyclophosphamide, methotrexate, and bleomycin.71
In most patients, pulmonary function is impaired, but few are
symptomatic. Chest radiotherapy for lung metastases causes
pulmonary fibrosis in adolescents, but in younger children
it tends to impede chest wall growth, resulting in reduced
lung capacity. Abdominal radiotherapy has been associated
with chronic enteritis, strictures, and fistulas that can manifest many years after treatment. In an attempt to keep the
bowel out of the pelvis, some surgeons advocate the use of
a mesh sling that prevents the small bowel from entering the
pelvis during radiotherapy.72 Increased body mass index, high
incidence of hyperlipidemia, increased body fat content, and
persistent psychological stress have been reported in rhabdomyosarcoma survivors.67
Second Tumors
Long-term studies indicate that survivors of childhood rhabdomyosarcoma have a 2% to 6% chance of developing a
second tumor within 10 years of finishing treatment.73 Bone
tumors (osteogenic sarcoma) and acute nonlymphoblastic leukemia were the most common second neoplasms.72 Most solid
tumors occurred within the original radiation field, and most
of these patients had an initial tumor size greater than 5 cm.74
Risk factors for a second malignancy were genetic predisposition, such as Li-Fraumeni syndrome and neurofibromatosis;
a high radiation dose (>40 Gy); and high doses of cyclophosphamide.14
PROGNOSIS
Prognosis depends on the anatomic site and clinical group.
The histologic appearance may also be important, but the
histologic subtype and anatomic site are often associated;
chapter
51: Rhabdomyosarcoma
693
120
100
80
60
40
20
0
2
3
Years
Group I
Group II
Group III
Group IV
CONCLUSION
Enormous advances have been made in the treatment of children with rhabdomyosarcoma. Work now needs to concentrate
on two areas. First, improvements are needed in controlling
disease in patients who present with disseminated disease.
These represent more than half the total patients, and their
prognosis is still poor. Second, therapy needs to be continually
modified so that organ function can be preserved, specifically
the bladder, without affecting survival. There are many exciting areas in which progress may occur; new chemotherapeutic
agents are continually being developed, and with an increasing understanding of the molecular biology and growth factor
biology that is responsible for rhabdomyosarcoma, is it hoped
that more specific therapies will become available. Despite
a growing reliance on chemotherapy, surgeons still have an
important role to play in the management of children with
genitourinary rhabdomyosarcoma.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
52
TESTICULAR TUMORS
Jonathan H. Ross
SURGICAL APPROACH
The standard approach to a testis tumor is an inguinal orchiectomy (Fig. 52-2). Through an inguinal incision, the spermatic
cord is isolated and clamped with a noncrushing clamp. The
testis is delivered into the inguinal incision with the tunica
vaginalis intact. When a testis tumor is confirmed by direct
palpation, the cord is ligated and divided at the internal ring.
Increasing consideration has been given to performing
testis-sparing surgery for benign testicular tumors.1 This
idea is particularly attractive in prepubertal patients because
more than one third of tumors are benign in these patients.
The preoperative evaluation plays a significant role in patient
selection for testis-sparing surgery. An elevated AFP level in a
child older than 1 year virtually always reflects the presence of
a yolk sac tumor and precludes a testis-sparing approach. In
infants and older children with a normal AFP, the likelihood
of a benign tumor is considerable. This is also true in boys
presenting with androgenization. For these patients, an inguinal exploration should be considered so that testis-sparing
surgery may be performed if a benign histology is confirmed
(Fig. 52-3). The initial approach is the same as for an inguinal
orchiectomy. When the testis is delivered into the inguinal
incision (the cord having been clamped with a noncrushing
694
chapter
clamp), the field is draped off with towels, and the tunica
vaginalis is opened. The tumor is excised with a margin of
normal parenchyma or enucleated and sent for frozen section. If a benign histology is confirmed, the testicular defect
is closed with chromic suture, and the testis is returned to the
scrotum. If a malignancy is detected, or the frozen section is
nondiagnostic, an orchiectomy is performed. Reports from
small series suggest that this approach is safe and is effective
in preserving testicular tissue.12
After orchiectomy, some children with testicular tumors
require additional evaluation and therapy. The type of adjunctive management selected depends on the histology of the
primary tumor and the results of radiographic and biochemical studies. The intensity of follow-up also depends on the
malignant potential of the primary tumor.
88
Yolk sac
62
Teratoma
23
Epidermoid cysts
Stromal tumors
10
Sertoli
Leydig
Mixed/unspecified stromal
Gonadoblastoma
350
300
40,000
250
30,000
AFP
AFP
695
50,000
20,000
200
150
100
10,000
0
50
0
3
4
5
6
7
8
2
B
Age (months)
Age (weeks)
Figure 52-1 Alpha-fetoprotein (AFP) levels (in ng/mL) as a function of age in normal infants. A, During the first 8 weeks of life. B, From 2 to
8 months of age. (Data from Wu JT, Book L, Sudar K. Serum alpha-fetoprotein [AFP] levels in normal infants. Pediatr Res. 1981;15:50.)
696
part
Figure 52-2 Technique of inguinal orchiectomy. A, A transverse incision is made in the inguinal crease midway between the anterior superior
iliac spine and the pubic tubercle. B, Electrocautery is used to divide the Scarpa fascia down to the level of the external oblique fascia. C, The
external oblique fascia is divided in the direction of its fibers directly over the spermatic cord. D, After the cord has been elevated, a noncrushing
clamp is placed at the level of the internal ring.
chapter
697
G
Figure 52-2 contd, E, The testis is delivered into the wound, and the gubernaculum is divided sharply using electrocoagulation. F, After the
intratesticular tumor has been confirmed, the cord is divided proximal to the crushing clamp. It is divided by isolating the vas from the spermatic
vessels and dividing the vas separately. G, The vas has been divided, and the spermatic vessels are clamped. The cord is sharply divided. (Reprinted with the permission of The Cleveland Clinic Foundation.)
698
part
E
Figure 52-3 Testis-sparing surgery. A, Scrotal ultrasound scan in a 4-year-old boy with a hydrocele reveals a hyperechoic testicular mass. Alpha-
fetoprotein was normal. B-E, The spermatic vessels were controlled through an inguinal incision, the tumor was enucleated, and when the frozen
section revealed an epidermoid cyst, the testicle was closed and replaced in the scrotum.
chapter
699
Table 52-2 Results of Four Large Multicenter Studies of Prepubertal Malignant Germ Cell Tumors of the Testis
No. patients
Stage I
Tumors (%)
Recurrence of
Stage I Tumors on
Observation (%)
62
68
100
110
95
15
100
80
94
67
17
100
100
36
72
19
100
100
302
78
14
100
98
Total
*Includes
the voice. Although feminization (particularly gynecomastia) is common in adults, it is rare in children and, when
present, is usually superimposed on the virilizing signs.
Other causes of precocious puberty include central nervous
system lesions, adrenocortical carcinoma, and congenital
adrenal hyperplasia (CAH). In the presence of a testicular
mass, a Leydig cell tumor is the most likely diagnosis. An
elevated testosterone level with low or normal folliclestimulating hormone and luteinizing hormone levels is
consistent with a Leydig cell tumor. Normal levels of 17hydroxyprogesterone exclude the diagnosis of CAH. Because
virilization may manifest before a tumor is palpable, all boys
with precocious puberty and no obvious cause should undergo
an ultrasound scan of the testicles to rule out a small tumor.
Leydig cell tumors may be treated by orchiectomy or
testis-sparing excision. Persistence of androgenic effects may
be due to a contralateral tumor, but this is rare in children.
Because Leydig cell tumors are sometimes difficult to detect
on physical examination, an ultrasound scan may be necessary to rule out a contralateral tumor. Even after successful
removal of a solitary tumor, however, androgenic changes are
not completely reversible, and some children may proceed
through premature puberty owing to activation of the hypothalamic-pituitary-gonadal axis.
700
part
Gonadoblastoma
Gonadoblastomas contain germ cells and stromal cells. Usually three distinct elements are present: (1) large germ cells
resembling seminoma, (2) sex cord nongerminal elements
such as Sertoli or granulosa cells, and (3) stromal elements
such as Leydig cells.36 Gonadoblastomas occur more frequently in postpubertal patients, but they may be seen in
children. Gonadoblastoma occurs almost exclusively in dysgenetic gonads, usually in association with an intersex disorder. Dysgenetic gonads are gonads that have failed to develop
normally and are composed of gonad-type fibrous tissue. They
are also termed streak gonads. Although the nomenclature is
inconsistent, dysgenetic gonads may contain some primitive
ovarian structures. Conversely, when partial differentiation
along testicular lines is present, the gonad is referred to as a
dysgenetic testis. Gonadoblastoma is more likely to occur in
dysgenetic gonads or dysgenetic testes in patients with a Y
chromosome or evidence of some Y chromatin. Gonadoblastomas occur in 3% of patients with true hermaphroditism, and
10% to 30% of patients with mixed gonadal dysgenesis or pure
gonadal dysgenesis and an XY karyotype.37,38 They also occur
commonly in the dysgenetic testis syndrome.
Gonadoblastomas are usually asymptomatic and often
detected incidentally when dysgenetic gonads are removed.
Virilization has been associated with some of these tumors,
however. Forty percent of gonadoblastomas are bilateral.37
Although gonadoblastomas are benign, overgrowth of the
germinal components leading to a dysgerminoma (also known
as seminoma) occurs in 50% of cases.38 Approximately 10%
develop overtly malignant tumors. Although most invasive
tumors associated with intersex occur in young adulthood,
there are several reports in children as well.38 Intraepithelial
germ cell neoplasia may be identified in many of these gonads
and is associated with germ cell tumors.
Gonadoblastomas are treated by orchiectomy. Any dysgenetic gonad in a child with a Y chromosome should be
removed prophylactically in infancy or early childhood.
Tumors are much less likely in patients who lack a Y chromosome, such as patients with Turner syndrome or XX patients
with pure gonadal dysgenesis. When malignant degeneration
is present, a metastatic evaluation and appropriate follow-up
are indicated. These tumors are radiosensitive and have a
favorable prognosis. If unfavorable elements such as choriocarcinoma or embryonal carcinoma are present, the outlook
is poor.
Five percent to 10% of patients with androgen insensitivity
syndrome develop germ cell tumors.38 Patients with androgen
insensitivity syndrome do not have dysgenetic gonads and
are not prone to gonadoblastoma. Similar to otherwise normal
boys with undescended testicles, the tumors associated with
androgen insensitivity syndrome are most often seminomas
occurring postpubertally. All standard types of postpubertal
germ cell tumors may occur, however. Patients with androgen insensitivity syndrome may also develop Sertoli cell
chapter
a denomas, which are benign hamartomatous nodules composed of multiple small tubules lined by prepubertal-type
Sertoli cells.
LEUKEMIA
Secondary malignancies of the testicle are rare. The most
important is ALL. Only 2% of boys with ALL have overt
clinical evidence of testicular involvement at diagnosis.45 This involvement is usually reflected in firm diffuse
701
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
53
PATHOLOGY
Tissue Pathology
The histopathologic features that define the malignant potential of adrenal tumors in children are unique; the diagnostic
Homer-Wright pseudorosettes that consist of eosinophilic
702
Molecular Pathology
Molecular understanding of neuroblastoma has identified several features of the disease that may aid in all aspects of its
management, including diagnosis, natural history, prognostic
stratification, and selection of treatment. Newer techniques
include analyses of nuclear and chromosomal material and
neuronal phenotyping through assessment of various neuronassociated growth factors. Although karyotyping has identified specific chromosomal abnormalities (see later), analysis
of DNA ploidy has also provided significant information.
Paradoxically, neuroblastomas of the hyperdiploid variety are
more likely to respond favorably to chemotherapy, whereas
diploid or near-diploid tumors are associated with higher
stage disease (including unresectable tumors), a poorer prognosis, a lower response to chemotherapy, and recurrence or
progression.8-11
An accepted genetic marker for neuroblastoma has been
amplification of the MYCN (or N-myc) proto-oncogene.12,13 The
association between MYCN amplification and high-grade,14
advanced-stage disease at presentation; rapid progression;
and an overall poor prognosis has become well established.
An etiologic relationship between MYCN and neuroblastoma
was tested in the late 1990s by two complementary studies.
MYCN gene amplification is present in approximately 40% of
patients with advanced-stage III or IV disease compared with
less than 10% in low-stage patients. Chan and coworkers15
presented data supporting the concept that MYCN expression
is directly involved in the cellular events of neuroblastoma
progression. Conversely, in the subgroup of patients who did
well with normal MYCN gene expression, Mycn protein levels
were undetectable.
Deletions of chromosome 1 and gains in chromosome 17
have been shown to carry strong prognostic information in
advanced neuroblastoma. A landmark report from a collaborative group in Europe has shown a powerful association
between gains in chromosome 17q and an adverse neuroblastoma outcome.16 The gain of 17q was linked to the loss of 1p.16
Most significantly, in univariate and multivariate analyses,
17q gain was independently predictive of a poor outcome
(30.6% 5-year survival with 17q gain versus 86% 5-year survival without 17q gain).16
A long-standing notion in tumorigenesis states that transformation (neoplasia) is the result of aberrant differentiation
chapter
Prognosis
Shimada
Favorable
Type 1
Type 2
Type 3
MYCN
amplification
None
None
Present
DNA ploidy
Hyperdiploid
Near-diploid
Near-tetraploid
Loss of
eterozygosity
h
Rare
25-50%
Present
Neurotrophin
gene expression
High
Low or absent
(except TrkB-high)
Low or absent
(except TrkB-high)
Age
1 yr
>1 yr
>1 yr
Unfavorable
Stage
I, II, IVS
III, IV
III, IV
3-yr survival
95%
25-50%
<5%
703
Imaging Techniques
The diagnostic algorithm in the imaging evaluation of abdominal masses in children has changed considerably since the
early 1990s with the advent and availability of ultrasonography. An abdominal examination by ultrasonography detects
most adrenal tumors. The term incidentaloma has been applied
to tumors that are detected in the adrenal gland as an incidental finding in the course of pursuing an otherwise unrelated
symptom, and this has become a more common way in which
these tumors are found.21 Two examples of such a presentation
are shown in Figure 53-1. This tumor was discovered during
the course of investigation of antenatally detected hydronephrosis, and a careful examination of the same area in previous ultrasound examinations confirmed the absence of the
tumor previously.
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part
Prognostic Markers
The patients age and tumor stage represent the most accurate
predictors of the clinical outcome. Patients diagnosed at 1 year
of age seem to show consistently better survival outcomes,
even in the presence of advanced disease at presentation.
Survival is dramatically related to the tumor stage at diagnosis, with 75% to 90% 5-year survival for stage I, II, and IVS
patients compared with 10% to 30% 2-year survival for stage
III and IV patients.
chapter
Staging
A disease with such diverse manifestations as neuroblastoma
in childhood needs a comprehensive staging system to allow
(1) precise diagnostic criteria and (2) a method of categorizing
and quantifying disease. An international working group published the outcome of its deliberations in 1988.28 This staging
system is known as the International Neuroblastoma Staging
System (INSS), and the response criteria are referred to as the
International Neuroblastoma Response Criteria (INRC). This
staging system has replaced previous systems by Evans and
coworkers,29 originally established by the Pediatric Oncology
Group (POG). Table 53-3 outlines the three staging systems for
comparison.
Treatment
Therapy of neuroblastoma requires close coordination of medical, surgical, and radiation oncologists and represents a prime
example of multimodal cancer therapy. Surgical intervention
plays a dual role. At the time of diagnosis, open or laparoscopic
approaches may be used to obtain adequate and thorough
samples for histologic and molecular diagnosis and marker
analysis. Needle biopsy materials are most often inadequate
for these purposes. This approach also permits staging confirmation when the stage remains uncertain after tumor imaging is complete. For selected tumors, particularly small, locally
confined ones, primary surgical excision may be possible. In
this regard, laparoscopy may be considered and has been used
successfully for small tumors identified by screening.30
Because the merits of screening seem lacking for the most
aggressive, metastatic, and later presenting tumors, detecting
instead tumors that may be the more biologically favorable to
begin with, it may be reasonable to consider the laparoscopic
approach as safe on oncologic grounds. Open surgical dissection is also employed to assess the response to therapy and
excise residual disease after initial courses of chemotherapy
have been completed. Two 1998 reports have suggested a
higher incidence of nephrectomy in children with neuroblastoma who were treated with primary surgical intervention.31,32 Two more recent reports of large series of patients
confirm the benefits in prognosis of total resection of tumor,
even in patients with local progression.33,34 Based on the evidence in these reports, chemotherapy seems to provide little
or no benefit in children in whom total surgical excision can
be performed.
Although chemotherapy plays little role in the treatment
of stage I and II tumors, it does seem to have a role in the
705
treatment of higher stage disease. Single-agent and synergistic multiagent drug regimens are used that combine cell
cyclespecific and cell cycleindependent drugs to achieve a
maximal ratio of therapeutic benefit to toxicity. Multiple-agent
regimens are many, varied, and ever-changing, and include
combinations such as cyclophosphamide, doxorubicin, cisplatin, teniposide, and etoposide, which led to encouraging
results of 40% survival in stage IV disease. Subsequent developments, based on these results, have led to more aggressive therapies, including myeloablative regimens, with bone
marrow replacement. More recently, further, more aggressive
therapy with marrow ablation, multiple monoclonal antibodies, and bone marrow transplantation have resulted in
complete responses, or suitable shrinkage to allow surgical
resection.35 The use of autologous stem cell transplantation is
being explored as an alternative to bone marrow transplantation in some centers.
Ionizing radiation has a role in neuroblastoma treatment
because the tumor is radiosensitive. It is most useful in
achieving local control and palliation of disease uncontrollable by other modalities. As a primary modality, however,
radiotherapy is limited by the extensive metastatic proclivity
of many neuroblastomas. The agent metaiodobenzylguanidine (MIBG), employed in the localization of neuroblastomas
and pheochromocytomas, has been studied for its ability to
bind neuroblastoma tumors systemically and carry with it
radioligands such as iodine 131 that are toxic to the tumor
cells.25,36,37 This approach has also been used as an adjunct
to guide surgical tumor tissue resection using the gamma
camera intraoperatively after the tumor is radiolabeled by
preoperative injection of iodine 131labeled MIBG.38
Because of the aggressive nature of advanced and higher
staged disease, efforts continue to improve disease control in
this subset of patients, while refining therapy to limit toxicity
in lower stage and more favorable disease.
Treatment
The ability to stratify patients into distinctly risk-related
groups by application of the varied but highly accurate histologic and molecular diagnostic and staging methodologies
has permitted a much more judicious and specific use of the
therapeutic regimens. Stage I and II tumors (low risk) are treatable by primary surgical resection alone, with no need for initial chemotherapy or radiotherapy. A survival rate of 89% has
been reported in this group of patients.2,36,39 Stage IVS tumors
undergo spontaneous remission and are considered low risk,
but if symptoms related to severe hepatic metastatic disease
or respiratory compromise are present, patients with these
tumors may benefit from chemotherapy or radiation therapy
in small doses.
Stage III patients (intermediate risk) still have an excellent
overall survival rate of 89%,39 but chemotherapy is advised
after primary surgical excision. Second-look surgery may also
be appropriate after chemotherapy. The goal of therapy in
these children is to reserve more intense therapy and multiple
courses of chemotherapy to children with biologically unfavorable tumors.
Stage IV patients (high risk) have derived minimal benefits
from even the most intensive regimens. Multiagent chemotherapy remains the standard primary treatment strategy for
these patients. The option of marrow ablative chemotherapy
and bone marrow transplantation has been pursued in single
institutions and resulted in some limited partial responses.
These intensive therapeutic regimens are currently being
explored in multicenter trials. The overall prognosis in these
children remains poor (15% to 35% survival).40
706
part
POG
INSS
Stage IVany primary tumor with dissemination to distant lymph nodes, bone, bone
marrow, liver, skin, or other organs (except
as defined for stage IVS)
PHEOCHROMOCYTOMA
Clinical Features and Presentation
Pheochromocytoma is an extraordinarily rare primary tumor
of the pediatric adrenal medulla, although it is the most common hyperfunctioning form of this tissue. The tumors arise in
the autonomic nervous system, and 90% originate in the adrenal gland. Catecholamine production is the norm and is the
basis of the clinical manifestations and the most long-standing
diagnostic method, which is based on measurement of circulating catecholamine levels. Over a 5-year period at The Hospital
for Sick Children in Toronto, only 1 of 30 patients presenting
with a primary adrenal tumor had a pheochromocytoma;
this was a 16-year-old girl. In infants and young toddlers
with ultrasound-diagnosed abdominal masses or hypertension, pheochromocytoma is extraordinarily rare. Pediatric
pheochromocytomas can be seen in association with various
diseases, including neurofibromatosis, von HippelLindau
disease, Sturge-Weber syndrome, and multiple endocrine
neoplasia 2. Pheochromocytomas associated with multiple
endocrine neoplasia 2 are more likely to occur later in life, and
tumors that occur in association with these diseases are more
likely to be bilateral.
chapter
707
Treatment
The historical importance of these tumors with respect to surgery is not the technical nature of their excision, but the cautions
associated with the induction of anesthesia. These cautions are
related to the potential for drastic changes in the excretion of
catecholamines on manipulation and subsequent removal of
the tumor. The challenges revolve around stabilization of blood
pressure intraoperatively and the prevention of potential cardiovascular collapse at the time of tumor removal or ligation
of the adrenal and associated veins delivering catecholamines
to the systemic circulation. In infants, particularly in the preoperative state, these cautions are of great concern to parents,
attending physicians, anesthesiologists, and surgeons. In view
of the high specificity of contemporary serologic and radionuclide diagnostic methods, with current therapy these concerns
may now be tempered.
ADRENAL CARCINOMA
Adrenal carcinoma represents less than 0.0001% of childrens
neoplastic tumors. The most common presentation is abnormal virilization, occurring in two thirds.48 Cushing syndrome
accounts for a further third. Individual case reports have
reported occasional aldosterone-secreting tumors. Given the
widespread availability of ultrasound imaging technology,
the most common presentation may now be as an incidental
finding on abdominal ultrasonography undertaken for vague
or varied indicators. A multicenter registry has published its
findings on the clinical and diagnostic characteristics in these
rare tumors in childhood.49
Adrenocortical tumors may also be a component of more
global genetic malformations; these include congenital adrenal hyperplasia or multiple endocrine syndromes (multiple
708
part
Clinical Presentation
Virilizing Adrenal Tumors
Of the functioning adrenocortical tumors, virilizing forms
account for two thirds and usually occur in children older than
2 years. The tumors produce dehydroepiandrosterone, a weak
androgen but one that is converted to 4-androstenedione
and testosterone, which are more potent virilizing hormones.
Boys with such tumors present with precocious puberty evidenced by excessive maturation of the genitalia. Girls develop
an abnormal increase in clitoral size, similar to that seen with
congenital adrenal hyperplasia. Pubic and axillary hair may be
seen in children of both sexes.
Alternate causes of increased virilization in boys include
sexual precocity or premature pubarche, interstitial cell
tumors of the testis, and delayed manifestation of congenital
adrenal hyperplasia. Clinical evaluation may give some clues
to distinguish these cases. Examination of the scrotum gives
some evidence of Leydig cell tumors by means of unilateral
or asymmetric enlargement of the testes. With sexual precocity, testicular enlargement is bilateral. With virilizing adrenal
tumors, the testes are usually small. The differential diagnosis
in girls includes ovarian arrhenoblastoma and other rare
tumors of the adrenal cortex.
Cushing Syndrome
Approximately one third of children with adrenocortical
tumors may have stigmata of Cushing syndrome. Carcinoma
may be responsible in half, with the others having evidence of
bilateral adrenal hyperplasia. A benign adenoma may rarely
be seen. The clinical presentation is related to excessive production of cortisol leading to protein catabolism, subsequent
increased gluconeogenesis, and the typical obesity associated
with cortisol excess. Moon facies, truncal obesity, and typical
evidence of Cushing disease are generally obvious in infants.
The differential diagnosis in cases exhibiting excess adrenocortical activity includes adrenal adenomas and iatrogenic
administration of steroids. This latter iatrogenic excess is commonly seen in children receiving transplanted organs.
Diagnostic Evaluation
In all these tumors, biochemical determination of adrenal
hyperfunction leads to the exact nature of the hormone excess.
Urinary steroid levels may be elevated, but serum levels of
free cortisol and 17-hydroxysteroid are generally available and
are abnormally elevated.
Provocative tests with corticotropin stimulation may aid in
distinguishing primary adrenocortical adenomas from adenomas in which endogenous corticotropin levels are increased.
Modern diagnostic imaging has given the greatest advances
since the early 1990s. Incidentalomas are now commonly
detected on ultrasonography. MRI in addition to ultrasound
has led to tremendous advances in the ability to distinguish
adrenal carcinoma from benign adenomas.51,52
Treatment
Treatment of adrenocortical carcinoma is surgical. The rate of
development of new instrumentation, particularly in laparoscopic
procedures makes any textbook summary of these techniques
outdated by the time the text is published. In children, open surgical removal may be accomplished by large transverse abdominal incisions or, in some instances, by extended flank incisions.
Laparoscopic removal is now widely employed in adult surgery,
but the current lack of small instrumentation limits its use in very
small children.53 The advances in imaging allow more limited
surgical approaches than may have been previously encountered.
A tumor diameter of more than 5 cm is a reasonable predictor of
malignancy, whereas small adenomas may be approached with
more conservative surgery. Despite the advantages of modern
imaging, the current data show a continued reliance on surgical
excision as the mainstay of therapy.54,55 Preoperative care must
recognize the need for corticosteroid replacement in cases in
which an excess of corticosteroids is anticipated.
The prognosis for adrenal carcinoma is poor. Surgery is the
primary therapy, and chemotherapy has not been effective in
controlling widespread disease.
REFERENCES
For complete list of references log onto www.expertconsult.com
P A R T
IX
54
URINE PRODUCTION
Oligohydramnios
After 16 weeks of gestation, the amniotic fluid begins to transition from a placental transudate to a reflection of actual fetal
urine production. By 22 weeks, nearly all of the amniotic fluid
is a product of fetal urine. Oligohydramnios represents either
an inability to produce urine or an impaired ability to void.
Typically, the more severe the oligohydramnios, the more ominous the underlying pathology. In its most extreme form (Potter syndrome, renal agenesis), oligohydramnios is associated
with limb contractures, low-set ears, and compressed facies.
Absent renal function is seen in bilateral renal agenesis, bilateral multicystic renal dysplasia, or juvenile polycystic kidneys.
These infants rarely survive beyond the first few hours. No
specific therapy is available, and the role of the urologist is
to provide counseling (Fig. 54-1). Otherwise, oligohydramnios
represents the inability to void because of obstruction in the
urinary tract.
Delayed Voiding
One of the most common urologic concerns of the newborn
period is the absence of voiding. Most commonly, this represents delayed voiding. It is imperative to recognize that
a normal neonate may not void for 24 hours or more.1 In
the face of a normal amount of amniotic fluid, one can be
reasonably assured that the fetus has been able to void
throughout fetal life. The most informative finding on
physical examination is the presence of a distended bladder. The examination itself may precipitate voiding. If voiding does not occur within 24 hours, or with a particularly
distended bladder, an abdominal ultrasound scan is warranted. If there has been oligohydramnios or bilateral prenatal hydronephrosis, an immediate investigation beginning
with a renal and bladder ultrasound followed by a voiding
Hematuria
Gross hematuria in a newborn, although uncommon, is a urologic emergency. Although no specific abnormality may be
found, life-threatening conditions, such as renal vein thrombosis and renal artery thrombosis, may be the cause (see later).
Immediate evaluation and appropriate treatment is mandatory.
Other causes include renal calculi, infections, ureteropelvic
junction obstructions, and other anomalies. One theory is that
urethral bleeding can result from a withdrawal of maternal
hormones.2 The evaluation should consist of a physical examination including blood pressure, urine culture, renal ultrasound, and complete blood count with platelet count. Further
workup is guided by these initial studies.
GENITAL CONDITIONS
Hypospadias
Hypospadias is a common urologic abnormality discovered in neonates. An inability to identify the location of the
meatus often leads to a urologic consultation. Obstruction is
almost never present, and gentle probing with a 5F feeding
tube (although unnecessary) proves patency. Hypospadias
does not represent an emergent condition, and no immediate
intervention is required. The more proximal the hypospadias,
the more common the presence of chordee and foreskin with
a characteristic dorsal hood appearance. A distal hypospadias
may be discovered at the time of circumcision; if so, the procedure should be aborted immediately in an attempt to salvage
foreskin that may be used for later corrective surgery. If an
incision has been performed, it should be repaired. Circumcision should not be performed until the time of corrective surgery later in life. The combination of hypospadias (especially
a more proximal hypospadias) and a nonpalpable testicle is
suspicious for an intersex condition and should prompt an
appropriate workup.
Circumcision Complications
The most common complication after circumcision is bleeding. Many of these bleeding episodes can be managed with the
application of gentle pressure. An epinephrine-soaked gauze
may help. If persistent, placement of interrupted dissolvable
sutures may be required for homeostasis. Particularly troublesome bleeding should raise the suspicion for an underlying
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may be an associated hernia. These carry the risk of future incarceration of bowel and must be followed closely, with surgical
correction on an elective basis. Noncommunicating hydroceles
are generally nontender. Most resolve spontaneously within
the first year of life. If persistent or progressive, they may be
corrected on an elective basis (Figs. 54-2 and 54-3).
Enlarged Scrotum
Newborns presenting with an enlarged scrotum need immediate evaluation. Differential diagnosis includes hydrocele with
or without hernia, epididymitis, orchitis, testicular torsion,
hemorrhagic infarction, torsion of the testicular appendix, and
neoplasm.
HY
HY
T
E
Lt
Rt
Figure 54-2 Bilateral hydroceles. A, Longitudinal ultrasound of right testicle (T) and head of the epididymis (E). HY, hydroceles. B, Transverse ultrasound of scrotum (the right [Rt] and left [Lt] hemiscrotum) show bilateral anechoic hydroceles (HY) with normal testicles (T) and epididymis.
TR L Scrotum
LG L Scrotum
Figure 54-3 Incarcerated inguinal hernia. A and B, Transverse and longitudinal images of left scrotum show bilateral anechoic hydroceles with
presumed patent processus vaginalis, and herniated loop of small bowel, which is also thickened.
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Ambiguous Genitalia
Newborns with ambiguous genitalia represent true urologic
emergencies and represent some of the most challenging clinical cases for the physician and family. Parents are faced with
uncertainty, confusion, and anxiety, and require education and
counseling often for an extended period. These children need
immediate medical evaluation to rule out a life-threatening
condition. This evaluation should always be a team approach
and include a neonatologist, pediatric endocrinologist, geneticist, pediatric urologist/surgeon, and the parents. The external
genitalia present a wide spectrum of abnormalities. The
evaluation should be thorough and include a detailed history,
including a list of medications taken during pregnancy, family
history of stillbirths, unexplained neonatal deaths, or intersex
conditions. A careful physical examination must emphasize all
phallic characteristics, including the position of the urethral
meatus, labial/scrotal development and pigmentation, and
the presence of palpable gonads in the labioscrotal folds or in
the inguinal canals. Initial laboratory studies include a basic
metabolic panel and a karyotype.
This initial evaluation is an emergency to detect and treat
neonates with salt-wasting seen in congenital adrenal hyperplasia (CAH) with 21-hydroxylase deficiency. Genetic female neonates with phenotypic virilization may have CAH, a pathologic
Trans Scrotum
Figure 54-4 Left testicular torsion. A, Longitudinal ultrasound of left testicle with color Doppler shows abnormal echogenicity of the left testicle
and thickening of the periphery with small hydroceles. On color Doppler, no blood flow was shown. This appearance is in keeping with testicular
torsion. B, Transverse image of scrotum showing both testicles. The left testicle is enlarged, showing abnormal mixed echotexture with edema of
the left hemiscrotum. The appearance with mixed echotexture is compatible with torsion. The normal homogeneous right testicle is shown and
is surrounded by an incidental hydrocele.
chapter
Intralabial Masses
A perineal mass in a newborn girl should prompt an immediate
examination. Appearance alone is suggestive of the diagnosis
in most instances; however, an ultrasound scan of the vagina
and bladder is important. Periurethral cysts are the most common and are derived from the periurethral glands. They are
whitish in appearance, are covered with normal-appearing
epithelium, and are located in the anterior vaginal wall, inferolateral to the meatus.14 No emergent intervention is required;
however, incision is curative. Hydrocolpos from an imperforate hymen manifests as a midline bulging mass at the posterior introitus. The mucosa is slightly transparent and appears
pearly white. A palpable suprapubic mass may be present. An
ultrasound scan confirms the distended fluid-filled vagina and
location of the bladder. Incision and drainage is curative.
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BLADDER
Megacystis
Prenatal detection of an enlarged bladder should prompt close
follow-up. Nonobstructive causes of bladder distention are usually associated with a thin-walled bladder and normal amniotic
fluid levels, whereas obstructive causes typically have a thickened bladder wall and associated oligohydramnios. There is a
varied spectrum between these presentations, however. It is difficult to categorize because of the variability with bladder fullness at time of the ultrasound scan. Complete bladder outlet
obstruction resulting in megacystis associated with severe oligohydramnios is often incompatible with life, with pulmonary
complications causing most of the immediate concerns.
The differential diagnosis mainly consists of posterior
urethral valves (PUV), anterior urethral valves, prune-belly
syndrome, urethral atresia, and bladder neck obstruction
from an ectopic ureterocele. These conditions represent a true
emergency in which immediate bladder drainage is required
(although not necessarily true for prune-belly syndrome; see
later section). An ultrasound scan and VCUG should assist
with the diagnosis and must be performed within the first 24
to 48 hours of life. As previously stated, complete obstruction
of urine has a poor prognosis. Often these obstructions are
diagnosed prenatally, and fetal interventions with the placement of a vesicoamniotic shunt or periodic vesicocentesis with
amnioinfusions have been performed.
Umbilical Drainage
Umbilical drainage may be a presenting sign for various conditions. The physical examination should help determine if
urgent intervention is required. The umbilicus may be swollen
and erythematous with or without purulent drainage, and a
midline abdominal mass may be identified. More often, asymptomatic serous drainage is discovered. The neonate may present with local or systemic infection. The differential diagnosis
includes an infected umbilical stump, persistent urachal sinus,
urachal cyst, urachal diverticulum, patent urachus, and a patent omphalomesenteric duct. Abdominal ultrasonography is
usually sufficient to characterize the extent of the tract and to
rule out cystic fluid collections. A VCUG is obtained to rule
out a persistent urachus, defined by a communication with the
bladder. Injection of the umbilicus with contrast fluid under
fluoroscopy may aid in the diagnosis; however, this is often
difficult to perform.
Many of these conditions can be managed conservatively.
The primary concern in the neonatal period is the presence
or absence of an infection. Antibiotic therapy is usually suffi
cient for local infections and should be the first-line therapy.
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Bladder Exstrophy
The diagnosis of bladder exstrophy is usually apparent at birth
and may be suggested on prenatal imaging by an inability to
identify the bladder on multiple prenatal ultrasound scans. The
physical examination should pay particular attention to the
size and appearance of the bladder template. Although these
children are usually born at term and are otherwise healthy, a
renal ultrasound scan should be obtained to rule out any associated renal pathology. Immediate management centers on the
protection of the exposed bladder epithelium. The umbilical
cord is tied off with a 2.0 silk suture away from the bladder.15
Clear plastic (usually Saran Wrap) is used to drape the exposed
bladder epithelium. This should be changed and the mucosa
irrigated with normal saline at all diaper changes.15 Adhesive
or adherent dressings should be avoided. Creating a plan for
bladder closure is the next step. The technique of closure is
debated. The most important aspect of surgical management
is the use of a specialized exstrophy center with surgeons who
are particularly experienced with this condition and have the
appropriate resources.
UPPER TRACT
Hydronephrosis
The most common urologic abnormality identified in the prenatal period is the presence of hydronephrosis. Hydronephrosis
may be an isolated finding or be associated with various
urologic abnormalities. Following some general principles,
one can readily identify potential emergencies from more elective evaluations. As previously mentioned, the history of any
oligohydramnios is of paramount importance. In the case of a
normal amount of amniotic fluid throughout pregnancy, one
can be assured that the fetus has been able to urinate. The urologist must inquire about any family history of hydronephrosis
or other urologic pathology, especially in previous pregnancies.
Characterizing the hydronephrosis as unilateral versus bilateral
and noting any ureteral involvement or distended bladder narrow
the differential diagnosis (Table 54-1). Viewing the prenatal
ultrasound scan is helpful, but the scan is often unavailable.
The infant should be placed on prophylactic antibiotics immediately until vesicoureteral reflux (VUR) has been
ruled out. For otherwise healthy newborns, amoxicillin,
10mg/kg/day, is sufficient. An ultrasound scan after birth is
Most Common
Common Causes
Rare Causes
Unilateral hydronephrosis
UPJ
Bilateral hydronephrosis
VUR
PBS, PUV
Unilateral hydroureteronephrosis
VUR
Bilateral hydroureteronephrosis
PUV
Urethral atresia
MCDK, multicystic dysplastic kidney; PBS, prune-belly syndrome; PUV, posterior urethral valves; UPJ, ureteropelvic junction obstruction; VUR, vesicoureteral reflux.
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Figure 54-5 Ureteropelvic junction obstruction. A and B, Longitudinal and transverse images of the right kidney in a 5-day-old infant showed
early grade 4 hydronephrosis with anechoic (arrow in A) urine in the dilated collecting system. Note the hypoechoic pyramids, which are often
mistaken as dilated calyces; in this case the distinction is visible. The transverse image shows the large and dilated renal pelvis (arrow in B) as well;
the ureter was not visible (not shown here).
Ureteroceles
Prenatal ultrasonography has led to an increase in the diagnosis of ureteroceles, most of which are associated with duplicated systems in girls and solitary systems in boys.18 Most do
not require immediate surgical management, but should be
evaluated promptly. If a child has an antenatal history of a ureterocele, a confirmatory renal/bladder ultrasound scan and
VCUG need to be obtained. Various degrees of hydronephrosis or even multicystic dysplasia may be detected because the
ureterocele typically causes some level of obstruction of that
renal unit (Fig. 54-6). More concerning are the ectopic or very
large ureteroceles that can cause bladder outlet obstruction.
This latter group would need to be managed more urgently
with drainage. With severely obstructing ureteroceles, or in
the presence of infection, drainage with endoscopic incision
is usually performed in the first few days of life. Prophylactic
antibiotics should be administered because the incidence of
VUR after incision of ureterocele is high. In the setting of a
nonfunctional kidney with an associated ureterocele, observation and prophylactic antibiotics are appropriate.19
Megaureter
Primary megaureters can be divided into three major categories: obstructing; refluxing; and nonobstructing, nonrefluxing megaureters. Many megaureters are detected on prenatal
ultrasonography, but they may manifest with infection. Prophylactic antibiotics should be administered until VUR is ruled out
by VCUG. Megaureters rarely require emergent treatment. As
shown by Confer and colleagues,20 72% of lower grade (grade I
to III) nonobstructing, nonrefluxing megaureters resolve spontaneously in 12 to 36 months. If infection or severe obstruction
is identified along with impaired or deteriorating renal function, surgical intervention in the form of cutaneous ureterostomies is required. This is usually found after the neonatal period
and is discussed in further detail in other parts of the text.
Abdominal Mass
An abdominal mass in a neonate is a common finding. More
than 60% are urologic in origin with hydronephrosis the most
common cause.21 A thorough physical examination is required
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Long bladder
U2
Li
Adr-m
rk
U1
image of the right abdomen shows an echogenic mass in the right adrenal gland (Adr-m) causing the right kidney (rk) to be distorted and
displaced. Note the liver (Li) located immediately above the right kidney, with which the echotexture of the kidney is usually compared.
chapter
LG RT
717
TR RT adrenal
Figure 54-8 Neonate with adrenal hemorrhage. A and B, Longitudinal and transverse ultrasound images of the adrenal and the right kidney
show a solid adrenal mass with numerous small cysts. A few days later, a noncontrast CT scan showed a smaller cystic lesion with calcification in
the periphery (not shown here).
Adrenal Hemorrhage
Adrenal hemorrhage is common. Although its exact etiology
is unclear, risk factors include birth trauma, septicemia, and
hemorrhagic disorders.29 Many hemorrhages are discovered
on prenatal imaging. Postnatally, the infant may present with
an abdominal mass, anemia, or shock. Acute scrotal swelling
or hematoma or both have also been reported as presenting
signs in several case reports.30,31 Adrenal hemorrhage typically
appears as a cystic suprarenal mass on an ultrasound scan
(Fig. 54-8). The differential diagnosis includes adrenal cysts,
adrenal hemorrhage, neuroblastoma, renal malignancies, and
renal duplication. A renal ultrasound scan should readily differentiate between most of these entities, although neuroblastoma often cannot be ruled out, and a computed tomography
(CT) scan is obtained. A urine collection for homovanillic acid,
vanillylmandelic acid, and catecholamines aids in the exclusion of neuroblastoma. Most adrenal hemorrhages resolve
without intervention. Involution of the mass on repeat ultrasound scan is the usual clinical course. If the mass fails to show
signs of regression by 6 weeks, or in the case of uncontrollable
bleeding, surgical resection is appropriate.
OTHER CONDITIONS
Posterior Urethral Valves
PUVs should be suspected in any male infant with a history
of bilateral hydronephrosis. PUV is the most likely cause of
bladder outlet obstruction in a newborn boy and is the most
common urologic cause for renal failure and need for transplantation in children.32 PUVs manifest with a distended bladder and hydronephrotic, often palpable, kidneys. Abdominal
ascites may also be present indicating a forniceal rupture.
Renal ultrasound scan reveals varying degrees of bladder
dilation with bladder wall thickening and a dilated posterior
Prune-Belly Syndrome
Prune-belly syndrome (Eagle-Barrett syndrome, triad syndrome) is readily identified on physical examination by the
thin, lax, prune appearance of the abdomen. The diagnostic
criteria of abdominal wall musculature hypoplasia, large
hypotonic bladder with dilated tortuous ureters, and bilateral cryptorchidism are specific for prune-belly syndrome.
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well understood, it is generally believed not to be a true outlet
obstruction. Rarely does an infant with prune-belly syndrome
need emergent intervention. The immediate problems are
usually pulmonary (pneumothorax and pneumomediastinum
are common). Renal failure may be evident, however. Any
instrumentation of the urethra exposes the child to infections
that can be difficult to eradicate; a conservative approach is
the best initial choice.
Although approximately 50% void spontaneously, the true
bladder function requires an ongoing evaluation. In the setting of deteriorating bladder function or persistent infection,
a cutaneous vesicostomy should be considered with plans for
future undiversion tailored for the individual patient.
Urethral Atresia
Congenital urethral atresia in a boy results in complete urethral
obstruction caused by a constricting membrane usually located
in the distal prostatic urethra with accompanying hypoplastic urethra distally.33 By itself, this anomaly is incompatible
with life. Survival is possible, however, if a communication
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Figure 54-10 Comparison of posterior urethra in prune-belly syndrome and posterior urethral valve. A, Left anterior oblique view of the bladder
in a patient with prune-belly syndrome shows the dilated bladder and posterior urethra mimicking a posterior urethral valve. Note the bladder
is elongated and at the dome (not shown) gives a false impression of urachal cyst or remnant often giving an hourglass appearance. Dilation of
the posterior urethra is also seen, and this is due to hypoplasia of the prostate and the lack of thickening of the base of the bladder. This distinctly
differs from the appearance of the posterior urethra in a patient with posterior urethral valve (B). B, Left anterior oblique view of bladder in a
patient with posterior urethral valve shows the thickened bladder neck and dilated posterior urethra; the posterior urethral valve also is seen.
Note the distinction in the appearance from A.
Myelomeningoceles
A child born with a myelomeningocele defect needs prompt
urologic evaluation. Appropriate urologic management is
crucial for long-term renal and bladder function. The voiding characteristics are highly variable and tend to change over
time. Initial evaluation is required to determine the bladder
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
55
Trauma is the leading cause of morbidity and mortality in children today and results in more childhood deaths than all other
causes combined. Historically, two factors have led to the current importance of trauma in childrens health care. Over the
past half century, the advent of antibiotics improved treatment
of infectious disease, and at the same time society became
dependent on the automobile leading to more motor vehicle
accidents involving children.
Trauma to the urinary tract is second only to trauma of the
nervous system in childhood injuries.1 Significant trauma to
the genitourinary tract is found in 2.9% of children evaluated
at pediatric hospital trauma centers.2 The genitourinary tract
may be injured bluntly from falls, motor vehicle accidents,
sports injuries, physical assault, and sexual abuse.3 Sharp or
penetrating injuries can result from falls onto sharp objects or
from assaults with guns or knives.
The urologist is seldom the first physician to evaluate or
treat trauma. Modern management of trauma has evolved
into a team activity involving pediatricians, emergency physicians, surgeons, urologists, and other appropriate physicians.
Because genitourinary injuries are seldom life-threatening,
urologists are generally called as consultants after the initial
evaluation has been completed. Although genitourinary injuries may not dominate the initial management period, they
often linger on, and the urologist may care for the child for
most of the hospitalization. Because of the potentially legal
nature of the events that lead to childhood trauma, it is imperative that each physician document the injuries and treatment
completely in the medical record. In cases of suspected physical or sexual abuse, the urologist must carefully evaluate and
record all information available about the injuries, and contact
the local child protective agencies who have the responsibility
and authority to complete the investigation.
RENAL TRAUMA
The kidney is the most frequent site of genitourinary trauma,
resulting in half of all urinary system injuries. The kidneys
may be injured either with blunt force or by penetrating injuries resulting from gunshots or knives. Kidney injuries occur
in 8% to 12% of patients sustaining blunt and penetrating
chapter
721
Figure 55-1 A, CT scan of a 9-year-old boy injured in a fall reveals a perinephric hematoma and underlying hydronephrosis. B, Another CT
scan done 6 weeks later reveals that the hematoma resolved, and the hydronephrosis resulting from a ureteropelvic junction obstruction is clearly
shown. (From King LR. Urologic Surgery in Infants and Children. Philadelphia: Saunders; 1998:266.)
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Grade I
Grade II
723
Grade III
Figure
Grade IV
Grade V
724
part
Description
II
III
IV
Based on the renal injury scale of the American Association for the Surgery
of Trauma: Moore EE, Shackford SR, Pachter HL, et al. Organ injury scaling:
spleen, liver, and kidney. J Trauma. 1989;29:1664.
Renovascular Injuries
Renovascular injuries secondary to blunt trauma are unique in
that the renal parenchyma is usually not traumatized. These
rare injuries involve the renal artery and occur in 1% to 3%
of all blunt renal traumas.49,50 The mechanism of injury is
rapid deceleration of the kidney and stretching of the renal
Figure 55-4 A, A child was crushed by a piece of construction equipment and sustained a renal injury that resulted in formation of a urinoma.
B, The urinoma was treated with percutaneous drainage, but extravasation continued until a double-pigtail stent was placed to assist renal drainage.
chapter
A
B
Figure 55-5 A and B, Mechanism of injury to the renal artery secondary to deceleration and stretching. The adventitia and muscularis
of the artery stretches, whereas the intima lacks elasticity and tears.
Disruption of the intima exposes the subendothelial tissue to the blood
flow and promotes clotting of the artery. (From Peters PC, Bright TC
III. Blunt renal injuries. Urol Clin North Am. 1977;4:18.)
725
Figure 55-6 A, CT scan after blunt trauma shows no apparent perfusion of the left kidney in a child involved in a motor vehicle accident. The size
and contour of the kidney are normal, and there is no perirenal bleeding. B, Arteriogram shows complete occlusion of the left renal artery. Surgical
exploration revealed an intact artery with an intimal tear and subsequent infarction of the kidney. (From King LR. Urologic Surgery in Infants and
Children. Philadelphia: Saunders; 1998:269.)
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RETROPERITONEAL HEMATOMAS
In the case of severe trauma, the urologist may be consulted
to evaluate a retroperitoneal hematoma found at the time of
emergency laparotomy. Without a preoperative IVP or CT
scan, the urologist has no information about the function of
the kidneys or the extent of damage to the kidney within the
hematoma. This scenario occurred 24% of the time in the San
Francisco series of renal gunshot wounds because the patient
was too unstable to undergo imaging of the kidney before
surgical intervention. In these cases, a single-shot intraoperative high-dose IVP can be performed on the operating table.
Although suboptimal for visualization of the kidneys, this
study can provide important information to help with management decisions. The status of the contralateral kidney can
be established, and the surgeon may avoid opening a retroperitoneal hematoma if the IVP shows an intact and functioning kidney within the hematoma.76 The decision to explore a
retroperitoneal hematoma rests on the characteristics of the
hematoma, the presence or absence of hematuria, findings on
the IVP, and the mechanism of renal injury.64
Expanding or pulsatile hematomas of the retroperitoneum
must be explored, as should hematomas associated with severe
injuries visible on IVP. The findings of gross hematuria or
injury from a high-velocity gunshot wound should encourage
exploration of the hematoma. In the case of blunt injuries, stab
wounds, or low-velocity gunshot wounds, management may
be more conservative. If the IVP shows an intact functioning
kidney, and the hematoma is stable, it need not be opened.
If the physician believes that the hematoma must be
opened, the surgical technique is important. Although there is
some controversy, most authors believe that the initial maneuver should be to control the renal vessels before opening the
hematoma.77 A midline incision in the posterior peritoneum
allows visualization of the great vessels and isolation of the
renal artery and vein. The hematoma is opened laterally along
the white line of Toldt, the colon is reflected medially, and
Gerota space is entered to inspect the kidney (Fig. 55-7).78
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Right
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Left renal vein
Left renal
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Gonadal vein
Aorta
Right renal
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BLADDER INJURIES
The bladder is the largest organ in the urinary tract when it is
full of urine. It is well protected in adults because it lies within
the confines of the bony pelvis. The rigid pelvic ring and the
rectus abdominis muscle guard it. The bladder occupies a less
protected position in infants and children; it is a more abdominal organ and lies exposed above the pubis. The abdominal
wall in children offers less protection because the rectus is less
developed. There is also less pelvic and abdominal fat surrounding the bladder to cushion the bladder in trauma.
The exposed position of the bladder in children makes it
more susceptible to blunt trauma when the bladder is full.
This type of injury has been seen most often in motor vehicle
accidents when the child is wearing a lap seat belt. Even with
this relatively exposed position, the bladder is seldom injured
jured ureter is dbrided and either spatulated or cut diagonally to create a longer anastomosis and to prevent stricturing. Inset, The ureteral
ends are sutured together, ensuring that the anastomosis is not under
tension and that adequate internal stenting and external drainage are
provided. (From Armenakas NA. Ureteral trauma: surgical repair.
Atlas Urol Clin North Am. 1998;6:79.)
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731
Damaged ureter
Incision for flap
Figure 55-10 Methods of reconstruction when the distal ureter is lost. A, A modified Boari flap may be created by tabularizing a wide-based
flap of bladder and rotating it toward the shortened ureter. A standard ureteral reimplant may be performed into the flap. B, The bladder may be
moved closer to the ureter by shifting its position in the pelvis to the injured side and sewing it to the psoas muscle with a psoas bladder hitch.
A ureteral reimplant may be performed with the shortened ureter. (From Guerriero WG. Urologic Injuries. East Norwalk, CT: Appleton & Lange;
1984.)
closed bladder neck causes the bladder to rupture at its weakest and most mobile point, the dome. The dome of the bladder is covered only by peritoneum, and a forceful tear in this
area results in a communication with the peritoneal cavity.
The diagnosis is made when the cystogram reveals contrast
fluid within the peritoneal cavity classically outlining loops
of bowel. These injuries account for one third of all bladder
ruptures (Fig. 55-12).
Intraperitoneal bladder rupture often produces abnormal
serum chemistries, including potassium, sodium, nitrogen,
and creatinine. In a series of 22 children treated for traumatic
bladder rupture, 44% were diagnosed immediately, and 56%
had delayed diagnosis after 24 hours.109 Of these children,
56% had intraperitoneal and 44% had extraperitoneal bladder
rupture. Patients with intraperitoneal bladder ruptures and
late presentation had increased serum levels of blood urea
nitrogen, creatinine, and potassium. They had low levels of
serum sodium. Patients with intraperitoneal bladder ruptures
who presented early had increased creatinine and potassium.
Patients with extraperitoneal ruptures had normal serum
chemistries.
The accepted management of intraperitoneal bladder rupture is open surgical exploration and primary repair. This is
considered an urgent procedure and includes irrigation of
the peritoneal cavity. The peritoneal cavity is not drained,
but the bladder is drained with either a suprapubic tube or a
urethral catheter. Historically, suprapubic tube drainage has
been the standard of care when the bladder is repaired from
either blunt or penetrating injury, but more recent data have
indicated that urethral catheters provide equally effective
drainage and fewer complications resulting in shorter periods
of diversion.110,111 Several cases of intraperitoneal bladder rupture successfully repaired with laparoscopic techniques have
been reported.112,113 Rarely, intraperitoneal bladder ruptures
have been treated with a urethral catheter alone.114,115 After 7
to 10 days, the bladder is studied again with a cystogram to
ensure healing, and the catheter is removed.
The second type of bladder rupture is extraperitoneal,
and it occurs in the lower half of the bladder and is almost
exclusively associated with pelvic fractures. With disruption
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Figure 55-11 Mechanisms of blunt bladder injury. A, Extraperitoneal bladder injuries occur most often with pelvic fractures. The distortion of
the bony pelvis and, in some cases, perforation of the bladder with bone fragments tear the lower bladder. B, Intraperitoneal bladder ruptures
usually occur when blunt force is applied directly to the distended bladder. The bladder ruptures at the dome, resulting in a simultaneous tear of
the overlying peritoneum and intraperitoneal urine extravasation. (A and B, From Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr, eds. Campbells
Urology. 5th ed. Philadelphia: Saunders; 1986.)
URETHRAL INJURIES
Because of its shape, elasticity, and location, the urethra is seldom injured from trauma. The urethra begins at the bladder
neck and extends to the external urinary meatus. The bones
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733
Figure 55-13 A, Colles fascial attachments, which define the limits of extravasation of urine or blood from a urethral injury. B, A patient with
a perineal butterfly hematoma with bleeding limited by Colles fascia. (A, From Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr, eds. Campbells
Urology. 5th ed. Philadelphia: Saunders; 1986; B, from King LR. Urologic Surgery in Infants and Children. Philadelphia: Saunders; 1998.)
of the pelvis and extensive soft tissue of the perineum protect the entire urethra with the exception of the penile urethra.
Injuries of the penile urethra are discussed in association with
genital injuries. Injuries to the female urethra are rare and are
discussed separately.
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part
Radiographic evaluation of the urethra requires a retrograde urethrogram (Fig. 55-14). This study may be performed
in the emergency department if necessary to save time or
to avoid unnecessary movement of the injured patient. The
urologist pulls the patients penis upright to straighten the
urethra, and a catheter is placed in the distal urethra to allow
injection of contrast fluid under pressure into the lumen.
The radiograph should include views of the entire urethra
including the bladder neck, and it is helpful either to place
the patient in the oblique position or to rotate the imaging
equipment to provide an oblique view. If the study shows
continuity of the urethra, a Foley catheter may be placed into
the bladder under radiographic control. If a catheter has been
placed previously into the bladder, and urethral trauma is in
question, the catheter should not be removed. A small feeding tube can be placed in the distal urethra along the bladder
catheter, and contrast material can be injected to outline the
urethra for injury.
The management of posterior urethral injuries differs from
the management of injuries of the bulbous urethra because of
associated severe injuries and the amount of tissue damage
resulting from trauma to the posterior urethra. Bulbous
urethral or straddle injuries are often uncomplicated by
associated injuries to other systems and cause minor tissue
damage. The management of bulbous urethral injuries is
simple and involves either observation or urethral catheter
drainage to prevent urethral bleeding or painful voiding.
Often the patient has minor dysuria and transient hematuria.
Straddle injuries often resolve without the patient being evaluated by a physician and come to light later when a stricture
develops at the injury site (Fig. 55-15).
The initial management of injuries to the posterior urethra
is not so straightforward and produces considerable ongoing
controversy. The main feature of the debate is whether performing a primary realignment of the urethra with a catheter
provides better long-term results than simple suprapubic
drainage and later reconstruction of the urethra. The measures
of success in injuries of the posterior urethra are the ability to
provide a stricture-free urethra, while avoiding the complications of urinary incontinence and impotence. Historically,
immediate surgical repair of these injuries resulted in significant bleeding and high rates of incontinence (21%) and impotence (56%).124 Because of these poor results, the concept of
suprapubic catheter drainage and late urethral reconstruction
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REFERENCES
For complete list of references log onto www.expertconsult.com
P A R T
reconstruction and
surgery for incontinence
S E C T ION
bladder reconstruction
and substitution
CHAPTER
56
Urethral Catheter
The simplest and most frequently used incontinent urinary
diversion is the urethral catheter. This can be used for the
immediate drainage of bladder outlet obstruction (e.g., posterior urethral valves, ureterocele), for instillation of a contrast
agent for radiographic study, and for the accurate recording
of urine output in a seriously ill child. We prefer to catheterize
neonates with a 5F or 8F feeding tube; however, care must be
taken not to insert too much tubing because it may become
knotted inside the bladder and become difficult to remove.2 In
an older child who requires bladder drainage, a 6F or 8F balloon (Foley) catheter is a reasonable alternative. Intermittent
catheterization is another option for children with urinary
retention and has proved to be safe even in neonates. Complications of urethral catheters in children are usually related
to improper placement or prolonged use, and include urethral
injury, urethritis or meatitis, UTI, urethral stricture, urethral
erosion, and bladder stones.
Although usually very simple to insert, urethral catheterization in patients with posterior urethral valves can be
difficult if the urethra has become elongated and dilated
with an elevated bladder neck. In this scenario, a coud tip
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Cutaneous Vesicostomy
Cutaneous Ureterostomy
Cutaneous vesicostomy is the most common form of incontinent urinary diversion in neonates and young children. This
technique has limited use for older children and adults, however, because the bladder is much more difficult to mobilize and
secure outside the pelvis. Neonates with bladder outlet obstruction (e.g., posterior urethral valves or a cloaca)6 are occasionally too small to undergo definitive surgery, and a vesicostomy
offers an excellent means of reducing intravesical pressure until
a definitive reconstructive procedure is possible. Infants with a
neuropathic bladder and unsafe storage pressures may require
vesicostomy if the patients caregivers are unwilling to perform
CIC, or, despite maximal medical treatment, safe bladder pressures cannot be maintained. Very rarely, young infants with
high-grade vesicoureteral reflux, hydronephrosis, and multiple
breakthrough UTIs may also benefit from temporary vesicostomy to reduce bladder and renal pressures.7,8
Several studies have confirmed the effectiveness of a vesicostomy, with regards to either a reduction in upper tract dilation
or improvement in renal function.7-12 Reflux has been reported
to improve significantly enough to decrease the need for ureteral tapering at reimplantation.7,8 Although bacterial colonization of the open system is expected, symptomatic infections
and urosepsis are uncommon.10,11 A pressing contemporary
argument against a vesicostomy, or any supravesical diversion,
is the impact of preventing the congenitally abnormal bladder
from undergoing the normal cycle of filling and emptying,
and potentially resulting in a more diseased bladder in the
long-term.13-15 Several studies have shown good bladder function after closure of the vesicostomy, however.8,16,17
Although first described by Lapides and colleagues,18
most contemporary surgeons employ the technique described
by Blocksom19 and Duckett20 (Fig. 56-1). The Blocksom
vesicostomy is fashioned through a small transverse incision halfway between the umbilicus and the pubis. A vertical
incision may be used if future reconstruction is anticipated,
minimizing excess cutaneous scar. The fascia is incised, and
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739
Rectus fascia
Peritoneum
Proposed excision
line around urachus
Flaps of fascia
Flaps of fascia
Figure 56-1 A-G, The Blocksom vesicostomy, showing the incision in the dome of the bladder, the fixation to the overlying fascia, and the
everted stoma. (From Cain MP, Metcalfe PD, Rink RC. Urinary diversion. In: Docimo SG, Canning DA, Khoury AE, eds. Clinical Pediatric Urology.
5th ed. Boca Raton, FL: Informa Healthcare; 2007, Figure 57.2.)
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Figure 56-3 Eversion of stoma at the skin level creates a nipple effect
that allows a snug-fitting appliance, decreasing the risk of peristomal
problems. (From Cain MP, Metcalfe PD, Rink RC. Urinary diversion.
In: Docimo SG, Canning DA, Khoury AE, eds. Clinical Pediatric Urology. 5th ed. Boca Raton, FL: Informa Healthcare; 2007, Figure 57.6.)
Figure 56-2 Nonrefluxing ureterocolonic anastomosis with ureters
reimplanted within taeniae coli. (From Cain MP, Metcalfe PD, Rink
RC. Urinary diversion. In: Docimo SG, Canning DA, Khoury AE, eds.
Clinical Pediatric Urology. 5th ed. Boca Raton, FL: Informa Healthcare;
2007, Figure 57.7.)
Incontinent Ileovesicostomy
The incontinent ileovesicostomy (ileal chimney) was reported
by Schwartz and associates in 1994,32 as a variation of the
vesicostomy adapted for adults. Because the adult bladder
frequently does not reach the abdominal wall, a segment of
ileum can be anastomosed to the in situ bladder, and brought
out as a urinary stoma (as per an ileal conduit). This procedure
allows for a low-pressure system, the ability to use a urinary
appliance, the avoidance of diapering, and the avoidance
of the inherent complications of the ureterointestinal anastomosis. Another advantage to the incontinent ileovesicostomy
is flexibility regarding body habitus and position of ostomy
because a significant length of ileum can be used.33 Several
series report excellent results with regard to preservation
of renal function, incidence of UTI, urolithiasis, and stomal
complications.33-36
Preoperative preparation is identical to the ileal conduit,
with bowel preparation and selection of a stoma site. The
bladder is bivalved in the coronal plane and anastomosed
to the widely spatulated ileum. A rosebud stoma is fashioned
chapter
bladder agenesis, cloacal exstrophy, and pelvic organ destruction secondary to trauma or malignancy would be candidates
for a CUR.
Although common in pediatric urology, the decision to pursue a continent diversion must be weighed against the risk of
potential morbidity. Although techniques for gastrointestinal
urinary reservoirs are plentiful and commonly used, they are
associated with significant complications.47 Meticulous preoperative, intraoperative, and postoperative care and attention
to details are necessary to ensure satisfactory outcomes.
741
Kock Pouch
Kock first described a continent ileostomy in 1971,63,64 and
from this the Kock pouch was developed in 1982.65 This continent ileal reservoir was among the original nonorthotopic
bladder substitutions used, and it remains popular today.47,66,67
Continence and prevention of reflux are attained via afferent
and efferent limbs fashioned with nipple valves. This technically demanding aspect usually requires the use of stapling
devices, and these can be the source of the most significant complications (e.g., stone formation) and long-term failure rate.68
Approximately 80 cm of distal ileum is harvested in adults,
with the proximal 15 to 20 cm used in an isoperistaltic fashion
to create the antireflux mechanism, and the distal 12 to 15 cm
used for the continent cutaneous stoma. These lengths are
decreased appropriately depending on the size of the patient.
The bowel is intussuscepted through its full thickness and is
secured by three rows of staples, although the use of absorbable mesh has also been described.69 Several technical modifications to overcome the more common complications have
been described, including removing the distal six staples from
the device,70 stripping the distal mesentery,71 and the use of
absorbable staples.72
Gastroileal Pouch
A composite reservoir consisting of gastric and ileal segments maximizes the advantages of both, while offsetting
their complications. The metabolic derangements potentially
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Figure 56-4 A-D, The Indiana pouch uses the tapered and reinforced ileocecal valve as the continence mechanism and the cecum for urinary
storage. (From Cain MP, Metcalfe PD, Rink RC. Urinary diversion. In: Docimo SG, Canning DA, Khoury AE, eds. Clinical Pediatric Urology. 5th ed.
Boca Raton, FL: Informa Healthcare; 2007, Figure 57.22.)
Indiana Pouch
The use of the ileocecal segment was developed and popularized to take advantage of the ileocecal valve as a continence
mechanism. Many surgical techniques have been described to
improve cutaneous continence, to simplify the surgical procedure, and to minimize complications. The Indiana group modified the pouch described by Gilchrist and associates80 with a
unique plication method that has remained popular. An Indiana
pouch uses the detubularized cecum as its reservoir, with ureters
implanted in a nonrefluxing manner into the taeniae. The distal
ileum is narrowed and plicated into the ileocecal valve, which is
reinforced by Lembert sutures, and brought to the skin as a continent catheterizable channel (Fig. 56-4). Continence has been
reported in 95% to 99%,80a, 81 in part owing to the large capacity and compliance of the reservoir.82 Complication rates have
been acceptable (0.6%),80a but not all surgeons have reported
such success.83 Although the Indiana pouch has achieved great
popularity in adult patients, its use has been limited in children
because the removal of the ileocecal valve can lead to late development of diarrhea and vitamin B12 malabsorption.
MAINZ Pouch
The MAINZ (mixed augmentation of ileum n zecum) pouch
was introduced by Thuroff and colleagues in 198584 as an
ileocecal reservoir with two limbs of distal ileum. It has
undergone multiple variations and has been well accepted
worldwide, in part because of its numerous applications as
a rectosigmoid pouch,84 continent urinary reservoir, bladder
chapter
B
Figure 56-5 Mitrofanoff principle. A, The appendix is readily ac-
cessible and mobilized with its vasculature. B, It is implanted easily beneath the bladder mucosa to provide a reliable catheterizable
channel.
743
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F
Figure 56-6 A-E, The Monti-Yang channel is constructed from a 2-cm segment of ileum that is opened on the antimesenteric border and retubularized longitudinally. F, The reconstructed Monti-Yang channel has the advantage of a centralized mesentery.
chapter
745
3.5 cm
1214 cm
Figure 56-7 A-G, The Casale spiral Monti channel is created by incompletely dividing the bowel segment in the middle, opening on opposite
sides of the mesenteric border, then retubularizing to provide a much longer tube than the standard Monti-Yang technique.
Structural complications
Reaugmentation
Perforation
Bowel obstruction
Malignancy
Figure 56-8 The Mitrofanoff channel is secured to the posterior bladder wall with a direct, straight, short path from the abdominal wall
to the bladder. (Courtesy of Indiana University Medical Illustration
Department.)
Structural Complications
Structural complications include the requirement for a reaugmentation, spontaneous perforation, and long-term malignancy potential. A secondary augmentation was required in
9.4% of augmentations in our series of 500 augmentations.76
The most common indication for reaugmentation was for
persistent high intravesical pressures from bowel contractility.114,115 The hallmark clinical signs are incontinence or
hydronephrosis with screening ultrasound, and this is confirmed by urodynamic studies. This complication occurred
a mean of 7 years after the original augmentation, and was
746
part
CONCLUSION
A low-pressure conduit or reservoir is fundamental to preserving renal function, and this is the primary goal of urinary
diversion. With CIC and pioneering surgeons, lower urinary
chapter
747
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
57
AUGMENTATION CYSTOPLASTY
GASTROINTESTINAL CYSTOPLASTY
Operative Technique
Regardless of the gastrointestinal segment used for augmentation cystoplasty, the initial incision is generally made in the
lower midline from pubis to umbilicus. This incision allows
access to the entire abdomen, and additional exposure can
be obtained easily by extending the incision superiorly. In
particular, it provides superb exposure for creation of a continent stoma at the umbilicus. A lower Pfannenstiel incision
can be used, but may limit exposure. Initial laparoscopic
mobilization of bowel may insure that a lower transverse incision is adequate.8 Laparoscopic bladder augmentation has
chapter
15
749
cm
Figure 57-2 The ileal segment is isolated 15 cm proximal to the ilFigure 57-1 Two ways to prepare the bladder for gastrointestinal
eocecal valve, and a two-layer ileoileostomy is performed. The isolated segment is detubularized on the antimesenteric border. (From
Rink RC. Bladder augmentation: options, outcome, future. Urol Clin
North Am. 1999;26:111-123. Indiana University Medical Illustration
Department.)
cystoplasty. Wide sagittal incision to bivalve the bladder (left) and supratrigonal cystectomy (right). (From Rink RC, Adams MC. Augmentation cystoplasty. In: Marshall FF, ed. Textbook of Operative Urology.
Philadelphia: Saunders; 1996:917.)
Ileocystoplasty
Many experienced reconstructive surgeons consider ileum to
be the most compliant intestinal segment for urinary storage,
and it is the most commonly used segment for cystoplasty.17-19
Generally, a segment of ileum 20 to 30 cm in length is appropriate for use, although the length may be adjusted based on
the urinary output of the patient or the amount of native bladder present and the patients age (Fig. 57-2). The distal 20 cm of
ileum has unique physiologic responsibilities and should not
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Figure 57-3 A, The detubularized ileum is folded in half, and the medial edges are anastomosed to complete the U patch. B, The U patch can
be folded further to create a cup of ileum. Longer ileal segments can also be reconfigured as an S-shaped patch. (From Rink RC, Adams MC.
Augmentation cystoplasty. In: Marshall FF, ed. Textbook of Operative Urology. Philadelphia: Saunders; 1996:918-919. Indiana University Medical
Illustration Department.)
Ileocecal Cystoplasty
Cecocystoplasty alone is rarely used and so is not discussed.
Ileocecal cystoplasty is usually done in its place and is a reliable form of augmentation with the advantage of a constant
ileocolic arterial supply. Generally, there are two main types
of ileocecal cystoplasties, although many variants have been
described. In one, the cecum alone is used as the augmenting
segment, and the ileum is used either to reach short ureters or
to create a continent stoma by plication.20 In the other form,
the distal ileum one to two times the length of isolated cecum
is used as a patch for part of the reservoir as described for the
MAINZ (mixed augmentation with ileum n zecum) pouch
(Fig. 57-4).21
Typically, 15 to 30 cm of ileum and 10 to 15 cm of cecum are
used based on volume requirements. When the cecum alone
is used as reservoir, its open end can be anastomosed to the
bivalved native bladder. The limb of ileum can be plicated
to create a catheterizable channel or antireflux mechanism
as described for urinary diversion. The appendix can also be
used in situ as a catheterizable channel, or an appendectomy
is performed if the appendix is not to be used in the reconstruction. Most children undergoing an intestinal cystoplasty
may also have neuropathic bowel. Removal of the ileocecal
valve from the fecal stream in this group can result in severe
diarrhea.22,23 Cain and Husmann20 have extensive experience
Sigmoid Cystoplasty
The sigmoid colon has commonly been used for bladder
augmentation in pediatric patients with spinal dysraphism
because it is often redundant and dilated from chronic constipation. A 15- to 20-cm segment of sigmoid is isolated and
removed from the gastrointestinal tract, and a colocolostomy
performed (Fig. 57-5A). The segment is isolated from the
remainder of the abdominal contents by soaked sponges and
irrigated clear with 0.25% neomycin before incision. Early on,
Mitchell24 described incision of the antimesenteric border and
closure of the ends of the isolated segment for easy anastomosis to the bladder (Fig. 57-5B). This technique would not
adequately dampen contractile activity; it is preferable to fold
the open segment in a short U shape as described for ileum
(Fig. 57-5C) in a maximum effort to break strong unit contractions of the colon. Regardless of the technique of reconfiguration, the segment can be brought on either side of the native
sigmoid reanastomosis and sewn to the bladder.
Gastrointestinal Cystoplasty
Three basic techniques of gastrointestinal cystoplasty have
been described. Although superior to augmentation with
body in some adult series,25 antral gastrointestinal cystoplasty
with Billroth I gastroduodenostomy has not been used to a significant extent in pediatric patients and is not described here.
Gastrointestinal cystoplasty using a wedge-shaped segment
of body from the greater curvature gained some popularity in
children based on theoretical advantages after an initial report
by Adams and colleagues.26 Although initial enthusiasm has
dampened, it may continue to have a place in lower urinary
tract reconstruction in selected children.27 Lastly, a long segment of stomach along the greater curvature, including body
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751
Figure 57-4 Ileocecal cystoplasty. A, Proposed isolation and detubularization of the ileocecal segment. B, After detubularization, the medial
cecal and ileal edges are approximated. A composite patch is created for anastomosis to the bivalved bladder. (From Rink RC, Adams MC.
Augmentation cystoplasty. In: Marshall FF, ed. Textbook of Operative Urology. Philadelphia: Saunders; 1996:920-921. Indiana University Medical
Illustration Department.)
POSTOPERATIVE CARE
Some morbidity of the operative procedure can be minimized
by good postoperative management. Parenteral antibiotics are
given until the child is eating and drinking. Fluid and electrolyte status must be closely monitored because third-space
fluid losses may be significant in the first several days after
surgery. It is imperative that bladder drainage be continuous
and free. Mucus production early on is considerable and can
easily occlude the drainage catheters. The bladder should be
irrigated free of mucus at least three times per day initially and
immediately if occlusion of a catheter occurs.
The suprapubic tube is left indwelling for 3 weeks, as are
most stents through catheterizable stomas. The suprapubic
tube is clamped about 3 weeks postoperatively only after a
careful static cystogram showing no leak is performed under
low pressure. CIC is begun every 2 hours during the day at that
point and every 4 hours at night. The interval between catheterizations can be increased to every 4 hours during the day and
every 8 hours at night over the next several weeks. H2-blockers
are given in the early postoperative period after gastrointestinal
cystoplasty.29 Daily bladder irrigation continues indefinitely.
Long-term evaluation includes periodic ultrasound scans
of the kidneys and bladder and a plain abdominal film to rule
out stone formation. Because of potential metabolic changes,
serum creatinine and electrolyte values are also monitored at
least yearly. Any deterioration of the upper urinary tract or
persistence of incontinence must be evaluated by repeat urodynamics and by a careful history of bladder emptying. It has
been suggested that annual or biannual cystoscopy with urine
cytology examination be performed beginning 5 years postoperatively for tumor surveillance, but the efficacy has not
been evaluated. Daily irrigation to decrease mucus buildup is
encouraged and may have a role in decreasing infection and
stone formation. Reliable and timely CIC is essential.
Although intra-abdominal adhesions and mechanical
bowel obstruction are well-known complications of major
abdominal operations, the incidence of bowel obstruction
after augmentation cystoplasty is lower than the reported
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part
C
Figure 57-5 Two techniques for sigmoid cystoplasty. A, A 15- to 20-cm segment of the sigmoid is divided, and a colocolostomy is performed.
B, Mitchell technique. The segments can be anastomosed to the bladder in either the transverse or the sagittal plane. C, Full detubularization
and reconfiguration of the sigmoid reduces high-pressure contractile activity. The authors have abandoned use of the Mitchell technique. (A and
B, From Rink RC, Adams MC. Augmentation cystoplasty. In: Marshall FF, ed. Textbook of Operative Urology. Philadelphia: Saunders; 1996:919, 920.
C, Indiana University Medical Illustration Department.)
PRIMARY RESULTS
The goals of augmentation cystoplasty are to increase capacity, reduce pressure, and improve compliance. Although some
early patients underwent augmentation with a tubular segment
chapter
753
A
B
Figure 57-6 Gastrointestinal cystoplasty. A, Isolation of a wedge from the greater curvature. Short gastric vessels are ligated and divided, and
the gastroepiploic artery is divided distal to the patch. B, The patch is extended on its pedicle, and the stomach is closed in two layers. ( Indiana
University Medical Illustration Department.)
of gastrointestinal cystoplasties, but only 1.4% of ileocystoplasties.37 Evaluating continent urinary reservoirs in adults,
Berglund and colleagues39 and Studer and Zingg36 noted
lower basal pressures and less motor activity in ileal reservoirs
compared with cecal reservoirs.
There are series of patients with better results after colocystoplasty than noted in Indiana40; in most, the sigmoid segment
was folded rather than simply closed on the ends. Likewise,
the segment of stomach used in early gastrocystoplasties
was small in surface area; using a larger, rhomboid-shaped
segment may decrease the risk of issues with compliance,
but does place more acid-producing cells in the bladder.41
No clinical study has ever critically compared the different
segments while controlling for surface area and the exact
technique used. Most failures with any segment are the result
of rhythmic sinusoidal pressure contractions that generate too
much pressure too early in filling. Such contractions of low
amplitude late in filling are present after many cystoplasties
and may be of no clinical significance. Failure because of a
steep increase in the tonus limb is rare and usually the result
of a technical error.
Gastrointestinal cystoplasty increases capacity and
improves baseline pressure, but significant contractile activity can occur even after detubularization and reconfiguration
of the intestinal segment. Urodynamic studies should be
repeated in any patient who exhibits persistent incontinence,
recurrent febrile infection, or new hydronephrosis. Patients
and families should be told preoperatively to expect approximately a 0.5% to 10% failure rate in achieving a compliant
noncontractile reservoir. Other morbidity is also potentially
created by augmentation cystoplasty because bowel is not a
perfect physiologic substitute for bladder; these complications
are discussed in decreasing order of incidence.
COMPLICATIONS
Mucus Production
Because gastrointestinal segments maintain their intrinsic
properties after incorporation into the urinary tract, mucus
production by bowel mucosa continues after reconstruction.
Canine experiments revealed that colonic segments produce
more mucus than ileum does, and that stomach produces
the least amount.42 Most surgeons also have noted this pattern clinically and find that mucus is rarely problematic after
gastrointestinal cystoplasty. Mucus production becomes more
noticeable in the early postoperative period as the patient
resumes oral intake. Production is also increased during urinary tract infection. Although some atrophy of ileal mucosa
within the augmented bladder occurs eventually, no decrease
in mucus production over time has been documented quantitatively.43 Glandular atrophy in colonic segments is not evident histologically after long-term exposure to urine.44
Excessive mucus production or accumulation in the bladder can interfere with bladder emptying via CIC. Poor emptying may predispose the patient to urinary tract infection and
stone formation. Routine saline irrigation of the bladder at the
time of one catheterization each day and whenever drainage is
obviously incomplete may help reduce the incidence of clinical problems related to mucus production.
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Calculi
Many potential factors influence the incidence of stone formation after augmentation cystoplasty, including urinary stasis;
abnormal urine pH and citrate; bacteriuria; mucus production;
and the presence of foreign bodies such as sutures, staples, or
catheter fragments. Most calculi in this population are found
in the bladder, although patients are also at increased risk for
upper tract stones. Bladder calculi after enterocystoplasty
have been reported in 12% to 50% of patients.46-49 In the largest series, which reviewed 500 patients, bladder stones were
found in 15% of patients, requiring 1.72 stone surgeries per
patient. There was no statistically significant difference in stone
occurrence in ileum versus colon. There were no stones in pure
gastric augmented bladders.38 Kronner and colleagues49 also
showed a statistically significant increase in stone risk with
the additions of a bladder outlet procedure and a continent
abdominal wall stoma to augmentation.
Most bladder stones in this setting are composed of struvite, and bacteriuria with urea-splitting organisms has been
implicated in the etiology. Poor bladder emptying can play a
role as well. Palmer and associates48 recommend meticulous
attention to emptying and daily bladder irrigations to remove
nidi (mucus, crystals) for stone formation. Stones occur
infrequently after gastrointestinal cystoplasty, affecting only
2% to 9% of patients in several series.34,50,51 Stone formation
after gastrointestinal cystoplasty is discouraged by the acidic
environment and low incidence of mucus and infection. Most
stones noted after gastrointestinal cystoplasty are actually uric
acid in composition.
Calculi can be removed from the augmented bladder either
endoscopically or by open cystolithotomy. In the series of
Kronner and colleagues,49 a higher stone recurrence rate was
noted after cystolithotripsy (54% versus 33%) compared with
open removal, although this difference did not reach statistical significance. Extracorporeal shock wave lithotripsy has
not been used with good success after augmentation. Bladder
irrigation with hemiacidrin may have a role in the dissolution
of stone particles after treatment, but is not beneficial in treatment of intact stones.47 Care must be taken to avoid magnesium intoxication from absorption if it is used.
Metabolic Complications
Since Ferris and Odel52 noted profound electrolyte abnormalities in patients after ureterosigmoidostomy in 1949, the
potential metabolic implications of incorporating bowel into
chapter
decrease in percentile height in the group with augmentation was troubling. Mingin and colleagues57 in a well-done
study did not show similar problems. All children with
chronic metabolic acidosis after augmentation cystoplasty
should be given oral alkaline therapy. The impact of subclinical acidosis in these patients may be underestimated, and
better understanding of the issue is needed.
755
acidic fluids, but also failure of continence results in less dilution and buffering of the secreted acid. Except under distinct
indications, gastrointestinal cystoplasty should be avoided
in patients with normal sensation from the native bladder
because of this syndrome.
When treatment of these signs or symptoms is required
after gastrointestinal cystoplasty, adequate oral intake of
fluids helps dilute the acid. Symptoms usually respond to
H2 blockers or H+,K+ ion pump inhibitors.66 Treatment with
oral agents or with bicarbonate bladder irrigations is particularly important during periods of catheter drainage or bladder
defunctionalization because the exposure of urothelium to
acid may be unbuffered at those times.68 The potential impact
of aciduria is emphasized by a report of ulceration and perforation in a defunctionalized gastrointestinal cystoplasty.69
Composite Reservoirs
The metabolic derangements created by stomach and ileum/
colon in the urinary tract can be used to oppose each other,70,71
and decrease the limitations of each segment alone in some
patients. Composite continent reservoirs or augmentations
have generally been done in very complex patients or patients
requiring secondary augmentation for problems after primary
cystoplasty with remarkably good results. Potential changes
in serum electrolytes, including chloride and bicarbonate, and
elevations in serum gastrin levels or signs of the hematuriadysuria syndrome have not been noted.70,71 Although the
combination can achieve apparent metabolic neutrality, widespread use of composite augmentation for routine, primary
cystoplasty is unlikely because it is cumbersome and requires
two bowel anastomoses.
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Malignancy
Development of adenocarcinoma at the ureterointestinal
anastomosis site is another well-recognized complication of
ureterosigmoidostomy.80 The procedure creates a 7000-fold
increase in the risk of developing adenocarcinoma of the colon
after a mean latency period of 26 years.81 Although the exact
mechanism for tumor induction after urinary diversion is not
well understood, carcinogenic substances may be produced by
the admixture of urinary and fecal streams after ureterosigmoidostomy. N-nitroso compounds are found in that setting,
and have been found in urine after augmentation cystoplasty
and loop diversion.82,83 Animal studies have revealed hyperplastic growth in various enteric segments after augmentation
cystoplasty,84-86 and tumors have been discovered anecdotally
in humans after augmentation with either ileum or colon.87 The
earliest note of tumor formation was only 4 years after bladder augmentation.88 Dysplasia and metaplasia of urothelium
and adenocarcinoma or transitional cell carcinoma have been
observed near the vesicoenteric anastomosis in humans.89,90
Soergel and coworkers91 reported three cases of transitional
cell carcinoma after augmentation cystoplasty. They believed
that intestinal cystoplasty was an independent risk factor for
malignancy, noting a risk of 1.2% to 3.8%.
Because the latency for tumor formation after ureterosigmoidostomy is so lengthy, the long-term tumor risk after
augmentation cystoplasty may be grossly underappreciated
at this point. Yearly endoscopic evaluation of the augmented
bladder for tumor surveillance beginning about 8 years after
reconstruction seems prudent, although the efficacy of such a
program is not proven. Urinary cytology or flow cytometry
may ultimately be useful in surveillance as well.
ALTERNATIVES TO GASTROINTESTINAL
CYSTOPLASTY
As noted earlier, gastrointestinal cystoplasties can result in significant complications even when a good technical result and
compliant reservoir are achieved. Although early and aggressive treatment of primary bladder dysfunction may prove
effective at decreasing the need for surgical augmentation of
the bladder, alternatives to gastrointestinal cystoplasty have
been developed in an effort to decrease morbidity for a patient
who still fails conservative measures. The alternatives, in principle, attempt to provide a compliant reservoir of adequate
size with urothelial lining.94 Further work and experience in
the area are warranted.
Autoaugmentation
Cartwright and Snow95 proposed that excision of the muscularis
of the bladder dome leaving the urothelium to bulge in a manner similar to a diverticulum could improve bladder dynamics.
This urothelial bulge, if persistent, could theoretically augment
capacity, decrease contractility, and improve compliance.
Technique
Patients should undergo the same bowel preparation as
described earlier for intestinal cystoplasty because if capacity is not markedly improved after detrusorectomy, intestinal
cystoplasty should be performed.96 The bladder is distended
with saline and exposed through a lower abdominal incision.
Although it has been shown that vesicomyotomy (incision)
achieves similar results to vesicomyectomy (resection), resection of the bladder muscle is generally favored.97,98 A midline
bladder incision is made to the level of the lamina propria with
a needle-tipped electrode, and the musculature is elevated
from the urothelium with either a hemostat or Kitner dissector
on either side (Fig. 57-7).
At least 50% of the detrusor muscle should be excised
according to Cartwright and Snow.95 Fixation of the remaining bladder muscle bilaterally may aid in preservation of
the diverticulum. These authors recommend measurement
of compliance and capacity after resection. If both are significantly improved, a suprapubic tube is placed through the
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Figure 57-7 Autoaugmentation. Midline bladder incision to the urothelium. Muscle is separated from the urothelium, and the detrusor is excised leaving the urothelium to bulge as an augmentation segment. (From Rink RC. Bladder augmentation: options, outcome, future. Urol Clin
North Am. 1999;26:111-123.)
remaining bladder musculature, and the drainage tubing is
elevated to a height of 15 cm to keep the urothelium expanded
in the early postoperative period. Alternatively, an intravesical balloon may be temporarily placed to keep the bladder
distended. If there is no improvement in compliance and
capacity, intestinal cystoplasty should be performed instead.
Results
The results of autoaugmentation have been mixed. Some
patients have shown clinical improvement without significant
objective urodynamic improvement. Any increase in capacity
may be inadequate.99 Landa and Moorhead100 reported that the
increase in volume is modest at best. Despite several small
series reporting good results in pediatric patients,101,102 Stothers and coworkers98 noted an increase in capacity by only 15%
to 70%. In a combined series of 25 patients from two groups,
a good clinical result was achieved in only 52% of patients,
with 28% having acceptable outcomes and 20% having poor
outcomes.96 Experimentally, fibrosis and thickening around
the urothelium are demonstrable and lead to a decrease in the
surface area of the diverticulum by 50% at 12 weeks97; these
changes may contribute to the marginal clinical results. Use in
adults with hyperreflexia but good capacity, a rare situation in
children, has been reported to achieve good results,103,104 but
Milam (DF Milam, personal communication, 2000) reported
that nearly 50% of patients achieving a good result initially for
hyperreflexia fail on long-term follow-up.
Ureterocystoplasty
Ureter is an ideal tissue for bladder augmentation if enough is
present. It has long been recognized that a refluxing megaureter
can behave as an effective pressure pop-off for an abnormal
bladder.105 Early reports of ureterocystoplasty described use
of massively dilated ureters subtending a nonfunctioning or
poorly functioning kidney. Initially, only ureter was used106,107;
more experience showed that, with care, the renal pelvis could
be used in some cases with the ureter.108-110
Technique
A single midline intraperitoneal approach can be used, but
several groups have reported the use of separate extraperitoneal flank and suprapubic incisions.107,110,111 In either case,
Results
Landau and colleagues118 first compared ureterocystoplasty
with ileocystoplasty in age-matched, diagnosis-matched
patients, and found the bladder capacity to average 417 mL
after using ureter and 381 mL after using ileum. Bladder volumes at 30 cm H2O were 413 mL for ureter and 380 mL for
ileum. In several subsequent series, the results were good, and
complications were rare.119,120 In contrast, Gonzalez121 reported
that one quarter of his patients with posterior urethral valves
experienced failure after ureterocystoplasty owing to their
large urine output. In a multicenter experience, Husmann and
associates122 also noted problems, particularly if the ureter
used was not greater than 1.5 cm in diameter on preoperative
imaging.
Ureterocystoplasty works well to achieve the goals of
augmentation and can be considered as the augmentation of
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C
Figure 57-8 Ureterocystoplasty. A, Bladder is bivalved in the sagittal plane and to the ureteral orifice. B, Blood supply to the ureter is preserved,
and the kidney is removed. The ureter is detubularized along its length. C, The megaureter remains attached to the bladder and is reconfigured
for a spherical reservoir. (A, From Rink RC, Adams MC. Augmentation cystoplasty. In: Marshall FF, ed. Textbook of Operative Urology. Philadelphia:
Saunders; 1996:916. B and C, Indiana University Medical Illustration Department.)
Gonzalez and colleagues128 have used demucosalized sigmoid colon over urothelium. In their early clinical experience
with seromuscular colocystoplasty lined with urothelium
(Fig. 57-9), bladder capacity increased 2.4-fold in 14 of
16patients, with end filling pressures decreasing from 51.6
to 27.7 cm H2O.128 The remaining two patients experienced
failure and required ileocystoplasty. Ten patients eventually
underwent bladder biopsy; in one, urothelium with islands
of colonic mucosa was noted, and in two others only colonic
mucosa was found. These authors and others129,130 have
suggested that preservation of the entire submucosa on the
demucosalized enteric segment is important in preventing
contracture. Dewan and colleagues131 noted, however, that the
inner portion of the submucosa and muscular mucosa must be
removed to prevent enteric mucosal regrowth.
The use of demucosalized stomach over urothelium
was reported initially by Dewan and Byard132 in sheep
and humans. Several other reports of early work with the
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Figure 57-9 Seromuscular colocystoplasty plus autoaugmentation. Sigmoid colon is opened on its antimesenteric border, and the mucosal lining
is removed. The remaining seromuscular colonic segment covers the autoaugmented bladder. (From Rink RC. Bladder augmentation: options,
outcome, future. Urol Clin North Am. 1999;26:111-123.)
Tissue Engineering
Early efforts to create an artificial bladder were largely
unsuccessful and have been well reviewed by Gleeson and
Griffith.137 More recently, major advances made in the area of
tissue regeneration and engineering give promise of clinical
benefit. Some such work revolves around the use of biodegradable scaffolds for bladder wall growth either in vivo or in
vitro. So-called unseeded regeneration involves use of a biodegradable scaffold sewn to the native bladder as with any other
segment for augmentation, which is then modeled in place by
the body. Using pig small intestine submucosa, Kropp and colleagues138 showed regeneration of urothelium and muscle that
behave histologically and functionally as bladder.139-141 How
regenerated tissue will function, particularly in a bladder with
abnormal innervation, remains to be seen. Several other groups
have used acellular matrix or grafts as the scaffold with similar
early bladder regeneration.142,143
Atala and colleagues144,145 showed that bladder tissue can
be harvested, grown, and expanded in vitro for later bladder
augmentation. Growth of all bladder layers in this seeded
technique has been shown, and the engineered tissue has been
used anecdotally.146-149 Although these techniques hold great
promise,149 much is still to be learned, and routine clinical use
remains a future possibility.
Catheterizable Channels
Nearly every child who undergoes major urinary tract reconstruction with augmentation cystoplasty is committed to a
lifetime of CIC. Catheterization must be accepted into the lifestyle and daily routine of patients and their families, and surgical innovations may allow earlier independence for patients
by providing easier or more reliable access to the bladder. A
major contribution occurred when Mitrofanoff150 introduced
the principle of a continent catheterizable abdominal wall
stoma in 1980, and since the initial description using appendix, various tissues, including reconfigured or tapered intestinal segments, ureter, tubularized bladder, and fallopian tube,
have been used in a similar fashion. Detailed descriptions of
several of these techniques are found elsewhere in this textbook, but with each, a straight, uniformly tubular structure is
brought to the abdominal wall in a manner to provide easy
catheterization. Tunneling of the structure submucosally into
the bladder or reservoir creates continence. Despite potential
complications with catheterizable channels, of which stomal
stenosis is the most common,151 their intimate association with
augmentation cystoplasty is clear. The long-term results of
bladder augmentation depends on the routine use of CIC for
almost all patients; an adjunctive means of catheterization that
is easy and reliable may improve those results.
The complete needs of the patient and family should be
appreciated before surgical reconstruction is undertaken.
If catheterizable channels are needed to empty the bladder
regularly or for bowel irrigations and fecal continence, it is
beneficial to recognize these needs initially and to create the
channels at the time of augmentation cystoplasty. Successive
reconstructive procedures become more difficult for the surgeon and result in more morbidity for the patient.
CONCLUSION
Augmentation cystoplasty has been a remarkable advance
for children with small-capacity, poorly compliant bladders.
It provides an adequate urinary reservoir for almost every
patient when necessary. It has resulted in an entirely new set
of urologic complications, however; some are common but
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on the particular needs of that patient and not any bias of the
surgeon.
Finally, regardless of the technique used, the ultimate result
depends on a team effort. Patient selection and education, and
family and patient motivation are crucial factors. All individuals involved must understand that success requires a lifelong
commitment to good care.
REFERENCES
For complete list of references log onto www.expertconsult.com
S E CTION
58
PREOPERATIVE EVALUATION
Lower and upper urinary tract function should be thoroughly
assessed. A voiding cystourethrogram is necessary to assess
bladder capacity, shape, and trabeculation, and to determine
whether vesicoureteral reflux is present. Urodynamic studies of the bladder include a cystometrogram to assess bladder
capacity and to identify detrusor hyperreflexia. The predicted
normal bladder capacity is most easily determined by the
following formula: bladder capacity (ounces) = age (years)
+ 2. In children with a neuropathic bladder, bladder capacity
is often reduced. The peak detrusor pressure may be inaccurately measured as low in the presence of high-grade reflux,
and the bladder capacity may be inaccurately identified as low
if the outlet resistance is so low that fluid leaks out of the bladder before it fills. Occluding the bladder neck with a catheter
may ameliorate this problem. The ideal method of assessing
the lower urinary tract is with videourodynamics.
The bladder outlet can be measured in several ways, including leak point pressure and electromyography. No criteria predict with 100% accuracy whether the bladder outlet is intact
or incompetent. In the past, the urethral pressure profile was
used, but with experience it has not provided a reliably accurate assessment. The Valsalva leak point pressure also has been
reported to be helpful because it simulates circumstances that
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Although not universally accepted, the static urethral pressure profile performed in the standard manner provides the
initial baseline from which to gauge the success of any subsequent treatment.20 It allows monitoring of urethral pressures
continuously throughout filling and emptying of the bladder,
obtaining a true dynamic measure of urethral and bladder
neck function, and effectiveness of transmitted abdominal
pressure.
YOUNG-DEES-LEADBETTER PROCEDURE
Surgical Technique
Before considering the technical aspects of bladder outlet/urethral reconstruction, the importance of careful patient selection must be stressed. In most cases, a satisfactory outcome
depends on the continuing commitment of the patient or, in
younger children, the parents. Careful preoperative assessment is required to evaluate a patients motivation and intelligence, and the degree of manual dexterity needed to perform
CIC. Patients confined to wheelchairs may have difficulty
accessing the genitalia for self-catheterization and may require
an easier route to the bladder, which can be created by fashioning a catheterizable stoma to the abdominal wall (Mitrofanoff procedure).21 Several procedures to increase urethral
resistance have been described in the decades since Young first
addressed the subject.22 In children with a neuropathic bladder, the possibility of intermittent bladder emptying using CIC
has given rise to a variety of procedures for reconstruction of
the bladder outlet that provide continence, but, with a few
exceptions, do not allow volitional voiding.
The ideal surgical technique to correct urinary incontinence should fulfill the following criteria: (1) use the patients
own tissue, (2) use a minimal amount of bladder tissue,
(3) be durable and efficacious, and (4) allow easy access to
the bladder through catheterization. Surgical procedures to
achieve urinary continence are dictated by functional and
anatomic deficiencies, and by the ultimate goal of either continence (with normal voiding) or dryness (dependent on CIC).
Construction of a functional urethra allowing normal voiding
is rare in children with a neuropathic bladder. Optimistic
series reported spontaneous voiding in 5 of 19 patients (25%)
who achieved continence in a group of 32 patients with a neuropathic bladder treated with AUS observed for 15 years.23,24
Based on these data, it is fair to assume that most patients
with neuropathic bladder need intermittent emptying by catheterization after increasing bladder outlet resistance, and any
surgical technique aiming to achieve this goal should consider
this aspect.
Surgical techniques for the treatment of urinary incontinence are based on the following basic principles:
Surgical techniques for bladder neck reconstruction were initially described by Young in 1922,22 and were later modified
by Dees in 194925 and Leadbetter in 1964.26 The YDL technique
is often used in pediatric reconstructive surgery, especially in
cases with normal bladder innervation, such as bladder exstrophy and epispadias, in which continence rates of 70% to 86%
have been reported in large series.27-29
Results
The use of the YDL technique for correction of neuropathic
incontinence has not reached the same popularity as it has
in children with exstrophy/epispadias, and there have been
few reports with significant patient numbers. In 1987, Rink
and Mitchell7 reported an initial success rate of only 57% in
26 patients who ultimately achieved dryness after several
additional continence procedures. Similar success rates were
reported by Tanagho in 1981,31 Arap and coworkers in 1988,32
and Johnson and associates in 1988.8
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Surgical Technique
A pedicle 2 cm 8 to 10 cm in girls or 2 cm 12 to 14 cm in
boys consisting of rectus abdominis and pyramidalis muscle
with overlying fascia is raised parallel to the midline, taking
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care to preserve the blood supply via the distal pubic attachments. The flap is doubly looped beneath the urethrovesical
junction and sutured to the contralateral rectus sheath using a
nonabsorbable suture. Sufficient tension is applied to coapt the
bladder neck, while allowing for easy placement of a urethral
catheter. The occlusive effect of the sling is assessed during
surgery by filling the bladder and varying the tension on the
sling until urethral urine leakage ceases. Augmentation cystoplasty and ureteric reimplantation were used when necessary,
before suturing the rectus flap to the other side.
Urethral catheterization was maintained for 5 to 10 days
after surgery; a suprapubic cystotomy was placed for 2 to
3 weeks when bladder augmentation is combined with sling
suspension. Urethral catheterization was instituted 10 days
after surgery if the sling was the only procedure; if the bladder was augmented, urethral catheterization was begun
after clamping the suprapubic tube. Of 37 patients with a
neuropathic bladder, the bladder was augmented in 33, and
34 (92%) were dry between catheterizations. Using a similar
technique, with minimum 2-year follow-up, Albouy and
associates44 reported that 13 of 14 were continent; all of their
patients also underwent augmentation enterocystoplasty.
A similar concept using rectus fascia has been reported by
several groups.45,46 A 1 to 1.5 cm 6 to 7 cm strip of anterior
rectus is harvested. After a concomitant procedure such as ureteral reimplantation or augmentation or both, the fascial strip
is placed circumferentially around the bladder neck. Avertical
slit is made 1 cm from one end of the strip. The opposite free
end is passed through the slit and cinched snugly around
the bladder neck. The wrap is secured to itself at the point of
passage through the slit with 2-0 polydioxanone to prevent
slippage. The free end is secured to the symphysis or rectus
fascia, elevating the bladder neck and resulting in 360-degree
compression of the bladder neck. In a series of 15 patients,
Bugg and Joseph46 reported a 60% success rate. Using a similar technique, Walker47 has had slightly better success.
KROPP PROCEDURE
In 1986, Kropp and Angwafo48 reported a creative procedure
for the treatment of total urinary incontinence. This procedure
consists of performing urethral lengthening with a tubularized anterior bladder wall flap, which is reimplanted in the
posterior intertrigonal area, creating a one-way valve mechanism similar to the antireflux mechanism procedures used
for correction of vesicoureteral reflux. Increases in intravesical pressure are transmitted to the submucosal urethral tube,
increasing closure pressure and preventing incontinence.
Surgical success is based on the Mitrofanoff procedure and
results in an effective one-way flap valve and a completely
retentive patient who requires CIC for bladder emptying. It is
mandatory that the patient or family or both be compliant and
trained to perform catheterization routinely. As previously
discussed, the need of simultaneous bladder augmentation is
based on a provocative urodynamic evaluation using a balloon
catheter to occlude the bladder neck to avoid leakage during
the filling phase of the study. Kropp49 has advised the same
maneuver when performing a cystogram to evaluate the presence of vesicoureteral reflux and the need for reimplantation.
Surgical Technique
The patient is placed supine, with the sacrum over the kidney
rest, which can be elevated to increase exposure of the bladder neck and proximal urethra. An appropriately sized Foley
catheter is passed and kept sterile so that it can be accessible
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765
Figure 58-1 Kropp procedure. A, Anterior bladder wall flap (5 to 7 cm long 2 to 2.5 cm wide) is outlined. B, The junction of the trigone and
the bladder neck is identified from within, and the mucosa of the bladder neck is separated from the urethra. C, The anterior bladder flap is tubularized with a one-layer suture (interrupted suture in the last 2 cm). D, A posterior trigonal tunnel (6 cm long 3 cm wide) is created beginning
at the bladder neck and carried upward beyond the ureteral orifices. E, The tubularized flap is reimplanted in the posterior submucosal tunnel,
and the anterior bladder wall is sutured over the bladder neck at the base of the neourethra. (From Hinman F. Atlas of Pediatric Urologic Surgery.
Philadelphia: Saunders; 1994).
Results
The Kropp procedure relies on a flap-valve mechanism, and
patients achieve dryness because they become retentive. CIC is
required for bladder emptying. Although dryness is achieved
in 80% of patients,50 many can experience difficulty with
catheterization.38,51 In 1992, attempting to improve problems
related to catheterization after bladder neck reconstructions,
De Badiola and associates52 reported experimental work in
dogs in which an anterior bladder mucosal flap was sutured to
the posterior bladder wall in an onlay fashion, creating a flapvalve mechanism. Postoperatively, the animals did not have
problems with catheterization and showed minimal reduction
of bladder capacity.
Similarly attempting to reduce problems with catheterization, Belman and Kaplan53 suggested another modification to
the original Kropp procedure. Instead of complete transection
of the bladder neck, only the mucosa is incised transversely
to minimize any angulation that might occur when the bladder is totally separated from the urethra. The purpose of this
modification was to reduce postoperative catheterization
problems, and injury to the posterolateral neurovascular
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trusor of the distal end of the flap is removed, leaving only mucosa
and submucosa. This maneuver makes a thinner and more pliable
tube for reimplantation into the posterior bladder wall.
Surgical Technique
The patient should be in a hyperextended position whenever
this is possible and safe. This position allows better exposure
and visualization of the bladder neck. The bladder is exposed,
and a wide-based anterior bladder wall flap is outlined. The
base of the flap should be 2.5 cm wide, and the dimensions of
the flap should narrow progressively to the top, which should
be 1.5 cm wide. The flap should be at least 5 cm long (Fig.
58-3A). In the absence of vesicoureteral reflux (the most common scenario), the flap should be prepared with free mucosa
extending beyond the distal aspect of the full-thickness flap.
This can be facilitated by cutting only the muscular layer of the
distal flap and carrying the dissection upward in the submucosal plane, similar to the approach for extravesical ureteral
reimplantation. This maneuver results in redundant mucosa
hanging in the distal flap; this is used later for its coverage
(see Fig. 58-3B).
Additional removal of 0.1 cm of either mucosal edge of the
muscular part of the flap is done to avoid overlapping suture
lines later during the procedure (see Fig. 58-3C). This excision
allows construction of a rectangular mucosal area attached
to the flap, which has a larger part of denuded detrusor in
its base, the most dangerous place for fistula formation (see
Fig. 58-3D).
The ureteral orifices are catheterized and exteriorized laterally in the bladder. Two parallel incisions, 1 cm apart from each
other, are made in the posterior trigonal mucosa to expose the
muscle (see Fig. 58-3E). The anterior bladder flap is dropped
onto the incised posterior trigonal mucosa and sutured in
two layers (mucosa-mucosal and muscle-muscular) to the
posterior bladder wall in an onlay fashion. An 8F Silastic stent
is left in the lumen of the neourethra. The free mucosa at the
end of the flap is folded back over the intravesical neourethra,
allowing mucosal coverage and facilitating bladder closure
(see Fig. 58-3F).
If reimplantation is necessary, both ureters are disconnected before the flap is sutured to the posterior bladder wall
and reimplanted in a more cephalad position, using the crosstrigonal method (see Fig. 58-3G). In this case, mucosal coverage of the intravesical urethra is accomplished by dissecting
the posterior mucosa lateral to either side of the posterior
bladder incisions. After this mobilization, the free mucosa is
sutured in the midline, over the intravesical urethra (see Fig.
58-3H). The anterior bladder wall is closed in the midline
in a standard fashion, without causing tension on the neourethra. We endeavor to ensure that there is no tension over
the neourethra to avoid compression on its base and impairment of its vascular supply. To avoid such tension, it may be
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767
1.5 cm
5 cm
2.5 cm
C2
C1
Additional
mucosa on
either side
or both
Figure 58-3 Pippi Salle technique. A, Anterior bladder wall flap is outlined with a wide base to improve vascular supply. B, Only the muscular
layer of the distal aspect of the flap is incised. Dissection is carried upward in the submucosal plane to obtain redundant distal mucosa. C, Excision
of mucosal edges of the flap. D, Additional removal of mucosal edge of the muscular part of the flap is done to avoid suture overlapping when it is
sutured to the posterior wall. E, Two parallel incisions, 1 cm apart, are made in the posterior trigonal mucosa to expose the muscle. F, The anterior
bladder flap is dropped onto the incised posterior wall and sutured in two layers, in an onlay fashion. The redundant distal mucosa is folded back
over the neourethra and sutured to the lateral mucosa.
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Figure 58-3, contd G, When reimplantation is necessary, the ureters are reimplanted in a more cephalad position, using the cross-trigonal
method. In this case, it is unnecessary to fashion the flap with redundant distal mucosa. H, After reimplantation, mucosal coverage of the neourethra is accomplished, dissecting the posterior mucosa lateral to either side of the posterior bladder incisions. I, The anterior bladder wall is
closed in the midline, causing no tension in the neourethra. If tension is present, it can compromise the vascular supply of the flap leading to
ischemia and loss of the flap valve. In most cases, part of the neourethra is kept outside the bladder. J, Schematic lateral view of the neourethra.
The neourethra is situated inside the bladder and has a flap-valve mechanism. (From Pippi Salle JL. Pippi Salle onlay procedure. Atlas Urol Clin
North Am. 2001;9:97-107.)
Results
In a series of patients, most of whom had a neuropathic bladder, Pippi Salle reported dryness for at least 4 hours in 15 of
21 patients (72%),57,58 and 17 (80%) had acceptable social continence. After his initial experience, Pippi Salle changed the
dimensions of the flap to establish a balance between having a
narrow enough flap to achieve a good valve mechanism without jeopardizing its vascular supply. This goal was achieved
in most patients using a trapezoidal flap shape, removing its
mucosal edges. A similar success rate was reported by others.59-62 Mouriquand and associates59 reported good results
in 72% of patients who achieved dryness, and none experienced problems with catheterization. Similarly, Rink and colleagues62 reported the use of this technique, and continence
was achieved in five of six patients (83%). One of their patients
developed a fistula and problems with catheterization. Koyle60
reported continence in 16 of 17 patients with this technique
(94%). Overall, the combined results for this technique
achieved a continence rate of 80% (44 of 55 patients); 16% (9 of
55) had problems with catheterization. The success rate with
slings is higher in females than males.
Patient Selection
Children who are candidates for a suspension procedure usually have a neuropathic bladder secondary to myelodysplasia,
sacral agenesis, tethered spinal cord, sacrococcygeal teratoma,
or a spinal cord tumor. Other situations in which a suspension procedure should be considered include structural injury
to the external sphincter, including pelvic fracture; iatrogenic
causes (e.g., transurethral incision of the bladder neck in girls);
and selected cases of bladder exstrophy or epispadias.
Most children who are candidates for a suspension procedure have been unable to stay dry on CIC despite maximum pharmacologic therapy and optimal frequency of CIC.
Generally, children younger than 5 or 6 years have been given
insufficient time to assess whether they can stay dry with this
form of management. Another aspect regarding patient age
is that the bladder neck is much easier to dissect out in prepubertal patients because the bladder is an abdominal organ
in that age group. After puberty, in boys, particularly boys
who are overweight, isolating the bladder neck can be more
challenging.
Children also should have sufficient manual dexterity to
be able to perform CIC. Whether a child is ambulatory or
uses a wheelchair also is important because children who
sit in a wheelchair may have difficulty transferring to a
toilet to perform CIC, and often find it easier to empty their
bladder through a continent stoma. In such cases, a bladder
neck suspension procedure such as a sling often is an effective way of providing sufficient bladder outlet resistance to
produce dryness. Before a urethral suspension procedure is
performed, the planned method of bladder drainage needs
to be determined. It is easier to achieve a continent bladder
neck with a fascial sling in girls than in boys, and it is easier
to catheterize the female urethra than the male urethra after a
fascial sling repair. Consequently, it is appropriate to advise
boys that urethral catheterization may be difficult, and that a
backup abdominal stoma with the appendix or a Monti-Yang
tube might be necessary.
In children with a neuropathic bladder, bladder function
is almost always abnormal because they may have detrusor
hyperreflexia or poor vesical compliance and an incompetent
external sphincter. These children typically are performing
regular CIC and taking anticholinergic medications to eliminate detrusor hyperreflexia and -adrenergic medications
chapter
Surgical Technique
The sling is placed around the bladder neck. The plane around
the bladder neck is identical to that for placement of an AUS.
In girls, there are three approaches: retropubic, retrovesical,
and transvaginal. In boys, there are two approaches: retropubic and retrovesical.
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part
first option is to use rectus fascia and close the abdominal wall
using a polypropylene or Marlex mesh. Another option is to
use fascia lata from the thigh rather than rectus fascia for the
graft.67 The disadvantage of this approach is that most urologists are unfamiliar with the surgical anatomy of the thigh,
and it may be necessary to ask another surgeon to harvest the
fascia lata graft.
A synthetic material that has shown efficacy is small intestinal submucosa (SIS), which is available as 1-ply or 4-ply,
which is stronger.68 The material may be folded onto itself
to improve graft strength. The long-term efficacy of SIS has
been favorable. Other synthetic materials, such as monofilament polypropylene (Marlex, CR Bard, Covington, RI)
Sling
Segments to
be excised
Bladder neck
Sling
Figure 58-4 Technique for periurethral sling procedure. A, Incision is made along the endopelvic fascia on either side of the urethra. B and
C, Lottmann technique for developing retrovesical plane in girls. D and E, Lottmann technique for developing retrovesical plane in boys. F, The
graft is fixed on each end with a running baseball stitch using polypropylene suture. G, The bladder neck is tapered by excising part of the detrusor muscle on each side adjacent to the bladder neck. H, Distance around tapered bladder neck is measured. I, The sling is placed behind the
bladder neck. (B-E, From Lottmann H, Traxer O, Aigrain Y, et al. La voie dabord retro-vesicale pour limplantation du sphincter artificial AMS
800 chez lenfant et ladolescent: technique et resultants chez huit patients. Ann Urol (Paris). 1999;33:357.)
chapter
Sling Placement
Placement of the periurethral sling generally is done at the
end of the reconstructive procedure because the tension on
the sling can be adjusted, and one can test the strength of the
771
Rectus muscle
and fascia
Sutures
Fixation
suture
Sling
Urethra
Figure 58-6 Placement of the periurethral sling. A, The sutures on each end of the graft are crisscrossed anterior to the bladder neck, brought
through the rectus fascia on each side, and tied anterior to the rectus fascia, providing 360-degree urethral compression. B, Placement of sling in
girls. C, Placement of sling in boys.
772
part
A
Figure 58-7 A 10-year-old boy with myelodysplasia. A, Preoperative cystogram shows incompetent bladder neck and small trabeculated bladder. The patient underwent enterocystoplasty and periurethral sling. B, Postoperative cystogram shows elevation of bladder neck. (From Elder JS.
Periurethral and puboprostatic sling repair for incontinence in patients with myelodysplasia. J Urol. 1990;144:434.)
chapter
773
Age (yr)
McGuire et
al76
Raz et al77
Raz et
al78
Dry
Male
Female
Total
Technique
Male
Not reported
Transvaginal
8/8
8/8
Not reported
Transvaginal
3/3
3/3
8/11
8/11
9/10
12/14
Periurethral
Bauer et al79
11
11
Periurethral
Elder80
10
14
Periurethral
3/4
4/4
Herschorn and
Radomski73
13
13
Periurethral; bladder
neck tapering
9/11*
Decter81
10
Periurethral; rectus or
iliotibial fascia
3/6
10-19
15
15
Transvaginal
3-72
10
13
Periurethral; rectus or
fascia lata
17
Gormley et al82
Kakizaki et
al83
Walker et al45
Kurzrock et al84
7-23
15
24
Perez et al85
4-17 (mean 9)
15
24
39
Barthold et al86
Not reported
20
27
Austin et al87
10
18
Nguyen et al88
Dik et al89
1-17 (mean 9)
24
24
Transvaginal
Castellan et al90
15
43
58
Misseri et al91
3-10 (mean 9)
15
21
36
SIS sling
18
12
30
Female
4/4
9/11*
2/4
5/10
11/13
11/13
9/13
8/8
9*/9*
17/17
10/15
9*/9*
19/24
9/13
13*/23*
22/36
5/10
Snodgrass et
al92
Total
5/13
7/8
7/10
14/18
1/7
19/24
19/24
13/15
38/43
51/58
10/15
17/21
27/36
13/18
12/12
25/30
1/7
*Does
not include two patients with erosion secondary to use of Marlex mesh.
SIS, small intestinal submucosa.
is significant and does not respond to anticholinergic therapy, either augmentation cystoplasty or detrusor myotomy
(autoaugmentation) is necessary. It is important to be certain
that the sphincter tightness is sufficient, however. If urethral
erosion is caused by the sling, a secondary sling repair and
artificial sphincter implantation usually are unsuccessful,
and bladder neck ligation and creation of a continent stoma
are often necessary.
Another complication of the sling is difficulty with urethral
catheterization. This problem may occur if there is significant
urethral angulation, if the bladder neck was narrowed too
much, if the sling tension is too tight, or if the urethral mucosa
was circumferentially disrupted during the dissection, resulting in a urethral stricture. If there is significant angulation, use
of a coud or hydrophilic catheter often solves the problem.
Angulation may result if the sling was crisscrossed, however,
and in this situation a revision of the sling probably is necessary. Another option in the presence of difficult catheterization is to create a continent stoma.
A rare complication is distal ureteral obstruction if the
sling was placed too close to the insertion of one or both
774
part
MALE SLING
A newer form of anti-incontinence therapy that shows promise
in boys is the bone-anchored suburethral sling. The polypropylene male perineal sling system (InVance, American Medical Systems, Minnetonka, MN) has been used successfully in
adult males with post-prostatectomy incontinence. This procedure has demonstrated low morbidity and reliable improvement of post-prostatectomy incontinence in this patient
population.97
Patients are positioned in an exaggerated lithotomy position. A 3-cm incision is made in the midline of the perineum
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
59
The treatment of urinary incontinence by means of prostheses that compress the urethra and replace the function of the
sphincter dates back to the early part of the 20th century with
the Cunningham clamp, which provided external compression
of the penile urethra in incontinent men. In the 1940s, Foley1
published and patented a device that provided intermittent
compression of the surgically isolated penile urethra by means
of an inflatable cuff. Three decades later, Bradley, a neurologist
with a strong interest in bladder dysfunction; Timm, a bioengineer; and Scott, a urologist,2 developed an implantable device
that they called an artificial genitourinary sphincter. The use of
this device (AS 721), which had separate opening and closing
pumps and relied on a low-pressure valve to prevent overfilling of the cuff, was first reported in 1973.3 The problems
of tissue erosion and frequent mechanical malfunction led to
changes in design and technical refinements that resulted in
the device currently used, the AS800, which was introduced
in 1983.4,5
Since the 1980s, three other prostheses have become available. One, the Rosen prosthesis, had very poor results and has
been discontinued.6 An attempt to produce a less expensive
device for use in countries with fewer resources was described
in 1997, but the experience that has been published is limited, and the failure rate with 23 months of mean follow-up
is very high (40%).7 A more recently described new device
has not been used in children.8 This chapter deals only with
the mechanisms, technique of implantation, results, followup, and complications of the AMS 800 prosthesis (American
Medical Systems, Minnetonka, MN).
AMS 800
The AMS 800 artificial urinary sphincter (AUS) consists of
an inflatable cuff that can be implanted around the bladder
neck or bulbous urethra, a pressure-regulating balloon that
transmits a predetermined pressure to the cuff and maintains
it closed (inflated), and a unit containing a pump and valve
mechanism that allows the deflation of the cuff and its reinflation. This pump is implanted into the scrotum or labium (Figs.
59-1, 59-2, and 59-3). The cuffs are available in sizes ranging
from 4 to 11 cm in circumference, and the balloon pressure
ranges from 50 to 80 cm H2O at 10-cm H2O increments. At rest,
the pressure in the balloon is at equilibrium with the pressure
in the cuff, maintaining the urethra compressed at the predetermined pressure. By squeezing the pump, the fluid is transferred from the cuff to the balloon, opening the urethra and
permitting voiding or catheterization. The cuff refills slowly
and spontaneously through a system of valves and fluid resistors located in the pump unit (Fig. 59-4).
In the pump and control unit, there is a button that interrupts the flow of fluid from the balloon to the cuff so that the
cuff may be left empty (open) or deactivated. This is useful
during the early postoperative period when delayed activation is desired to allow tissue healing and resolution of the
scrotal or labial edema and tenderness. Vigorous squeezing
of the pump re-establishes fluid flow (activation), and the
cuff refills (see arrow in Fig. 59-1). Leaving the cuff open or
776
part
Balloon
Pump
Figure 59-1 AMS 800 artificial urinary sphincter. The arrow indicates
the deactivation button.
PREOPERATIVE PREPARATION
void spontaneously must be able to perform catheterization
because transient or permanent retention can occur after the
implantation. Evaluation of the social situation, family support, cognitive ability, and manual dexterity is also essential
to success. Despite contrary opinions, a lack of ambulation is
not a strict contraindication to implantation.
Fecal continence must be addressed at the time of considering surgery for urinary incontinence. Achievement of urinary
The preparation of the patient is important to minimize complications. Infection of the AUS is a catastrophic event that
requires the removal of the device and usually rules out the
possibility of a future implant at the same site. Most AUS
infections can be attributed to surgical contamination during
implantation. Every effort to prevent infections is necessary
even if there are no strong data to support all of the following
recommendations.
chapter
777
Open
Figure 59-5 Schematic representation of initial exposure of the anterior aspect of the bladder neck shows the veins of the Santorini plexus
on both sides (arrows).
Closed
B
Figure 59-4 Endoscopic views of a male bladder neck with the artificial sphincter open (A) and closed (B).
SURGICAL TECHNIQUE
The bladder is partially filled with an antibiotic solution, and
the catheter is removed. Boys are positioned supine on the
table, and the genitalia are included in the surgical field. Girls
are positioned flat with the legs spread apart. The vulva and
vagina are prepared with povidone-iodine solution. Impermeable drapes are secured to create a watertight field. Operating
team turnovers should be minimized. It is important that the
scrub nurse and circulating nurse are familiar with the procedure, and that a strict sterile technique is followed to avoid
infections.
The incision is most commonly a low transverse abdominal
incision. Flaps of skin and subcutaneous tissue are elevated,
allowing access to the fascia for a midline incision from the
umbilicus to the pubis. A midline skin incision can also be
778
part
RESULTS
Most pediatric patients in whom the AUS is implanted have
neurogenic incontinence. In this section, we analyze separately
the results according to the cause of incontinence.
Neurogenic Incontinence
Non-neurogenic Incontinence
We favor the use of the AUS to treat incontinence associated
with epispadias. A patient with untreated epispadias is an
ideal candidate for AUS implantation because the bladder
chapter
779
No. Patients/No.
Neurogenic Bladder
Kryger et al19
32/28
26
56/95
15.4
36
59/82; 83/100
10;5
19/19
27
84/84
79/74
43
80/90
12.5
49/38
47
7.5
90/90
22
92
76/87
68/92
7.5
80/85
3.5
91/100
5.5
al47
Levesque et
Gonzlez et al48
Hafez et
al18
Castera et al35
Singh and
Thomas49
Simeoni et al50
Herndon et
Barrett et
Spontaneous
Voiding (%)
107/107
al51
134/107
al52
22
59/46
Lopez-Pereira et al27
35/35
10
Table 59-2 Rate of Augmentation, Loss of Bladder Compliance, and Renal Damage in Major Series
No. Patients/
No. Neurogenic
Bladder
Reference
Loss of
Compliance
Requiring
Augmentation (%)
Overall
Augmentation
Rate (%)
Postoperative
Hydronephrosis
(%)
Postoperative
Reflux (%)
47
21
Kryger et al19
32/28
37
Levesque et al47
2 groups: 36/32;
18/17
37
Gonzlez et al48
19/19
27
37
11
79/74
12
10
49/38
27
107/107
25
41
134/107
28
5
Hafez et
al18
Castera et al35
Singh and
Thomas49
Simeoni et al50
Herndon et
al51
Barrett et al52
Lopez-Pereira et
al27
90/90
Postoperative
Renal
Insufficiency
(%)
15
0
7
59/46
35/35
31
57
neck is virgin, and bladder sensation and contractility are normal. The bladder may be reduced in capacity, but often expands
with time and anticholinergic therapy. Spontaneous voiding
is common (Gonzlez R, unpublished observations, 2000).
The situation is different in patients with bladder exstrophy after a failed bladder neck reconstruction. In these cases,
the erosion rate is higher.18,28 Because most patients with
failed exstrophy require a bladder augmentation and a continent catheterizable stoma, solutions other than the AUS
may be appropriate to increase bladder outlet resistance.
Nevertheless, other authors have proposed the use of the
AUS after failed bladder neck reconstruction as an alternative
to a repeat reconstruction or a continent diversion in selected
patients.29 More recently, Ruiz and colleagues30 reported
excellent continence rates in patients with bladder exstrophy,
epispadias, and anorectal malformations.
There are other rare situations in which the AUS is useful
in young patients. With AUS placement, we have successfully
treated incontinence secondary to urethral trauma in girls,
persistent postpubertal incontinence in boys with posterior
6
5
COMPLICATIONS
The potential complications of AUS implantation are infection,
erosion, AUS malfunction, and changes in bladder compliance
with subsequent recurrence of incontinence or the new development of hydronephrosis.
Infection
The infection rate for a newly implanted AUS should be less
than 5%. Preventive measures are discussed in the section
of preoperative preparation. We normally perform a preoperative bowel preparation even if an augmentation is not
780
part
Table 59-3 Complications and Survival of Artificial Urinary Sphincter in Major Reported Series
Reference
AUS
Model
Functioning
AUS at Last Mean Revisions
Follow- per Patient
Follow-up
(%)
up (yr) per Year
Mean
Time to
Failure
(yr)
Previous
Bladder
Neck
Surgery
(%)
Erosions
(%)
Infections
(%)
4.8
34
25
15
70
13
72
Kryger et al19
AS 792,
742, 800
58
15.4
Levesque et al47
AS 792,
742, 800
78
10, 5
0.1
0.2
Hafez et al18
AS 792,
742, 800
75
12.5
0.35
20
Castera et al35
AS 800
80
7.5
Gonzlez et al48
87
Herndon et al51
AS 792,
742, 800
76
7.5
Barrett et al52
AS 800
93
3.5
91
5.5
86
6.5
Ruiz et
AS 800
16
Simeoni et al50
al30
0.08 (0.03
after 1987)
20
7.8
4.6
0.085
80
2
65 (85
without
previous
bladder
neck
surgery)
6.7
28
17
22
14
27
Mean
Survival of
AUS (%)
62
91
86
c ontemplated. During the operation, the wound is repeatedly irrigated with antibiotics. With all these measures, if
an infection occurs, it is usually not acute but chronic, with
mild but persistent or recurrent inflammatory signs and
symptoms. Infections predispose to tissue erosion at the site
of the pump or, more rarely, at the bladder neck. If infection is suspected, cystoscopy to assess the bladder neck status should be performed. The treatment consists of removal
of the prosthesis. If no bladder neck erosion has occurred,
reimplantation can be attempted many months or years later
(Table 59-3).
Erosions
With older AUS models, erosions secondary to pressure necrosis were common.33,34 With the AMS 800 with a narrow back
cuff5 implanted around a bladder not previously operated,
erosions are rare. In the report by Castera and coworkers35
of 49 children with a mean follow-up of 7.2 years, the mean
time to erosion was 2 years (1 month to 9 years). Castera and
coworkers35 attributed the 20% rate of erosions in their series
to infection, previous bladder neck surgery, or fibrosis after
pelvic trauma. In the Toronto experience with 89 patients and
a mean follow-up of 12.5 years, 20% of the AUS were removed
because of erosion after a mean of 5.6 years.18 Bladder neck
erosions manifest with signs of infection or recurrent incontinence, but they may be silent for a long time, particularly in
patients without bacteriuria who void spontaneously. Scrotal
or labial erosions are usually the result of infection or pressure
Malfunction
Mechanical malfunction of the device leads to recurrent
incontinence or, more rarely, an inability to void. Inadvertent
deactivation of the AUS by the patient in the open or closed
position can lead to incontinence or urinary retention. Physical
examination establishes the diagnosis, and patient education
prevents its recurrence.
Similar to all mechanical devices, the AUS has a finite life
span. Among the technologic advances that made the AUS
an acceptable therapeutic modality, the increase in the revision-free interval has been as important as the decrease in the
risk of erosions. For sphincters implanted since 1987, 80% are
expected to function 10 years later without revision.18,19 The
most common cause for AUS replacement is a loss of fluid
because of breaks in the silicone membrane of the cuff. Others
have reported shorter half-life and discourage this method
of treatment, an opinion that based on our experience we do
not share (see Table 59-3).37 The fluid loss is usually gradual
and may not be obvious on the initial examination. Whenever
possible, we fill the system with dilute contrast medium
chapter
781
782
part
FOLLOW-UP
All patients with the conditions that lead to implantation of
an AUS require lifelong follow-up regardless of the treatment
they have received. Follow-up is particularly important after
AUS implantation because it is such an effective method to
increase bladder outlet resistance that changes in bladder and
kidney function may ensue. Shortly after implantation, renal
ultrasonography is necessary to rule out hydronephrosis secondary to compression or entrapment of the ureters by the
cuff. Mild, transient dilation is sometimes observed. In the
first year after implantation, we perform cystometrography
every 3 months to detect possible changes in bladder function,
particularly changes arising from preoperative misdiagnosis.
Thereafter, patients are followed with yearly examinations,
renal and bladder ultrasound scans, and cystometrography.
Any changes in continence or voiding habits are promptly
evaluated.
ALTERNATIVE TECHNIQUES
Although the technique described here has worked well for
us for many years, some authors have found dissection of
the bladder neck intimidating. Castro Daz prefers to open
CONCLUSION
Since 1975, the AUS has evolved into a reliable and effective
means of treating sphincteric incompetence in children and
young adults. Meticulous attention to detail during patient
selection, implantation, and follow-up are crucial to the
success of treatment.
REFERENCES
For complete list of references log onto www.expertconsult.com
CHAPTER
60
DIAGNOSIS OF INCONTINENCE
Understanding urinary incontinence in children requires a
complete evaluation. As a starting point, a structured elimination interview queries the nature and severity of the
incontinence (diurnal, nocturnal, fecal) with quantitative analysis.9 An incontinence symptom index for pediatrics has been
developed and validated by Nelson and colleagues.10 This tool
and others may offer more objective methods of evaluating the
degree of incontinence and the efficacy of therapies. Imaging
studies should include ultrasonography of the kidneys and
bladder and voiding cystourethrography. Urodynamic studies are essential for all patients with neurogenic incontinence,
bladder exstrophy, and posterior urethral valves to determine
better the respective contributions of the bladder and bladder
neck to incontinence.
784
part
1. Bladder neck
Proximal urethra
Close-up
Good
coaptation
Poor
coaptation
Better
coaptation
Material Properties
Nonimmunogenic
Nonmigratory
2. Normal
3. Abnormal
Minimal inflammation
Durable
coaptation.
Cost-effective
chapter
785
1. Antegrade
SYNTHETIC INJECTABLES
Polytef
2. Transurethral
3. Periurethral
Figure 60-2 Three basic methods deliver the bulking agent to the
area of interest: transurethral, periurethral, and antegrade.
Transurethral Method
We prefer transurethral delivery via cystoscopes with a 5F
working channel and a 0- or 12-degree lens. A good rule of
thumb is to employ the smallest size sheath feasible in boys
and the largest reasonable sheath in girls. The patient is placed
in the dorsal lithotomy position. General anesthesia is usually needed. In adults and very mature children, intraurethral
instillation of 2% lidocaine jelly may be sufficient. Additional
lidocaine can be injected into the subepithelial space before
administering the bulking agent to provide additional anesthetic and to help establish the appropriate tissue planes. Bulking agent is administered in the 3- and 9-oclock positions until
epithelial approximation is visually established. Care is taken
not to pass either the cystoscope or a large-bore catheter during
the perioperative period to avoid molding or extrusion of the
bulking agent. If prolonged catheter drainage is anticipated,
a suprapubic tube may be helpful. Repeat Cred maneuvers
often show continence when coaptation has been achieved.
Serial injections may be necessary.
Periurethral Method
Some authors advocate periurethral injection in women.23
After a local anesthetic is injected into the periurethral space
and under cystoscopic visualization, the injection needle is
guided through the periurethral space until the tip is seen just
beneath the urothelium at the 4- and 8-oclock positions. The
tip should be just in the subepithelial space beyond the bladder
neck. Bulking agent is administered as described previously
until epithelial coaptation is visualized.
Antegrade Method
Prior surgery or poor tissue compliance in the proximal urethra and bladder neck may limit the success of retrograde
injection. In these patients, bulking agents can be delivered in
Macroplastique
Macroplastique is a 40:60 mixture of particulate silicone
with a povidone gel (polyvinylpyrrolidone) carrier, which
creates a thick yellow injectable paste. Henly and coworkers29 examined particle migration of Macroplastique in
dogs to ascertain if the same concerns as for polytef existed.
They found that migration varied proportionally with
particle size. Large particles (>100 m) remained in place,
but smaller particles (<70 m) migrated. The difference in
migration was attributed to the ability of macrophages to
engulf smaller particles, but not the larger ones. A histiocytic
reaction occurred, but no granuloma formation was seen in
response to injections.
European series have reported on the successful use of
Macroplastique in incontinent adults. Sheriff and associates30
reported short-term success rates of 75% and long-term success rates of 48%. Duffy and Ransley31 reported on 12 boys
with epispadias treated with Macroplastique: 3 became dry,
6 improved, and 3 were unchanged. More recently, Guys
and associates32 reviewed 44 children with spina bifida
who received bladder neck injections with Macroplastique;
21 of these patients had undergone prior bladder neck
reconstruction, and 15 had prior augmentation cystoplasties.
Prior surgical procedures did not affect the ability to inject
Macroplastique effectively. The results were comparable with
other types of agents: 34% became dry, 25% improved, and
41% unchanged.
Macroplastique also has been used in the endoscopic treatment of vesicoureteral reflux. Dodat and associates33 injected
786
part
Bioglass
Ceramic biomaterials have been used as a bone mass replacement in orthopedic surgery. Stability and lack of reactivity led
to investigation for urologic use.39 Walker and colleagues39
examined injectable bioglass, a bioactive ceramic composed of
silicon oxide, calcium silicate, calcium oxide, and calcium fluoride. Tissues are bound with minimal inflammatory response
by the attachment of collagen fibers to the glass surface with
no evidence of toxic effects in vitro or in vivo. Studies in pigs
and rabbits found a stable implant with no evidence of particle migration or inflammatory response.39 Although it may
have potential application, to date bioglass has been limited to
orthopedic and periodontal applications. One concern is that
any subsequent surgery in an area injected with bioglass may
encounter a dense bioglass-collagen scar.
chapter
Autologous Fat
Plastic surgeons have used adipose tissue as free grafts for
decades.55 The principal barrier to the use of autologous fat
as a bulking agent is the loss of volume over time, especially
in large-volume injections. A large-volume injection is essentially a free graft dependent on inosculation and imbibition
for graft survival. To date, fat injections for the treatment of
urinary incontinence have been disappointing.56 Greater than
70% of female patients treated with fat injection for urinary
incontinence showed partial resorption of the implant after
22 months. Continence rates of 64% have been achieved, but
only by providing repeat injections every 3 months.57 A lack
of efficacy relative to other bulking agents and the very high
rate of resorption have limited the role of autologous fat as a
urologic bulking agent.
787
Comments
Synthetics
Polytef
Macroplastique
Silicone membrane
balloons
Bioglass
Deflux
Nonautologous Organics
Collagen
Autologous Organics
Autologous fat
Lacks durability
Autologous
collagen,
chondrocytes,
bladder muscle
CONCLUSION
Successful management of pediatric anatomic urinary incontinence is a challenge. The first step in successful treatment
is defining the various causes of failure of continence. When
bladder capacity and compliance are favorable, and incontinence is due to an incompetent outlet, bulking agents can
provide a minimally invasive therapeutic option in achieving
continence.
The quest for the ideal injectable agent continues (Table
60-2). The hosts reaction to the agent seems to be crucial in
determining long-term safety and durability. Newer substances avoid problems with particle migration, granuloma
formation, and inflammatory response. Cost and durability
remain obstacles. Tissue engineering technology may offer
materials that would be biocompatible and provide durable
continence.
788
part
REFERENCES
For complete list of references log onto www.expertconsult.com
S ECTION
Associated intestinal
abnormalities
C H A P TER
61
FECAL INCONTINENCE
IN PEDIATRIC UROLOGY
Padraig S. J. Malone
Problems with the gastrointestinal and urinary tracts frequently coexist. They may be part of a complex congenital
abnormality, they may share a common cause such as a neuropathy, or an abnormality in one system may affect the other.1
The gastrointestinal abnormality often manifests with chronic
constipation or fecal incontinence or both; the main causes of
fecal incontinence are listed in Table 61-1. The pediatric urologist must be aware of these gastrointestinal anomalies and be
conversant with their clinical presentation, management, and
prognosis. Patient care is usually shared with other specialists, such as pediatric surgeons or pediatricians. The urologist should be able to initiate and supervise simple treatment,
however, and with the development of new surgical techniques, the urologist also may be responsible for the operative
management of fecal incontinence, particularly during lower
urinary tract reconstruction.
PATHOLOGY
Cloacal anomaly is a rare condition that accounts for approximately 15% of high anorectal malformations in girls. In this
condition, a common channel connects the genital, urinary,
and gastrointestinal tracts (Fig. 61-1), and long-term urologic
management is required in many of these patients for the associated bladder dysfunction, chronic renal failure, and gynecologic abnormalities.2-5 Approximately 50% of these patients
have normal bowel function; patients without normal bowel
function present a complex management problem involving the genitourinary and gastrointestinal systems.2,4 Cloacal
exstrophy is another rare anomaly in which abnormal colonic
function is always present. A permanent colostomy has been
the treatment of choice, but more recently, reasonable fecal
continence has been achieved in some patients with an enema
program after an abdominoperineal pull-through procedure,
provided that a formed stool can be achieved.6,7 There is a
common association of gastrointestinal problems and prunebelly syndrome; short bowel syndrome, megacolon, and
Hirschsprungs disease all are described. These conditions
may cause chronic constipation or fecal incontinence or both.8
Of children with spina bifida, 84% have a neuropathic
bladder and bowel, causing urinary and fecal incontinence.9,10
Only 24% of adults with spina bifida are continent, and
30% have urinary and fecal incontinence.9 Similar problems
are also encountered in children with other forms of spinal
790
part
CLINICAL ASSESSMENT
A careful history and examination are required to differentiate
between enuresis or encopresis (or both) and true urinary or
fecal incontinence (or both). In most cases, the former can be
expected to improve given time and reassurance, but incontinence requires specific investigation and treatment.
History
A detailed history is required to identify the cause of fecal
incontinence. Abnormalities noted during the antenatal or
early postnatal period may explain the cause. A developmental
history with dates of milestones reached is important. Chronic
constipation must be excluded because this is the most common cause of soiling. Details of the number of times stools
are passed and whether they are liquid, soft, normal, or hard
may indicate whether chronic constipation or overflow fecal
incontinence is to blame. Rectal sensation may be lost with a
neuropathic bowel or with chronic constipation and a mega
rectum. Any medication that may affect bowel function must
be noted. The ability to hold on to stool but not flatus implies a
degree of sphincter weakness that may be due to a generalized
neurologic condition or a more localized problem with anal
sphincter innervation or muscle abnormality.
Anal stenosis
Examination
Dysfunctional
Hirschsprungs disease
Chronic diarrhea
Chronic constipation and overflow
Neuronal intestinal dysplasia
Segmental colonic dilation
Neuropathic
Spina bifida
Spinal dysraphism
Sacral agenesis
Spinal trauma
Spinal tumors
Transverse myelitis
Spinal cord ischemia
Sacrococcygeal teratoma
Neuropathic bowel
Generalized neurologic diseases
INVESTIGATIONS
If there is suspicion of a spinal abnormality, anteroposterior
and lateral films of the vertebral column are indicated. If a
sacral anomaly is suspected, spinal ultrasonography can be
performed in children up to 1 year of age because the vertebral
chapter
791
TREATMENT OF INCONTINENCE
AND CONSTIPATION
The management of constipation in childhood was detailed in
an excellent monograph by Clayden and Agnarsson28 in 1991,
and its principles still hold true today (Table 61-2).
Figure 61-3 A, ARGUS (AnoRectal, GenitoUrinary, and Sacral) protocol, an algorithm for initial neurologic screening of neonates with an
anorectal malformation (ARM). B, Initial management of structural urologic anomalies (1), intraspinal abnormality and tethered spinal cord
s yndrome (2), and neurogenic lower urinary tract dysfunction (3). CIC, clean intermittent catheterization; DMSA, dimercaptosuccinic acid; IVP,
intravenous pyelogram; MAG3, mercaptoacetyltriglycine; PSARP, posterior sagittal anorectoplasty; PSARVUP, posterior sagittal anorectoplasty
and vaginourethroplasty; VCUG, voiding cystourethrogram; VUR, vesicoureteric reflux. (From Boemers TM, Beek FJ, Bax NM. Guidelines for the
urological screening and initial management of lower urinary tract dysfunction in children with anorectal malformationsthe ARGUS protocol.
BJU Int. 1999;83:662-671.)
792
part
Ultrasonography
urinary tract
Neonate
with ARM
With perineal
bowel opening
Without perineal
bowel opening
VCUG
genitogram
Stop
Continue
Fig. 61-3B(1)
PSARP
PSARVUP
X-ray sacrum
Normal
Abnormal
Normal
Rectourethral fistulae
and sacral agenesis
Abnormal
Persistent cloaca
Stop
Spinal
ultrasonography
Normal
Abnormal
Stop
MRI
Urodynamics
Continue
Fig. 61-3B(2)
Continue
Fig. 61-3B(3)
A
1
Valve ablation,
urethrotomy, or
other procedures
Consider prophylactic
antibiotics in urethroejaculatory reflux
Spinal
ultrasonography
Abnormal
Abnormal
VCUG
MRI
Abnormal
Urethral anomalies
Cystoscopy
Ultrasonography
urinary tract
Normal
VUR
Consider
DMSA scan
Prophylactic antibiotics
Further urological treatment
if necessary
Urodynamics
Normal
Abnormal
Stop
Normal or
blunt conus
above L1 L2
Tethered conus
below L1 L2 or
other intraspinal
anomalies
Stop
Consider
neurosurgical
untethering
Urodynamic
assessment 1 month
and 6 months
following surgery
Prophylactic antibiotics
All patients
Anticholinergics
Detrusor hyperreflexia
Low bladder compliance
CIC
All patients
chapter
793
Enema Procedure
Biofeedback
If rectal sensation is present, some patients benefit from biofeedback with the use of a rectal pressure manometer. The
child can see the effect of muscle contraction displayed on
a monitor. This approach seems to be most successful for
patients with anorectal malformations in which there is some
preservation of the nerves supplying the anus and rectum.27,30
Reports of using biofeedback for patients with spina bifida
have been varied. In a small series of patients with myelomeningocele, several patients achieved voluntary bowel movements, but others have not reported such good results.31-33
Biofeedback works best in patients who have spinal cord
lesions below L2, and who have two or more bowel movements a day. In this group, biofeedback resulted in a greater
than 50% reduction in the frequency of incontinence.34 In
patients with neuropathic bowel and anorectal malformation,
the conservative measures described previously may control
constipation, but fecal incontinence often persists, and the
only treatment method that can be used is timed mechanical
colonic emptying (Table 61-3).
Enemas
Enemas have been the mainstay of treatment for years for
patients with neuropathic bowel. In 1987, Shandling and
Gilmour developed the enema continence catheter.35 The
catheter is inserted into the rectum, and a balloon is inflated
to aid retention. Initially, excellent results were obtained, but
the long-term compliance declined to 50% after 30 months.36
In addition, many patients with neurologic diseases or spina
bifida were unable to administer the enema independently,
which inevitably led to a reduction in compliance. The development of the enema continence catheter showed, however,
that complete colonic emptying can produce fecal continence.
This led to the development of the antegrade continence enema
(ACE) procedure in 1989 (Table 61-4).37
The combination of these principles, applied to the colon,
provided continent intermittent catheter access to the cecum
or proximal colon for the administration of antegrade enemas
while the patient sat on the toilet. This produced colonic
emptying and fecal continence. The preliminary series was
reported in 199037; subsequently, numerous reports have been
published, and the procedure is now widely practiced around
the world.40-45 Many modifications have been introduced
since the original description46 to simplify the procedure and
to reduce the high complication rates initially reported.47 In
this chapter, we concentrate on the techniques in current use,
patient selection and preparation, the enema regimens, and
the most recent results.
Patient Selection
and
Preparation
794
part
Operative Technique
An aggressive preoperative bowel preparation is essential to
facilitate the initial postoperative enema. Prophylactic antibiotics are always used, and the conduit is left intubated for 4 weeks
postoperatively before starting intermittent catheterization.
The original description of the ACE involved detaching the
appendix from the cecum, reversing it, and reimplanting it
back into a submucosal tunnel in the cecum, to produce continence.37,46 The procedure has now been significantly modified
in numerous ways to simplify the procedure and to reduce
the high complication rates initially reported.47 The current
techniques are described elsewhere by Malone.52
If the appendix is being used at the level of the cecum,
it is no longer necessary to disconnect it. It can simply be
folded onto the cecum, and a cecal wrap performed around
it as a valve mechanism, the in situ appendix.52,53 When the
antireflux mechanism has been constructed, the cecum or
colon is sutured to the back of the anterior abdominal wall
to ensure that the conduit is not lying free in the peritoneal
cavity because this can lead to kinking and difficulties with
catheterization. This is the approach recommended when a
combined Mitrofanoff procedure is also required,54 with the
Mitrofanoff being constructed from either a split appendix55
or a Yang-Monti conduit.56,57
The Yang-Monti is an ingenious technique that transversely tubularizes a 2-cm segment of ileum to produce a
catheterizable conduit approximately 7 cm in length, with the
valvulae conniventes running in the longitudinal direction of
the conduit, which facilitates catheterization. Both ends of the
conduit are free of mesentery, and this makes the creation of
the antireflux mechanism easy. When a Monti conduit is used,
a submucosal tunnel is created along one of the taeniae and
wrapped around it, as in the original description of the ACE.37
If the patient is obese, it is possible to use two segments of
ileum and produce a 14-cm conduit that is long enough for
almost any patient (Fig. 61-4). Experience with this technique
is encouraging, and it is the procedure of choice when the
appendix is unavailable.
There is controversy as to whether any continence maneuver is required at all, and some authors now recommend that
the tip of the appendix be simply excised and brought out to
the abdominal wall. Conduit incontinence rates would seem
chapter
Enema Regimen
The first enema is given via the indwelling catheter when
bowel activity returns, usually around postoperative day 5.
Many enema regimens are used in the different centers
795
796
part
Diagnosis
Complete
Success (%)
Partial
Success (%)
Failure (%)
Spina bifida
63
21
26
Anorectal
72
17
11
Hirschsprungs
disease
82
Constipation
52
38
38
Data from Curry JL, Osborne A, Malone PS. The MACE procedure: experience in the United Kingdom. J Pediatr Surg. 1999;34:338-340.
Results
The results of the ACE have been classified as follows:48
Full success: Patient is totally clean, or there is minor rectal
leakage on the night of the washout.
Partial success: Patient is clean, but there is significant rectal
leakage and occasional major leaks. The patient is still
wearing protection, but the situation is perceived by the
parent or child to be an improvement from previously.
Failure: Regular soiling or constipation persists, there is no
perceived improvement, and the procedure is abandoned,
usually to a colostomy.
In 1998, Curry and associates48 reported on 31 patients
with a mean follow-up of more than 3 years. ACE failed
in 12 of 31 (39%) patients; this included 5 of 8 patients
treated for chronic idiopathic constipation and 1 patient with
Hirschsprungs disease. When patients with neuropathic
bowel and anorectal malformation were analyzed separately,
partial or full success rates were 75% and 70%. In 1999, Curry
and coworkers41 reported on a survey of ACEs performed by
members of the British Association of Paediatric Surgeons.
They identified 300 cases, and the success rates dependent
on the original diagnosis are shown in Table 61-5. The overall
success rate, including full and partial success, for this large
national series was 79%. More recent studies have shown continued long-term success, even during pregnancy.71
Data from several studies of simultaneous combined
ACE procedure and bladder reconstruction, including the
Mitrofanoff procedure, suggest double continence rates of
95%.51,54,65,66,72,73 Current evidence requires that a synchronous
ACE procedure should always be considered when a patient
with fecal incontinence is submitted to bladder reconstruction.
The reconstructive urologist is the best individual to manage
the bowel because the operative techniques involved are those
routinely employed in lower urinary reconstruction, and the
infrastructure should be in place for meticulous follow-up.
If we adopt this combined approach, we have the ability to
enhance the quality of life for these patients.
Numerous publications of studies have assessed the
improvements in quality of life objectively, and all have
shown significant benefits from the ACE.43,51,74-76 Shankar
and coworkers74 studied 40 patients using a quality of life
improvement score. A score of 5 denoted a perfect result, and
the mean score for all patients was 3.5. In another publication from the same unit where there was a mean follow-up
of 5.4 years (3.25 to 8.25 years), 82% of 62 patients continued
Sphincter Reconstruction
The use of gracilis muscle to provide a sling to improve fecal
continence has been described.27,77 The muscle is transposed
around the anus and is stimulated via implanted electrodes
to provide patients with neosphincters. Conflicting results
have been reported, with some reports suggesting very poor
results78 and others claiming 50% to 100% of patients achieving satisfactory continence.79-81 This approach still must be
regarded as experimental. An alternative to the gracilis sling
is levatoroplasty, with one series reporting improvement in
continence in 75% of patients.82 Artificial anal sphincters also
have been used and a successful outcome has been reported in
approximately 70% of patients with short-term follow-up.83,84
Sepsis and rectal evacuatory dysfunction continue to be major
problems, however.27,85
Electrostimulation
Transcutaneous electrical stimulation has been tried to
improve fecal continence in patients with spina bifida, using
low-intensity, long-duration nighttime stimulation via patch
electrodes. Decreased fecal soiling was reported, with patients
describing an improved sensation of pelvic fullness facilitating
a better toileting regimen.86 Sacral nerve stimulation has also
been investigated in the management of fecal incontinence,
and although the mechanism of action is unclear, the results
are encouraging.87
CONCLUSION
Provided that the patient is well prepared, it should be possible to achieve urinary and fecal continence in most patients
without the use of urostomies and colostomies. Because the
reconstructive urologist has the required skills for bladder
reconstruction, most are also able to manage the neuropathic
bowel, but for more complicated surgery, a colorectal surgeon
with an interest in anorectal abnormalities should be involved
from an early stage.
REFERENCES
For complete list of references log onto www.expertconsult.com
Index
A
Abbe-McIndoe procedure, 484, 484f, 502
Abdomen, radiography of, 62, 66f
Abdominal mass, 715
Abdominal wall
defects in
in bladder exstrophy, 387
in prune-belly syndrome, 425, 426f
reconstruction of, in prune-belly syndrome, 433f,
435, 435f
Aberrant vessels, in hydronephrosis, 257258, 258f
Abortion, therapeutic, 266
N-Acetyl--glucosaminidase, in ureteropelvic
junction obstruction, 247
Acid-base disorders, 28. See also Acidosis; Alkalosis
Acidosis
metabolic, 28
anion gap, 28
augmentation cystoplasty and, 742
continent urinary diversion and, 746
nonanion gap (hyperchloremic), 28
in renal failure, 601602
respiratory, 28
Aciduria, after augmentation cystoplasty, 746
Acute interstitial nephritis, 598
Acute kidney injury, 595
acidosis in, 601602
anemia in, 602
clinical presentation of, 595
compensatory mechanisms in, 596
in cortical necrosis, 599
definition of, 595
drug-related, 597598
epidemiology of, 595596
etiology of, 596600, 596t
genetic risk factors in, 595596
in glomerulonephritis, 598
in hemolytic-uremic syndrome, 599
hyperkalemia in, 601, 602t
hyperphosphatemia in, 602
hypertension in, 603
hypocalcemia in, 602
hyponatremia in, 601
in hypoxic/ischemic acute tubular necrosis, 597
in interstitial nephritis, 598
intrinsic, 597600, 598f
in leukemia, 598
management of, 600603
antihypertensive therapy in, 602603
diuretics in, 600601
dopamine in, 600601
fenoldopam in, 601
fluid and electrolyte therapy in, 601602
hemodialysis in, 604605, 604t
hemofiltration in, 604t, 605
nutritional therapy in, 603
peritoneal dialysis in, 604, 604t
pharmacotherapy in, 603
renal replacement in, 603605, 604t
prerenal, 596597
prevention of, 600
prognosis for, 600
in renal hypoplasia/dysplasia, 599600
in renal thrombosis, 599
risk factors for, 595596
uric acidrelated, 598
urinary parameters in, 597
Acute tubular necrosis, 597598
hypoxic/ischemic, 597, 598f
vs. prerenal failure, 597
Adenine phosphoribosyltransferase deficiency,
640642
Adenocarcinoma
augmentation cystoplasty and, 746747
continent urinary diversion and, 746
Adenoma, cystic, 168169
Adhesions, labial, 476477, 477f
Adolescents, 500
development of, 513
female
clitoral hypertrophy in, 502503, 503f
treatment of, 503506, 505f
transverse vaginal septum in, 503504
urogynecology of, 500
uterine duplication in, 503
vaginal agenesis in, 500501
in androgen insensitivity
syndrome, 500
in Mayer-Rokitansky-Kster-Hauser
syndrome, 500501
treatment of, 501502, 501f, 504. See also
Vagina, construction/reconstruction of
vaginal duplication in, 503
male
gonadal neoplasia in, 511
hypogonadal hypogonadism in, 510511
Klinefelters syndrome in, 510, 511t
micropenis in, 507508, 508509f
function of, 510
treatment of, 508510, 510f
5-reductase deficiency in, 510
nursing interventions for, 197
transplantation care for, 629630
Adrenal gland
congenital hyperplasia of. See Congenital adrenal
hyperplasia
hemorrhage in, 717
tumors of, 702. See also Adrenocortical
carcinoma; Neuroblastoma;
Pheochromocytoma
epidemiology of, 702
imaging of, 703704, 704f
molecular pathology of, 702703, 703t
pathology of, 702703, 703t
prognostic markers in, 704705
staging of, 705
treatment of, 705
ultrasonography of, 64f
Adrenal rest, 577
Adrenalectomy, laparoscopic, 95
-Adrenergic blocking agents, in non-neuropathic
bladder dysfunction, 375
Adrenocortical carcinoma, 707708
Cushing syndrome with, 708
evaluation of, 708
feminizing, 708
treatment of, 708
virilizing, 708
Age
alpha-fetoprotein levels and, 695f
bladder capacity and, 355, 355f
kidney transplantation and, 623
renal scarring and, 186
ureterocele treatment and, 343
urinary tract infection and, 181, 187
urolithiasis and, 631
voiding frequency and, 354
Wilms tumor and, 665
AGTR2, 178, 285286, 290
Alarm, in enuresis, 383
Albumin, serum, in nutritional
evaluation, 29
Albuterol, in hyperkalemia, 602t
Aldosterone, production of, 466f
Alkalosis
metabolic, 28
after augmentation cystoplasty, 745746
respiratory, 28
Allantois, 13f, 4
Allopurinol, in uric acid stones, 641
Alpha-fetoprotein
age-related levels of, 695f
in congenital Finnish nephrosis, 42
in testicular tumor, 694
in yolk sac tumor, 695
Ambiguous genitalia. See also specific disorders, 35t,
459, 712713
classification of, 460
developmental effects of, 512. See also
Development
endoscopy in, 88, 89f
evaluation of, 460461, 466f
karyotype analysis for, 461
management of, 460461
neoplasia and, 511
physiopathology of, 459460
Prader scale for, 461, 466f
steroid enzyme defects in, 461, 466f, 469472,
470f, 502503
in undervirilized 46,XY male, 461473,
464t, 467f
in virilized 46,XX female, 464t, 474475
in 46,XX male, 466468
Aminoglycosides, nephrotoxicity of, 597
Ammonium chloride, in metabolic alkalosis, 28
Amniocentesis, 261
Amnion, in vaginoplasty, 502
Amniotic cavity, 1, 1f
Amniotic fluid, 32
Amoxicillin, prophylactic, 192, 192t
Amphotericin B, in candidal infection, 194195
AMS 800, 775, 776777f. See also Incontinence,
artificial urinary sphincter for
Anal sphincter, reconstruction of, 793
Androgen(s). See also Testosterone
maternal excess of, 475
placental excess of, 475
in processus vaginalis closure, 578
Androgen insensitivity syndrome, 472473, 500
complete, 472, 500, 508, 511
cryptorchidism in, 564
germ cell tumors in, 511, 700701
partial, 472473, 473f, 500, 502
Anemia, in renal failure, 602
Aneuploidy, 31
Angiography
magnetic resonance, 77
in renal trauma, 725f, 726727
Angiotensin-converting enzyme (ACE) inhibitors
in chronic kidney disease, 600
in obstructive nephropathy, 247
teratogenicity of, 175
Angiotensin II receptor, 245
Angiotensin II receptor blocking agents
in obstructive nephropathy, 247
teratogenicity of, 175
Anion gap, 28
Anorchidism, 566567, 567t
Anosmin 1, 178
Antegrade continence enema, 790793, 793t
cecal button in, 791
colostomy tube insertion in, 791792
laparoscopic, 105106
left, 791
pain with, 792
patient selection for, 790
Note: Page numbers followed by b, f, and t indicate boxes, figures, and tables, respectively.
797
798
Index
B
Bacteriuria. See also Urinary tract infection
asymptomatic
incidence of, 305
peak rates of, 306
renal scarring and, 305
treatment of, 191192
continent urinary diversion and, 746
Balanitis xerotica obliterans, 522523, 523f
after hypospadias surgery, 541
Balanoposthitis, 519520
Bardet-Biedl syndrome, 40t, 42, 176t
prenatal diagnosis of, 41t, 42
Bartter syndrome, 639
Bax, in apoptosis, 242
BCL2
in apoptosis, 242
in multicystic dysplastic kidney disease, 220
Beckwith-Wiedemann syndrome, 4041, 176t, 665,
665t, 672f
prenatal diagnosis of, 35f, 4041, 40t
renal size in, 59
Wilms tumor in, 671, 672t, 681
Bed-wetting. See Enuresis
Bell-clapper deformity, 558, 558f
Biofeedback
in fecal incontinence, 790
in non-neuropathic bladder dysfunction, 374375
in occult neuropathic bladder, 361362
in reflux-related voiding dysfunction, 316317
Bioglass, 783
Biophysics, 251252, 252f
Biopsy
kidney
in Henoch-Schnlein purpura, 233
in IgA nephropathy, 231232, 232f
in membranoproliferative glomerulonephritis,
228, 228229f
in postinfectious glomerulonephritis, 227, 227f
in rapidly progressive glomerulonephritis,
234235, 234235f
in systemic lupus erythematosus, 230
in ureteropelvic junction obstruction,
239240, 240f
in rhabdomyosarcoma, 690
Bladder. See also Bladder dysfunction
accommodation of, 134135
agenesis of, 422
anatomy of, 353354
augmentation of. See Augmentation cystoplasty
biophysics of, 251252, 252f
calculi of, 631, 658659, 661f
after augmentation cystoplasty, 741742
continent urinary diversion and, 746
endoscopic removal of, 90
capacity of
age-related increase in, 355, 355f
in cloacal exstrophy, 414
Bladder (Continued)
enuresis and, 362
expected, 358t
after exstrophy repair, 397398
in urodynamic study, 130
in video-urodynamic study, 132
in voiding cystourethrography, 64
catheterization of. See Catheterization
chemotherapy injury to, 669670
closure of, in exstrophy, 392, 393f
compartmentalization anomalies of, 424, 424f
compliance of
after artificial urinary sphincter placement, 778
in chronic kidney disease, 609, 610f
myelomeningocele and, 364
normal, 133134
urodynamic study of, 133134, 133f
distention of, 5054, 59. See also Megacystis
diverticulum of. See Diverticulum (diverticula),
bladder
duplication of, 423424
complete, 423424, 423f
incomplete, 424
in dynamic renography, 115
dysfunction of. See Bladder dysfunction
embryology of, 172
emptying efficiency of, 355
exstrophy of. See Bladder exstrophy
fetal, 32
absence of, 5455
distention of, 5054. See also Megacystis
nonobstructive abnormalities of, 52
ultrasonography of, 4950
function of
development of, 354357, 355356f, 365
posterior urethral valves and, 444445, 444t, 445f
heparin-binding epidermal growth factor
effects on, 240
hypoplasia of, 422423
immature, 288, 288f
infection of. See Cystitis; Urinary tract infection
innervation of, 354, 354f
leakage from, 135
multiloculated, 424
neuropathic. See Bladder dysfunction, neuropathic
in percutaneous pressure-flow study, 152154,
154f, 160161
prolapse of, in exstrophy, 480
in prune-belly syndrome, 427428, 429f
radiation injury to, 669670
reconstruction of. See Augmentation cystoplasty;
Bladder neck reconstruction; Bladder outlet
reconstruction
rhabdomyosarcoma of. See Rhabdomyosarcoma
rupture of, 732f
complications of, 732
extraperitoneal, 731732, 732f
intraperitoneal, 730, 732f
septation of, 424, 424f
spasms of
after bladder exstrophy treatment, 395397
after hypospadias surgery, 198199
after ureteral reimplantation, 334
tissue engineering of, 210
trauma to, 730732
blunt, 730
contusion in, 731
diagnosis of, 730732
hematuria in, 730
penetrating, 732
rupture in, 731732, 732f
ultrasonography of 6061f, 5960. See also
Ultrasonography
Deflux injection with, 5960, 61f
fetal, 4955
ureter entry into, 284, 285f
on voiding cystourethrography, 67, 67f
Bladder augmentation. See Augmentation
cystoplasty
Bladder diary, 358t
in enuresis, 362
in non-neuropathic bladder dysfunction, 367,
370t, 371f
Index
Bladder dysfunction, 353. See also Enuresis;
Incontinence
classification of, 357363, 359f
constipation and, 362
enuresis and, 362. See also Enuresis
infection and, 290
neuropathic, 363365
anorectal malformation and, 786
bladder neck cinch/wrap procedures for,
763764
bladder neck closure for, 774
bladder neck reconstruction for, 762763
bladder neck suspension alone for, 773774
categories of, 363
detrusor-sphincter dyssynergy in, 364
Kropp procedure in, 764766, 765766f
male sling for, 774
maternal varicella-zoster infection and, 173
in myelomeningocele, 363364
occult (Hinman syndrome), 361362, 378
pelvic floor inactivity in, 364
Pippi Salle procedure in, 766768, 767f
prenatal diagnosis of, 52
sphincter inactivity in, 364
spinal cord abnormalities and, 363364
suspension and sling procedures for, 768773,
768f, 770771f, 773t
urinary tract infection and, 183
urodynamic study in, 133135, 133f, 135f, 364
vesicoureteral reflux and, 364365
endoscopic treatment of, 327328
voiding cystourethrography in, 6768, 68f
Young-Dees-Leadbetter procedure in, 762763
non-neuropathic. See also Incontinence and
specific disorders, 359, 366, 376t
bladder diary in, 367, 370t, 371372f
classification of, 376, 376t
diet diary in, 368
differential diagnosis of, 378379, 378t
epidemiology of, 366
evaluation of, 366373, 367t
magnetic resonance imaging in, 372
patient history in, 367, 368369f
physical examination in, 367
postvoid residual urine in, 370
risk factors for, 366, 367t
stool diary in, 368
treatment of, 373376
-adrenergic blocking agents in, 375
antibiotics in, 376
anticholinergic drugs in, 375
biofeedback in, 374375
botulinum toxin in, 375376
bowel regimen in, 373
clean intermittent self-catheterization in, 375
neuromodulation in, 375
pharmacologic, 375376
urotherapy in, 373375, 374f
ultrasonography in, 372373
urinalysis in, 367
urinary flow in, 370, 373t
urine loss quantification in, 367368
urodynamic study in, 370372, 373t
voiding urethrocystography in, 370
after rhabdomyosarcoma treatment, 692
terminology for, 357358, 358t
urinary tract infection and, 361
vesicoureteral reflux and, 288290, 289f, 361
Bladder ears, 67, 422, 422f
Bladder exstrophy, 386, 714
abdominal wall defects in, 387
artificial urinary sphincter in, 779
bladder size in, 391, 391f
collagen in, 389390
continent diversion in, 405
embryology of, 5, 386
female, 387f
genital defects in, 389, 478. See also Urogenital
sinus, anomalies of
genetics of, 386
genital defects in, 387389, 389f, 478
histology in, 389
incidence of, 386
799
Bladder wall
anatomy of, 353
thickness of, 5960, 60f
Blastocyst, 1
Blockson vesicostomy, 738, 739f
Blood, urinary. See Hematuria
Blood group, in kidney transplantation, 622623
Blood pressure. See Hypertension; Hypotension
Boari flap, 729731, 731f
Body, composition of, 24
Bone marrow transplantation, acute hemorrhagic
cystitis and, 193
Bone scan
in renal tumor, 674
in rhabdomyosarcoma, 689
Botulinum toxin, in non-neuropathic bladder
dysfunction, 375376
Bowel
dysfunction of. See also Constipation; Fecal
incontinence
continent urinary diversion and, 746
myelomeningocele and, 363
non-neurogenic voiding dysfunction and, 378
urinary tract infection and, 185
function of, in patient history, 367
Bowel interposition grafts, for vaginal
reconstruction, 484485, 485f, 502
Bowel regimen, in non-neuropathic bladder
dysfunction, 373
Bowman capsule, pressure in, 253, 253f
Bracka procedure, 538, 539f
Brain, sexual dimorphism of, 515516
Branchio-oto-renal syndrome, 42, 176t
Breast feeding, in urinary tract infection prevention,
182
Broedel, Max, 249
Brown tumor, 602, 603f
Buccal graft urethroplasty, in hypospadias, 531,
535f, 540
Buccopharyngeal membrane, 1f
Bulbourethral glands. See Cowper gland/duct
Bulking agents, injectable. See Incontinence,
injectable bulking agents for
Buserelin, in cryptorchidism, 571572
C
C3
in glomerulonephritis, 226
in IgA nephropathy, 231
in membranoproliferative glomerulonephritis,
228229
C3 nephritic factor, 229
in membranoproliferative glomerulonephritis, 226
C4, in glomerulonephritis, 226
Cajal, interstitial cells of, absence of, 285
Calcitonin generelated peptide
in processus vaginalis closure, 578
in testicular descent, 565, 577
Calcium
deficiency of, 2728
urinary, 637638, 638t
fetal, 261
in megacystis, 5253
Calcium gluconate, in hyperkalemia, 602t
Calcium hydroxyapatite, in endoscopic vesicoureteral reflux treatment, 324
Calculi. See Urolithiasis
Calories, requirements for, 2425, 24t
Calyces, physiology of, 253
Camptomelic dysplasia, 176t, 463
Cancer. See also specific cancers
in horseshoe kidney, 216
multicystic dysplastic kidney disease and, 223
neovaginal, 485486
secondary
rhabdomyosarcoma treatment and, 693
Wilms tumor treatment and, 666, 683
Candidiasis, 194195
Cantwell-Ransley epispadias repair, 394, 396f, 408
Carbon dioxide pneumovesicum, 106
Carney syndrome, Sertoli cell tumor in, 700
800
Index
Citrate
in hyperoxaluria, 641
urinary, 637638, 638t
Claudin 1, in hypospadias development, 529
Clean intermittent self-catheterization
in augmentation cystoplasty, 759
in continent urinary diversion, 743744. See also
Urinary diversion, continent
in non-neuropathic bladder dysfunction, 375
Clear cell sarcoma, 667, 682
Clitoral index, 478
Clitorectomy, 503
Clitoris
abnormalities of, 478
bifid, 478
embryology of, 9
intentional cutting of, 478
reduction of, 503
Clitoromegaly, 478, 502503, 503f
Clitoroplasty, 487, 488f, 490, 494
outcomes of, 494, 504506, 505f
Cloaca, 251
anomalies of, 495499. See also Cloacal exstrophy
catheterization in, 497
colostomy in, 497
endoscopy in, 495496
evaluation of, 495, 786, 790f
fecal continence with, 498499, 786. See also
Fecal incontinence
history in, 495
management of, 496497, 497f
physical examination in, 495, 496f
prenatal diagnosis of, 52
radiography in, 495496
surgical reconstruction in, 496499
care after, 498
colostomy in, 414, 497
endoscopy for, 497
outcomes of, 498499
preparation for, 497498
steps in, 497
vesicoureteral reflux with, 498
septation of, 23f, 4
incomplete, 6
Cloacal exstrophy, 410415
anatomy of, 411412, 411f
embryology of, 6, 411412
gastrointestinal function in, 414, 786
gastrointestinal tract anomalies with, 412
gender assignment in, 412414, 508
immediate management of, 412
limb anomalies with, 412
prenatal diagnosis of, 411412
psychological issues in, 414
spina bifida and, 412
spinal cord untethering in, 414
surgical reconstruction in, 413414
bladder reconstruction in, 413
continence techniques in, 414
gastrointestinal function after, 414
osteotomy in, 413
phallic reconstruction in, 413414
psychological issues after, 414
upper tract anomalies with, 412
Cloacal membrane, 12f
CLTC, 667
Clubfoot, cloacal exstrophy and, 412
Clusterin, in apoptosis, 242
Cognitive behavioral therapy, 517
Cohen procedure, laparoscopic, 99, 100f
robot-assisted, 107
Colitis, neovaginal, 486
Collagen, injectable, 783784
autologous, 784
bovine, 323
Colocystoplasty, 617
Colonoscopy, in anorectal malformation, 788
Colostomy, in cloacal exstrophy patient, 414
Computed tomography, 7173
in adrenal tumor, 704, 704f
in bladder trauma, 730731
in congenital hydronephrosis, 258f
in duplex kidney, 7778, 78f
Index
Creatinine clearance
fetal, 13, 13f
neonatal, 1617, 17f
pediatric, 2324
premature infant, 13, 13f
Creatinine concentration, in prune-belly syndrome,
431, 435436
Cremasteric reflex
in acute scrotum, 557
overactive, 566
Crohn disease, 522
Cryptomenorrhea, 482483
Cryptorchidism, 563, 567t
absent testes in, 566567
ascended testis in, 568
bilateral, 567568, 568f
clinical syndromes with, 569
diagnosis of, 569570
environmental factors in, 569
epididymal anomalies in, 565f
family history in, 569570
fertility and, 570
genetic factors in, 569
hypospadias and, 569
incidence of, 569
inguinal hernia and, 571
laparoscopy in, 99101, 100f, 573575
diagnostic, 573574, 573574f
therapeutic, 574575, 574575f, 576t
localization studies in, 570
malignancy and, 570571
natural history of, 569
nonpalpable testes in, 565567, 568f
palpable testes in, 565566, 566f
patent processus vaginalis and, 578
physical examination in, 570
psychological factors in, 571
risk factors for, 569
torsion risk and, 571
trauma risk and, 571
treatment of, 570571
age at, 570
buserelin in, 571572
human chorionic gonadotropin in, 571
indications for, 570571
laparoscopic, 574575, 574575f, 576t
luteinizing hormonereleasing hormone in,
571
for nonpalpable testis, 573576, 573574f
nonsurgical, 571572
for palpable testis, 572573, 572t
surgical, 572576, 572t, 573f
wolffian duct abnormalities and, 569
Crystalluria, 637, 637t
Culture, in infection, 187188
Cushing syndrome, 708
Cutaneous ureterostomy, 738
Cutaneous vesicostomy, 738, 739f
Cyclooxygenase-2, in renal scarring, 311
Cyclophosphamide, in systemic lupus
erythematosus, 230
CYP11A1, 469-470
CYP17A1, 471
CYP19A1, 475
Cyst(s)
epidermoid, 698699
median raphe, 551
parameatal, 551
paraurethral, 479480, 479f
penile, 551, 552f
periurethral, 713
renal. See also Multicystic dysplastic kidney
disease; Polycystic kidney disease
and diabetes, 43
urachal, 419421, 420f
Cystatin C, 2324
fetal, 5253
Cystine, urinary, 637638, 638t
Cystinosis, 610, 610f
Cystinuria, 640
treatment of, 641
Cystitis, 183184. See also Urinary tract infection
hemorrhagic, 60f, 193
Cystitis (Continued)
interstitial, 195
ultrasonography in, 5960, 60f
Cystography
PIC (positioning the instillation of contrast), 304
radionuclide. See Radionuclide cystography
voiding. See Voiding cystourethrography
Cystometry, 131137. See also Urodynamic study
ambulatory, 138
fluoroscopy with. See Video-urodynamic study
Cystoplasty
augmentation. See Augmentation cystoplasty
autoaugmentation, 104, 756757, 757f
reduction, in prune-belly syndrome, 434
Cystoscopy. See also Endoscopy
in chemotherapy-related hematuria, 86
in ectopic ureter, 87, 88f
fetal, 5354
instrumentation for, 84, 8586f
in tumor, 8788, 88f
before ureteral reimplantation, 330
in ureterocele, 343, 344f
Cytokines, in renal scarring, 311
D
DAX1, 464
Daytime frequency syndrome, 379
Daytime voiding disorder. See Bladder dysfunction,
non-neuropathic
Deflux. See Dextranomer/hyaluronic acid
copolymer
7-Dehydrocholesterol reductase deficiency, 469
Delayed voiding. See also Voiding postponement
neonatal, 709
Dense deposit disease, 228229, 229f. See also
Membranoproliferative glomerulonephritis
Dent syndrome, 639
Denys-Drash syndrome, 176t, 462, 664, 665t
Wilms tumor in, 671, 681
Depigmentation, labial, 476
17,20-Desmolase deficiency, 471
Desmopressin, in enuresis, 383
Detrusor, 353. See also Bladder
acontractile, 136, 136f
overactive. See Detrusor overactivity
underactive. See Detrusor underactivity
during voiding dysfunction, 135137, 136f
Detrusor areflexia, 136
Detrusor overactivity. See also Overactive bladder
constipation and, 381
definition of, 358t
enuresis and, 362, 380381
after posterior urethral valve treatment, 137f
urinary tract infection and, 288
urodynamic study in, 134135, 134135f
vesicoureteral reflux and, 288, 290
Detrusor pressure. See also Bladder pressure;
Urodynamic study; Video-urodynamic study
voiding-related, 355357, 356f
Detrusor-sphincter dyssynergy, 135f, 137. See also
Bladder-sphincter dysfunction; Dysfunctional
voiding
definition of, 358t
in myelomeningocele, 364
in normal infant, 355, 356f
Detrusor underactivity, 136, 378
definition of, 358t
urodynamic study in, 135
Development, 512513
of adolescent, 513. See also Adolescents
in chronic kidney disease, 608
educational interventions during, 516
gender identity and, 514515
genital disorders and, 514
hospitalization effects on, 515
illness experience and, 513, 513f, 518t
of infant, 513
interventions during, 516518
treatment team for, 518
language, 512, 513f, 518t
maternal behavior and, 515
801
Development (Continued)
pharmacologic interventions during, 516517
psychiatric disorders and, 515516
psychosexual, 514, 514f, 518t
disorders of, 515516, 516f, 518t
of school-age child, 512513
stages of, 512, 513f, 518t
urinary disorders and, 514
Dextranomer/hyaluronic acid copolymer, 783
in vesicoureteral reflux treatment, 89, 90f,
322323, 325326, 325t
DHCR7, 469
Diabetes insipidus, enuresis in, 382
Diabetes mellitus
enuresis in, 382
maternal, fetal effects of, 43
renal cysts and, 43, 176t, 178
Diabetic ketoacidosis, 28
Diarrhea, metabolic acidosis with, 28
Diet
after hypospadias surgery, 199
maternal, embryonic renal effects of, 175177
in urolithiasis, 636637, 641
Diet diary, in incontinence evaluation, 368
Dietl crisis, 238
DiGeorge syndrome, 176t
prenatal diagnosis of, 43
Dihydrotestosterone cream, for penile enlargement,
510
Dilantin, reabsorption of, after augmentation
cystoplasty, 744746
Dilators, vaginal, 501
Diluting segment, of nephron, 1112, 12f
Dimercaptosuccinic acid (DMSA) scan. See DMSA
(dimercaptosuccinic acid) scan
Diphallia, 548, 548f
Direct radionuclide cystography, 122123
evaluation of, 122123
indications for, 122
method of, 122, 125f
in vesicourethral reflux, 189190
Distal convoluted tubule, 12, 12f
Diuretics
in acute kidney injury, 600601
for renography. See Radionuclide dynamic
renography, diuretic
Diverticulum (diverticula)
bladder, 416417
acquired, 416
clinical presentation of, 416417
congenital, 416, 417f
definition of, 416
etiology of, 416, 417f
incidence of, 416
location of, 416, 417f
management of, 417
outlet obstruction with, 416417, 418f
perforation of, 417
periureteral, reflux and, 314315, 315f
tumor in, 417
ureteral obstruction with, 416
urinary tract infection and, 417, 419f
vesicoureteral reflux with, 416417, 418f
voiding cystourethrography in, 68, 68f, 417,
417419f
periurethral, vesicoureteral reflux and, 314315,
315f
urethral, 91, 451452
after hypospadias surgery, 200
vesicourachal, 420421f, 421422
DMRT1, 464
DMRT2, 464
DMSA (dimercaptosuccinic acid) scan, 108111
acquisition technique for, 108
in duplex kidney, 118120, 121f
in experimental reflux nephropathy, 292,
292293f
before extracorporeal shock wave lithotripsy,
645, 645f
focal defect on, 109, 110t
in horseshoe kidney, 120, 124f, 216f
indications for, 109, 109t
interpretation of, 109110
802
Index
E
Echocardiography, in Wilms tumor, 674
Ectoderm, 1, 1f, 250251
Ectopic kidney, 213214, 213t
abdominal radiography in, 62, 66f
associated anomalies with, 213, 214t
computed tomography in, 7778, 77f
crossed, 213t, 214, 216, 217f
anatomy of, 216
associated abnormalities with, 216
diagnosis of, 216
DMSA scan of, 122
MAG3 renography of, 122
magnetic resonance urography of, 217f
malignancy in, 216
diagnosis of, 213
embryogenesis of, 4, 6f
hydronephrosis and, 259260
iliac, 213t
magnetic resonance urography in, 167168
malignancy in, 216
outcomes of, 213214
pelvic, 4, 6f, 213t, 214f
prenatal diagnosis of, 3334, 34f
prenatal diagnosis of, 3334, 34f
thoracic, 213t, 215f
Ectopic scrotum, 553, 553f
Ectopic testis, 566, 566f
Ectopic ureter. See Ureter(s), ectopic
Ectopic ureterocele. See Ureterocele, ectopic
(extravesical)
Ectrodactyly, ectodermal dysplasia, and clefting
(EEC) syndrome, 42
Ectropion, mucosal, after hypospadias surgery, 541
Edema
after hypospadias surgery, 199
labial, 476
penile/scrotal, 522, 555
ureteral, after megaureter treatment, 280281
Electrocautery, instrumentation for, 84, 86f
Electrolytes. See also specific electrolytes
requirements for, 2528, 25t
Electromyography
in anorectal malformation, 788
in bladder neck obstruction, 139f
in bladder overactivity, 134f, 137f
in bladder underactivity, 136f
in detrusor-sphincter dyssynergia, 135f
in dysfunctional voiding, 131f, 359f
Elejalde syndrome, 42
Elimination syndrome, 378
Embryology. See also at specific structures, 250251
Embryonic disc, 1, 1f
Embryonic stem cells, in tissue engineering,
209210
Endocrine disruptors, cryptorchidism and, 569
Endoderm, 1, 1f, 250251
Endopyelotomy, 268
complications of, 270
crossing vessels and, 258
outcomes of, 268269, 269t
patient selection for, 268
results of, 271
Endoscopy, 84
in ambiguous genitalia, 88, 89f
in anterior urethral valves, 9091
in bladder calculi, 90
in cloacal anomalies, 495497
fetal, 84
in hematuria, 8591, 86f
instrumentation for, 8485, 8586f
positioning for, 84
in posterior urethral valves, 54, 86, 87f, 441443
in reconstruction evaluation, 8990
in rhabdomyosarcoma, 689, 689f
in tumors, 8788, 88f
in ureteral ectopia, 87f, 88f
in ureterocele, 8687, 8788f
in urethral polyps, 91
in urethral strictures, 88, 8990f
in urogenital sinus anomalies, 486, 487f
in urolithiasis, 646652, 650t, 651f
in vesicoureteral reflux, 8889, 90f, 311312
Endothein-1, in renal scarring, 311
Enema. See Antegrade continence enema
Energy
expenditure of, 24t, 25
law of conservation of, 252
Enteral alimentation, 29, 29t
Enterocystoplasty, laparoscopic, 103
Enuresis, 380
arousal thresholds and, 381
bladder dysfunction and, 362
constipation and, 362, 384
daytime incontinence and, 382
definition of, 358359, 358t, 380
detrusor-dependent, 381382, 382f
detrusor overactivity and, 380381
epidemiology of, 380
evaluation of, 382
genetics of, 380
monosymptomatic, 380
pathogenesis of, 380382
patient history in, 382
physical examination in, 382
polyuria and, 380
psychiatric factors in, 381
refractory, 362, 383384
secondary, 380, 382
subtypes of, 381382, 382f
treatment of, 382383
alarm therapy in, 383
anticholinergics in, 384
desmopressin in, 383
fluid intake in, 382383
psychological aspects of, 383
resistance to, 383384
second-line, 384385
tricyclic antidepressants in, 384385
urotherapy in, 384
voiding habits in, 383
urinary tract infection and, 185
in urofacial (Ochoa) syndrome, 179
vesicoureteral reflux and, 304305
voiding diary in, 362
Enuresis alarm, 383
Epidermal growth factor
in hypospadias development, 529
in testicular descent, 565
in ureteral obstruction, 242, 242f, 247
Epidermal inclusion cyst, penile, 551, 552f
Epidermoid cyst, 698699
Epididymis, in testicular descent, 565, 565f
Epididymitis, 193194, 559560
Epididymo-orchitis, 193194
Index
Epispadias, 407410
embryology of, 407
female, 379, 408f, 408409. See also Urogenital
sinus, anomalies of
surgical management of, 408410, 409f
male, 407410
penopubic, 407, 407f
surgical management of, 394, 396f, 407408
artificial urinary sphincter in, 778779
with bladder exstrophy repair, 400, 401f,
404405
nursing interventions in, 202
Epophoron, 7
Epstein-Barr virus infection, after kidney
transplantation, 626
Escherichia coli infection, 180181
experimental studies of, 290
Estradiol, production of, 466f
Estrogen(s), in testicular descent, 564565
Ethylene glycol poisoning, 28
Excretory urography
in megaureter, 275
in prune-belly syndrome, 427f
Exotoxin B, 227
Exstrophy. See Bladder exstrophy; Cloacal exstrophy
Extracellular matrix, in obstructive disease, 244, 244f
Extracorporeal shock wave lithotripsy, 642646
anesthesia for, 644
complications of, 644646, 650t
DMSA scan evaluation for, 645, 645f
evaluation for, 643644
follow-up after, 644
fragmentation effects of, 644
generator for, 643
patient positioning for, 644
principles of, 642643, 642643f
results of, 645646, 646t, 647f
targeting for, 643644
F
Factor H, in membranoproliferative
glomerulonephritis, 229
Fanconi anemia, 176t
Fat injection, autologous, 787
Fecal continence, cloacal anomalies and, 414, 498499
Fecal incontinence, 786
evaluation of, 787788, 790t, 791792f
history in, 787
pathology of, 786
physical examination in, 787, 791f
treatment of, 788793, 793t
biofeedback in, 790
electrostimulation in, 793
enema in, 790793, 793t, 794795f, 796t
manual evacuation in, 790
sphincter reconstruction in, 793
Feces, bacterial flora of, 182183
Female genital cutting, 478, 478f
Fenoldopam, in acute kidney injury, 601
Fertility
after bladder exstrophy treatment, 405406
in cryptorchidism, 570
in hypogonadal hypogonadism, 510511
in Klinefelters syndrome, 510, 511t
in 5-reductase deficiency, 510
varicocelectomy effects on, 593594, 594f, 594t
after Wilms tumor treatment, 667
Fertilization, 1
Fetus
ambiguous genitalia in, 35t
bladder of. See Bladder, fetal
gender of, 32
kidneys of, 3132, 32t, 145146
renal function in. See Kidney function, fetal
ultrasonography of, 3132, 55. See also Prenatal
diagnosis
urine production by, 3, 32
absence of, 5455
urogenital tract of. See Urogenital tract,
embryology of
voiding in, 354, 357
G
Gastrocystoplasty, 611, 612f, 617, 750751, 753f
Gastroileal pouch, 741742
Gastrointestinal tract, in prune-belly syndrome, 426,
426t, 427f
Gender
fetal, 32
urinary tract infection and, 181
urolithiasis and, 631
Gender assignment, 475, 515
in aphallia, 545
in cloacal exstrophy, 412414, 508
803
804
Index
H
HDR (hypoparathyroidism, sensorineural deafness,
and renal anomalies) syndrome, 176t
Heart
doxorubicin toxicity to, 666, 683
in prune-belly syndrome, 425, 426t
Hemangioma
labial, 476
scrotal, 554555, 555t, 556f
Hematocele, 560
Hematoma
after hypospadias surgery, 199
retroperitoneal, trauma-related, 728, 729f
urethral, trauma-related, 733
Hematometrocolpos, 482
Hematuria
after augmentation cystoplasty, 746
in bladder trauma, 730
continent urinary diversion and, 746
endoscopy in, 8586, 86f
in Henoch-Schnlein purpura, 233
in IgA nephropathy, 231
in membranoproliferative glomerulonephritis,
228
neonatal, 709
in postinfectious glomerulonephritis, 226
in rapidly progressive glomerulonephritis, 234
in renal trauma, 722, 726
Hemihypertrophy, Wilms tumor and, 671, 672f
Hemodialysis, in renal failure, 604605, 604t
Hemofiltration, in renal failure, 604t, 605
Hemolytic-uremic syndrome, 599
Hemorrhage
adrenal, 717, 717f
pulmonary, antiglomerular basement membrane
antibody disease and, 235
renal, computed tomography in, 8283
Henoch-Schnlein purpura
glomerulonephritis in, 231, 233234
pathogenesis of, 233
pathology of, 233
scrotal pain in, 559
Heparin-binding epidermal growth factor, 240, 242
Hepatitis C virus infection, membranoproliferative
glomerulonephritis and, 229
Hepatocyte growth factor, in processus vaginalis
closure, 578
Hermaphroditism, 468469. See also Pseudo
hermaphroditism
laparoscopy in, 101102
neoplasia and, 511
Hernia, inguinal. See Inguinal hernia
Hinman, F., 249
Hinman syndrome, 361362, 378
HNF1B, 178
Horseshoe kidney, 214216
anatomy of, 214, 215f
associated anomalies with, 215
blood supply to, 214
diagnosis of, 214215, 216f
DMSA scan of, 120, 124f
embryology of, 4, 6f
multicystic dysplastic kidney disease and, 221
outcomes of, 215216
ureteropelvic urine transport efficiency problem
in, 259
HSD17B3, 471
Index
Hypospadias (Continued)
bladder spasms after, 198199
Bracka procedure in, 538, 539f
buccal graft urethroplasty in, 531, 535f, 540
care after, 197199
for cases with distal division of corpus
spongiosum, 538
for cases with proximal division of corpus
spongiosum, 538540, 539f
chordee correction in, 531, 531f
complications of, 199200, 540542
cripple hypospadias after, 542
diet after, 199
dressing for, 197198, 198f
dressing removal after, 199
dysuria after, 199
edema after, 199
glanular dehiscence after, 541
in glanular hypospadias, 535538
hairy urethra after, 541
hematoma after, 199
historical perspective on, 530531
for hypospadias cripple, 540
Koff procedure in, 535
Koyanagi procedure in, 531, 537f
long-term outcomes of, 542
Mathieu procedure in, 531, 534f, 535
meatal regression after, 541
meatal stenosis after, 199200
mucosal ectropion after, 541
multistage procedures in, 540
nursing interventions in, 196
onlay procedure in, 531, 533f, 538
parental support after, 199
penile covering in, 534535, 538f
persistent chordee after, 200, 541
preparation for, 197
psychological implications of, 542
Snodgrass procedure in, 531, 535, 540
technical aspects of, 542543
Thiersch-Duplay procedure in, 531, 532f,
535
transverse preputial island flap technique in,
538540
unsatisfactory cosmetic result of, 540
urethral diverticulum after, 200
urethral fistula after, 199, 541, 541f
urethral stent after, 198, 198f
urethral stricture after, 200, 541
urethrocele after, 541, 542f
urethroplasty in, 531534, 532537f
urinary tract infection after, 199
wound infection after, 199
vesicoureteral reflux and, 307
Hypotension, in blunt renal trauma, 722
Hypovolemia, 26
I
Ileal conduit, 739740, 740f
Ileocecal cystoplasty, 750, 751f
Ileocystoplasty, 749750, 749750f
Ileovesicostomy, incontinent, 740
Imipramine, in enuresis, 384385
Immune deficiency syndromes, urinary tract
infection in, 182
Immune system
in renal scarring, 186
in urinary tract infection, 182
Immunoglobulin A (IgA)
in Henoch-Schnlein purpura, 233
in urinary tract infection, 182
Immunoglobulin A (IgA) nephropathy, 231233,
232f
vs. Henoch-Schnlein purpura, 231
histology of, 231232, 232f
pathogenesis of, 232
Immunoglobulin G (IgG), in urinary tract infection,
182
Immunosuppression, for kidney transplantation,
625, 626t, 627
Incidentaloma, 703
805
J
Juvenile granulosa cell tumor, 700
K
KAL, 178
Kallmanns syndrome, 176t, 178
fertility in, 510511
Karyotyping, 31, 32t, 34
Kayexalate, in hyperkalemia, 602t
Kennedys disease, 472
Ketoacidosis, diabetic, 28
Ketorolac, in bladder spasms, 334
Keyhole sign, 50f, 52
Kidney(s). See also at Renal
agenesis of. See Renal agenesis
anomalies of. See specific anomalies
biophysics of, 251252, 252f
blood flow in. See Renal blood flow
calculi of. See Urolithiasis
carcinoma of, 667, 682
806
Index
Kidney(s) (Continued)
clear cell sarcoma of, 667, 682
compensatory hypertrophy of, 59
in multicystic dysplastic kidney disease, 221
computed tomography of, 7374. See also
Computed tomography
cystic. See Multicystic dysplastic kidney disease;
Polycystic kidney disease
duplex. See Duplex kidney
dysfunction of. See also Acute kidney injury;
Chronic kidney disease
after rhabdomyosarcoma treatment, 692
after Wilms tumor treatment, 666667, 683
dysplasia of. See Dysplastic kidney; Multicystic
dysplastic kidney disease
ectopic. See Ectopic kidney
embryology of, 23f, 12, 3132, 172173, 213, 250251
animal studies of, 173, 174175t, 178
obstruction effects on, 241246
differentiation-related, 243244
growth-related, 242243, 242f
perturbations of, 173177. See also specific
developmental abnormalities and syndromes
end-stage disease of, 606. See also Chronic kidney
disease; Kidney transplantation
function of. See Kidney function
growth of, 59
epithelial-to-mesenchymal transformation in,
243
ureteropelvic junction obstruction effect on,
242243, 242f
vesicoureteral reflux and, 299
hemodynamics of, 252253, 253f
horseshoe. See Horseshoe kidney
hypoplasia of, 172, 599600
magnetic resonance imaging of, 7577, 7576f. See
also Magnetic resonance imaging (MRI)
in prune-belly syndrome, 427
rhabdoid tumor of, 667, 682
sodium regulation by, 11
solitary, reflux and, 315
transplantation of. See Kidney transplantation
trauma to, 720726
blunt, 721724, 723724f, 724t
computed tomography in, 8183, 83f, 723724f
congenital anomalies and, 721
contusion in, 722723
devascularized segment in, 723724, 726
gunshot injury in, 727
hypotension with, 722
laceration in, 723724, 723f, 724t
long-term outcomes of, 726
microhematuria with, 722
multiorgan injuries with, 721
penetrating, 726727
renal function after, 726
retroperitoneal hematoma with, 728, 729f
sports participation after, 727728
stabbing injury in, 726727
ultrasonography in, 722
urinoma with, 724, 724f
vascular, 724726, 725f
ultrasonography of, 5759. See also
Ultrasonography
prenatal, 31, 32t. See also Prenatal diagnosis
Wilms tumor of. See Wilms tumor
Kidney failure
acute. See Acute kidney injury
chronic. See Chronic kidney disease
Kidney function, 11
adult, 22
differential, 164166, 165f
supranormal, 145146
elements of, 11
fetal, 1214, 13f, 241
filtration fraction in, 13
glomerular filtration rate in, 1213, 13f
measurement of, 12
renal blood flow in, 13
sodium excretion in, 13, 14f
urinary concentration in, 1314
urinary dilution in, 1314
urine flow rate in, 1314
L
Labia
adhesions of, 476477, 477f
agglutination of, 476477
depigmentation of, 476
edema of, 476
embryology of, 9
hemangioma of, 476
hypertrophy of, 477478, 477f
infections of, 476
intentional cutting of, 478, 478f
lichen sclerosis of, 476
masses between, 478481, 479f, 713
paraurethral cyst between, 479480, 479f
periurethral condyloma between, 479f, 480
sarcoma botryoides between, 479f, 481, 685686,
685f, 713
ureterocele prolapse between, 479f, 481
urethral polyp between, 480
urethral prolapse between, 479f, 480
varices of, 476
Labioplasty, in urogenital sinus anomalies, 490, 493f
Lacuna magna, 457
Laparoscopy, 92
in adrenalectomy, 95
advantages of, 92
anatomy for, 93
in antegrade continence enema procedure, 105106
in bladder neck reconstruction, 104, 104105f
complications of, 106
access-related, 106
intraoperative, 106
in cryptorchidism, 99101, 100f, 573575,
573575f, 576t
in detrusorraphy, 104
in enterocystoplasty, 103
in incontinence, 103106
instruments for, 106
in intersex, 101102
in Mitrofanoff appendicovesicostomy, 105
in nephrectomy, 9394, 94f
in nephroureterectomy, 94
in partial nephroureterectomy, 9495
in prostatic utricle, 102103, 103f
in pyeloplasty, 9597, 96f
retroperitoneal approach to, 93, 95f
robot-assisted, 106107
technical aspects of, 9293
transperitoneal approach to, 93
in ureterocystoplasty, 103104
in urolithiasis, 657658, 660f
in vaginoplasty, 102
in varicocelectomy, 101
ventriculoperitoneal shunt function and, 106
Veress needle access technique for, 106
in vesicoureteral reflux, 9798, 9899f
LaPlaces law, 252
Law of conservation of energy, 252
Law of conservation of mass, 252
Laxatives, 788793
Lazy bladder. See Detrusor underactivity;
Underactive bladder
Legal considerations
in female genital cutting, 478
in testicular torsion, 561562
Leukemia
acute kidney injury in, 598
testicular, 701
Leukocyte esterase, urinary, in infection, 188, 188t
Levator ani, bladder exstrophyrelated defects in,
387, 388f
Leydig cell agenesis, 469
Leydig cell hypoplasia, 469
Leydig cell tumor, 699
LHCGR, 469
Index
Li-Fraumeni syndrome, 684
Lichen sclerosis, labial, 476
Lipoid congenital adrenal hyperplasia, 469470, 470f
Lithiasis. See Urolithiasis
Loop of Henle, 1112, 12f
Lungs, in prune-belly syndrome, 426, 426t
Luteinizing hormone receptor gene, mutations in,
469
Luteinizing hormonereleasing hormone, in
cryptorchidism, 571
Lymphedema, penile/scrotal, 522, 555
M
Macrophage, in interstitial fibrosis, 245
Macroplastique, 785786
MAG3 scan. See Radionuclide dynamic renography
Magnesium
in hyperoxaluria, 641
urinary, 637638, 638t
Magnetic resonance angiography (MRA), 77
Magnetic resonance imaging (MRI), 7173. See also
Magnetic resonance urography (MRU)
in adrenal tumor, 704, 704f
in bladder exstrophy, 390
in cloacal anomalies, 496
contrast-enhanced, of kidneys, 7677, 76f
diffusion-weighted, 8081
of kidneys, 7577, 7576f
in non-neuropathic bladder dysfunction, 372
in pheochromocytoma, 707
in prostatic utricle, 102f
in pyelonephritis, 7980, 80f
in renal agenesis, 78
in renal infection, 7980, 80f
in rhabdomyosarcoma, 688689, 689f
in syringocele, 452, 456f
of testes, 561, 561f
in urinary tract infection, 190
in urogenital sinus anomalies, 486
in Wilms tumor, 81, 674, 675f
Magnetic resonance urography (MRU), 7677, 79f, 162
clinical applications of, 167171
in congenital malformations, 167169, 168169f
in crossed ectopic kidney, 217f
in cystic disease, 168169, 168f
for differential renal function determination,
164166, 165f
in duplex kidney, 7778, 79f
in horseshoe kidney, 216f
in hydronephrosis, 169
limitations of, 171
in megaureter, 169170, 170f, 276
in pyelonephritis, 171
for renal drainage, 166167, 167f
in renal scarring, 171
renal transit time on, 166167
for single-kidney glomerular filtration index
determination, 164166, 166f
standardization of, 162
technique of, 162164, 163166f
in ureteral anomalies, 169
in ureteropelvic junction obstruction, 169170
in vascular malformations, 170, 170f
in vesicoureteral reflux, 170171
Magnetic resonance voiding cystourethrography,
170171, 304
MAGPI (meatal advancement and glanuloplasty
incorporated) procedure, in hypospadias,
535538
MAINZ pouch, 742
Male sling, 774
Malformation. See also specific malformations and
syndromes
murine model of, 173, 174175t
nonsyndromic, 178179
syndromic, 176t, 177178
Mannitol, in acute kidney injury, 600
Manual evacuation, in fecal incontinence, 790
Mass, law of conservation of, 252
Masturbation, 517
Mathieu procedure, 531, 534f, 535
807
808
Index
N
Neonatal emergencies, 709
bladder distention in, 59
delayed voiding in, 709
hematuria in, 709
hypospadias in, 709. See also Hypospadias
megacystis in, 713714. See also Megacystis
oligohydramnios in, 710f. See also Oligohydramnios
renal artery thrombosis in, 716717
renal vein thrombosis in, 715716
scrotal enlargement in, 711712, 711712f
testicular torsion in 712f, 711712. See also Testis
(testes); torsion of
testicular tumor in, 712. See also Testis (testes),
tumors of
umbilical drainage in, 713714
weight loss in, 24
Nephrectomy
donor, 620622
in ectopic ureterocele, 347348
before kidney transplantation, 615, 616t
laparoscopic, 9394, 9394f
in multicystic dysplastic kidney disease,
222225
in Wilms tumor, treatment of, 675677, 676f,
679680, 680f
Nephritis. See also Glomerulonephritis
of chronic infection, 226, 230231
interstitial, acute, 598
lupus, 230
Nephroblastoma. See Wilms tumor
Nephroblastomatosis, 672, 673f, 680681
SIOP protocol for, 680681
Nephrocalcinosis, prenatal diagnosis of, 41t
Nephrolithiasis. See Urolithiasis
Nephrolithotripsy. See Percutaneous
nephrolithotripsy
Nephroma
embryonal. See Wilms tumor
mesoblastic, congenital, 682, 682f, 715
Nephron(s)
embryology of, 3, 12, 13f, 172
obstruction effects on, 243244
functional segmentation of, 1112, 12f
number of, 172, 175177
Nephropexy, in congenital hydronephrosis,
258259
Nephrostography, antegrade, 158, 158159f
Nephrostomy, percutaneous
for incontinent urinary diversion, 738739
for pressure-flow study, 146, 148f
for ureteropelvic junction abnormality, 267268
Nephroureterectomy
laparoscopic, 94
partial, laparoscopic, 9495
Nerves
bladder, 354, 354f
renal, 246
Neuroblastoma, 702
diagnosis of, 703705, 704f
fetal, 715, 716f
molecular pathology of, 702703, 703t
pathology of, 702, 703t
prognosis for, 704705
screening for, 702
staging of, 705, 706t
treatment of, 705
Neurofibromatosis1, 684
Neurogenic bladder. See Bladder dysfunction,
neuropathic
Neuromodulation therapy
in non-neuropathic bladder dysfunction,
375
in overactive bladder, 376377
Neuropathic bladder, 363365. See also Bladder
dysfunction, neuropathic
Neuropeptide Y, in neuroblastoma, 702703
Nitric oxide, in obstructive disease, 245
Nitrite, urinary, 188
in infection, 188t
Nitrofurantoin, prophylactic, 192193, 192t
Nocturnal enuresis. See Enuresis
Normalized residual activity, in dynamic
renography, 115
NR0B1, 464
Nuclear factor B, in renal cell apoptosis, 242243
Nursing interventions, 196
for artificial urinary sphincter, 204
for bladder augmentation, 202203
for bladder exstrophy, 201202
for bladder neck reconstruction, 203204
for disorders of sexual differentiation, 204
educational, 196197
for adolescents, 197
for children with special needs, 197
for parents of infants, 196
for preschool children, 196
for school-age children, 196197
for epispadias, 201202
for hypospadias, 197200, 198f
for posterior urethral valves, 204
for ureteropelvic junction obstruction, 201
for urinary continence procedures, 202204
for vesicoureteral reflux, 200201
Nutrition, 2830
enteral, 29, 29t
intravenous, hypertonic, 30, 30t
parenteral, isotonic, 29
in renal failure, 603
O
Obstruction. See also Ureteropelvic junction
obstruction; Ureterovesical junction
obstruction
definition of, 237238
Occult neuropathic bladder, 361362, 378
OEIS (omphalocele, exstrophy, imperforate anus,
and spinal abnormalities) complex. See Cloacal
exstrophy
Oligohydramnios, 32, 709, 710f
in posterior urethral valves, 440
in prune-belly syndrome, 425427
pulmonary hypoplasia and, 5153
Omega-3 fatty acids, in IgA nephropathy, 232
Omphalocele, cloacal exstrophy and, 412413
Onlay procedure, in hypospadias, 531, 533f, 538
Opitz syndrome, 35t
Oral-facial-digital syndrome, 176t
Orchiectomy, inguinal, 694695, 696f
Orchiopexy
Fowler-Stephens, 101, 575
laparoscopic, 100101, 574575, 574575f, 576t
complications of, 576
open, 575576, 576t
complications of, 576
inguinal, 572
transscrotal, 573
in prune-belly syndrome, 432433f, 434435
Osmolality, plasma, 24
Osteopontin, in obstructive disease, 245
Ovary (ovaries), development of, 7, 8f
Overactive bladder, 358360, 376377. See also
Detrusor overactivity
clinical manifestations of, 376, 376t
definition of, 358t, 359f
enuresis and, 362
treatment of, 376377, 377t
anticholinergic drugs in, 375
Ovotestis, 468
Oxalate, urinary, 637638, 638t
Oxalobacter formigenes, 639
Oxybutynin
in enuresis, 384
in overactive bladder, 375
P
P450 aromatase deficiency, 475
P blood group, urinary tract infection and, 182
P450 oxidoreductase deficiency, 474475
Pad test, twelve-hour, 367368, 372f, 373t
Pain, in urolithiasis, 640
Parameatal cyst, 551
Paraphimosis, 520, 521f
Paraurethral cyst, 479480, 479f
Parenteral nutrition
partial (isotonic), 29
total, 30, 30t
Parents, information for, 196
Parophoron, 7
Patent processus vaginalis. See Processus vaginalis,
patent
PAX2, 177-178
in multicystic dysplastic kidney disease, 220
PAX-FKHR, 668, 687
Pelvic excretion efficiency, in dynamic renography,
115
Pelvic floor
bladder exstrophyrelated defects in, 387, 388f
inactivity of, in neuropathic bladder, 364
Pelvic organ prolapse, in female bladder exstrophy,
406
Pelvic osteotomy
in bladder exstrophy, 391392, 391392f, 404
in cloacal exstrophy, 413
Pelviectasis, 58
Pelvis
bladder exstrophyrelated defects in
bony, 386, 387f
muscular, 387, 388f
on voiding cystourethrography, 68
Peas posterior sagittal anorectovaginourethroplasty, 497498
outcomes of, 498499
Penicillamine, in cystinuria, 641
Penis
absence of, 507508, 544545, 546f
autologous fat injection of, 508
bifid, 548
bladder exstrophyrelated defects in, 387389,
389f
buried, 520522, 522f, 548549, 549f, 550t
chordee of
correction of, 395, 531, 531f
persistent, 200, 541
circumcision-related loss of, 524
construction/reconstruction of
in bladder exstrophy, 394395, 396f, 404
in cloacal exstrophy, 413414
in epispadias, 407408
in micropenis, 508509, 510f
Index
Penis (Continued)
curvature of, 550
cyst of, 551, 552f
development of, 910, 10f, 544, 545546f
dihydrotestosterone cream for, 510
duplication of, 548, 548f
lengthening of, 508
lymphedema of, 522, 522f
normal size of, 508, 509f
small. See Micropenis
tissue engineering of, 211
torsion of, 551, 551552f
transposition of, 553554, 553554f
trapped, 548
webbed, 520522, 521f, 549, 550f
Penoscrotal fusion, 520522, 521f
Penoscrotal transposition, 553554, 553554f
Percutaneous nephrolithotripsy, 652656
bleeding with, 655656
complications of, 655656, 658t
drainage after, 655
forceps extraction for, 655
instrument introduction for, 654, 654f
lithotripsy for, 654f, 655
nephrostomy tract creation for, 653, 653654f
nephrostomy tract dilation for, 653654, 654f
perforation with, 656
results of, 657t
sepsis after, 656
stone extraction techniques for, 655
Percutaneous nephrostomy
for incontinent urinary diversion, 738739
for pressure-flow study, 146, 148f
for ureteropelvic junction abnormality, 267268
Percutaneous pressure-flow study, 141, 142f,
146152
biomechanical principles of, 141143
bladder pressure in, 152154, 154f, 160161
clinical application of, 161
constant-pressure, 150151
contrast material in, 157158
diuresis (furosemide), 151152, 153155f, 161
fluoroscopic monitoring in, 157158, 158159f
individualized infusion, 149, 149f, 150t
lower tract anomaly effects on, 160161
in megaureter, 276
multiple obstructions on, 158160, 158f
nephrostomy access for, 146, 148f
normal renal pelvic pressure in, 146148
optimal flow rate for, 148149
in pain evaluation, 158
pressure decay and, 155157, 156157f
protocol for, 147t
renal pelvisbladder pressure gradient in,
152154, 154f
ureteral opening pressure in, 157158, 159f
ureteropelvic junction configuration in, 157158,
157f
in ureteropelvic junction problems, 263264,
263264f
vesicoureteral reflux and, 154155, 155f
Percutaneous suprapubic cystotomy, 736
Peritoneal dialysis
complications of, 583
in renal failure, 604, 604t
Peritoneum, in vaginoplasty, 502
Periureteral diverticulum, vesicoureteral reflux and,
314315, 315f
Periurethral area, bacterial colonization of, 181
Periurethral cyst, 713
Periurethral sling, 768773, 770f
complications of, 772773
material for, 769771
patient selection for, 768769
placement of, 771772, 771f
results of, 772773, 772f, 773t
surgical technique for, 769772
Perlman syndrome, 41
prenatal diagnosis of, 41, 41t
Wilms tumor in, 671
Persistent mllerian duct syndrome, 473
Peutz-Jeghers syndrome, Sertoli cell tumor in, 700
pH, normal, 28
Pheochromocytoma, 706707
clinical features of, 706
diagnosis of, 706707, 707f
treatment of, 707
Phimosis, 549550, 550f
classification of, 551t
incidence of, 549550
physiologic, 519, 520f
treatment of, 550
Phosphate, urinary, 637638, 638t
PIC (positioning the instillation of contrast)
cystography, in vesicoureteral reflux, 304
Pili, bacterial, in urinary tract infection, 180181
Pippi Salle procedure, 767f, 766767
Placenta
excess androgens of, 475
in hypospadias development, 529
Poiseuilles law, 251252
Polands syndrome, 176177t
Polycystic kidney disease, 3940
autosomal dominant, 40
magnetic resonance urography in, 168, 169f
prenatal diagnosis of, 40, 41t
prognosis for, 40
autosomal recessive, 3940, 709, 710f
prenatal diagnosis of, 35f, 38, 40t
prognosis for, 3738
Polydimethylsiloxane, in endoscopic vesicoureteral
reflux treatment, 323
Polyp(s)
bladder, 389, 391, 391f
urethral, 91, 453
protrusion of, 480
Polysaccharide microspheres, 783
Polytetrafluoroethylene
in endoscopic vesicoureteral reflux treatment, 323,
325326f, 326327, 328f
in incontinence treatment, 782
Polyuria, nocturnal, 358t, 362, 380
Positron emission tomography, in Wilms tumor, 674
Posterior urethral obstruction, after bladder
exstrophy treatment, 392394
Posterior urethral valves, 49, 52, 437, 717
anatomy of, 437438
bladder function and, 444445, 444t, 445f
classification of, 437438
creatinine measurement in, 441
genetics of, 179
hydronephrosis in, 440, 441f
mild cases of, 438
nursing interventions for, 204
postnatal diagnosis of, 440441, 441442f
prenatal diagnosis of, 4750, 5051f, 439440, 440f
pressure pop-off mechanisms in, 439
prognosis for, 717
renal pathology and, 439
renal transplantation and, 445
respiratory distress and, 440
spectrum of, 438
treatment of, 441443, 717
case report of, 443, 443f
endoscopic ablation in, 54, 86, 87f, 441443
historical perspective on, 438439
management after, 442443
prenatal, 173
sphincter anatomy in, 442
suprapubic catheter drainage in, 438
urinary diversion in, 438439, 735736
growth and, 608609, 609f
urodynamic study after, 136, 137f
vesicoureteral reflux resolution after, 444, 444f
type I, 437
type II, 437
type III, 437
ultrasonography in, 441, 443f
vesicoureteral reflux and, 438
endoscopic treatment of, 328
voiding cystourethrography in, 70, 73f, 86,
440441, 442443f, 443445, 445f, 718, 718f
Postinfectious (poststreptococcal) glomerulonephritis,
226228, 227f
Postvoid residual volume, 130
in non-neuropathic bladder dysfunction, 370
809
Potassium
abnormalities of, 27
deficiency of, 27
excess of, 27
Potter syndrome, 64f, 709, 710f
Pouch of Douglas, in bladder exstrophy, 390
Power, 252
Prader scale, 461, 466f
Prednisone, in membranoproliferative glomerulonephritis, 229
Pregnancy
augmentation cystoplasty and, 745
bladder exstrophy and, 406
cloacal anomaly treatment and, 499
kidney failure in, 318
vaginoplasty and, 485
vesicoureteral reflux and, 318
Pregnenolone, impaired formation of, 469470, 470f
Premature infant. See also Neonatal emergencies
renal function in, 1621
glomerular filtration rate in, 1617, 17f
renal blood flow in, 17, 18f
sodium excretion in, 1719, 1819f
sodium reabsorption in, 1920, 20f
urinary acidifying capacity in, 2021, 21f
urinary concentration in, 20
urinary dilution in, 20
urine flow rate in, 20
weight loss in, 24
Prenatal diagnosis, 31, 54t
of absent bladder, 5455
of Bardet-Biedl syndrome, 42
of Beckwith-Wiedemann syndrome, 4041
of bilateral single ectopic ureters, 55
of bladder abnormalities, 4955, 390
of branchio-oto-renal syndrome, 42
of cloacal abnormalities, 52, 411412
of congenital Finnish nephrosis, 42
of congenital mesoblastic nephroma, 682
of DiGeorge syndrome, 43
of duplex kidneys, 4749, 48f
of dysplastic kidney, 3639, 3738f
of ectopic (pelvic) kidney, 3334, 34f
of ectrodactyly, ectodermal dysplasia, and clefting
syndrome, 42
of Elejalde syndrome, 42
of Fraser syndrome, 42
of hydronephrosis, 4347, 61, 116118, 250
hyperechogenic kidney in, 3443, 36f, 36t
indications for, 260
management after, 55
choices for, 266
evaluation for, 265266
intrauterine intervention in, 266, 270271
postnatal, 266267
termination in, 266
of Meckel-Gruber syndrome, 4142
of megacystis 5051f, 5054. See also Megacystis
of megaureter, 274, 282
of MURCS association, 41
of neuropathic bladder abnormalities, 52
of overgrowth syndromes, 4041, 40t
of pelviureteric junction anomalies, 46, 45f
in penoscrotal transposition, 553, 554f
of Perlman syndrome, 41
of polycystic kidney disease, 3940
of posterior urethral valves, 49, 5051f, 52,
439440, 440f
principles of, 32, 32t
in prune-belly syndrome, 429430, 429f
of renal agenesis, 33, 33f
of renal cysts and diabetes syndrome, 43
of renal pelvis dilatation, 4347, 43f, 44t
of Schinzel-Giedion syndrome, 4243
of Simpson-Golabi-Behmel syndrome, 41
Society of Fetal Urology Grading System in, 261,
261t
timing of, 260261
of upper tract dilatation, 4347, 43f, 44t
of ureterocele, 46f, 49
of ureteropelvic urine transport inefficiency, 250,
251f
of VATER association, 41
810
Index
R
Radiation therapy
abdominal complications of, 693
gonadal dysfunction after, 693
in neuroblastoma, 705
pulmonary complications of, 666, 693
in rhabdomyosarcoma, 691, 692f
in yolk sac tumor, 697
Radiography. See also Pyelography; Urography,
Voiding cystourethrography
abdominal, 62, 66f
in brown tumor, 603f
in cloacal anomalies, 495496
in urachal sinus, 420f
Radiography (Continued)
in urogenital sinus anomalies, 486
in urolithiasis, 634635, 634f, 636f
in Wilms tumor, 674
Radionuclide cystography, 6667
direct, 122123, 125f
in vesicoureteral reflux, 303f
indirect, 123124, 126f
in vesicoureteral reflux, 302, 304f
in vesicoureteral reflux, 69, 72f, 301302, 303304f
Radionuclide dynamic renography, 111118
in acute tubular necrosis, 597, 598f
diuretic, 112115
bladder status in, 115
evaluation of, 112115, 112t
frusemide administration protocol for, 112
gravity in, 115
hydration for, 112114
normalized residual activity in, 115
pelvic excretion efficiency in, 115
pelvic volume in, 114115
after pyeloplasty, 113f
renal function in, 115
renal pelvis dilatation on, 115116, 115t,
116f118f
in ureteropelvic junction problems, 261263, 262f
in vesicoureteric junction dysfunction, 114f, 115
guidelines for, 111
in megaureter, 275276
split function on, 112
supranormal differential renal function on,
145146
tracers for, 111112
in urinary tract infection, 190
Radionuclide imaging, 108. See also DMSA (dimercaptosuccinic acid) scan; Radionuclide cystography; Radionuclide dynamic renography
in pheochromocytoma, 707
in renal tumor, 674
in rhabdomyosarcoma, 689
testicular, 561
Rapidly progressive glomerulonephritis, 234235,
234235f, 598
pauci-immune, 235
pulmonary hemorrhage and, 235
Rayer, Pierre-Franois Olive, 248
Reactive oxygen species, in obstructive disease, 245
Receptor(s)
estrogen, xenobiotic binding to, 473
testosterone
defects in, 472473, 473f
xenobiotic binding to, 473
Rectum
distention of, voiding cystourethrography and, 68
masses of, voiding cystourethrography and, 68
5-Reductase deficiency, 472, 502, 503f
fertility and, 510
Reflex, cremasteric
in acute scrotum, 557
overactive, 566
Reflux nephropathy 291f, 283, 291299. See also
Renal scarring; Vesicoureteral reflux
demography of, 293294
DMSA scan in, 292, 292293f
dysplasia in, 292293, 317
pathogenesis of, 294299
intrarenal reflux in, 294295, 294295f
urinary infection in, 295297, 296f
pathology of, 292293
Renal. See also Kidney(s)
Renal agenesis, 3
bilateral, 33, 33f
computed tomography in, 78
definition of, 172
genetic model of, 178
multicystic dysplastic kidney disease and, 221
neonatal diagnosis of, 61, 64f
prenatal diagnosis of, 32t, 33, 33f
unilateral, 33
vesicoureteral reflux and, 307
Renal artery
thrombosis of, 599, 716717
trauma to, 724726
Index
Renal blood flow
in experimental hydronephrosis, 254, 255f
fetal, 13
neonatal, 1415
in obstructive disease, 245
premature infant, 17, 18f
pressures and, 252253, 253f
Renal cell carcinoma, 667, 682
molecular biology of, 667
treatment of, 667
Renal-coloboma syndrome, 176177t, 177178
Renal cysts and diabetes (RCAD) syndrome, 43,
176177t, 178
Renal dysplasia. See Dysplastic kidney
Renal failure. See Acute kidney injury; Chronic
kidney disease
Renal function. See Kidney function
Renal mesenchyme, 172
Renal osteodystrophy, 602
Renal pelvic pressure, 253, 253f
bladder pressure and, 152154, 154f
in congenital hydronephrosis, 143145, 145f
decay of, 155157, 156f
normal, 146148, 253
subtracted (relative), 154
Renal pelvis, physiology of, 253
Renal pelvis dilatation. See also Hydronephrosis
fetal, 4347
aneuploidy and, 4445
degrees of, 4344, 43f
management of, 4546
mild, 4445, 43f
natural history of, 45
neonatal, 5859
radionuclide dynamic renography in, 115116,
116f118f
Renal plasma flow, 2122
Renal reserve power, 250
Renal scarring
age and, 186
bacteriuria and, 305
continuous antibiotic reflux prophylaxis and,
310311
age in, 310311
genetic predictors in, 311
micromolecular predictors in, 311
radiographic predictors in, 311
DMSA scan in, 110111, 110t, 111f
genetic factors in, 186187, 298
hypertension and, 317
incidence of, 184
magnetic resonance imaging in, 171
pathogenesis of, 185187, 186f
cellular mechanisms in, 297298
experimental studies of, 294299, 294296f, 298f
in fetal sheep, 298299
infection in, 295297, 296f, 305306
intrarenal reflux in, 294295, 294296f
reperfusion injury in, 298
tubular cell damage in, 298
vesicoureteral reflux and, 185, 297, 298f, 299
without vesicoureteral reflux, 297
patterns of, 185186, 186f
renin-angiotensin system in, 186187
Renal transit time, on magnetic resonance
urography, 166167
Renal vein thrombosis, 599, 715716
Renin-angiotensin system
in glomerulosclerosis, 244245
local, 244245
in obstructive disease, 244246
in renal scarring, 186187
in ureteropelvic junction obstruction, 239
Renography, radionuclide. See Radionuclide
dynamic renography
Resectoscopy, instrumentation for, 84
Respiratory disorders
posterior urethral valves and, 440
in prune-belly syndrome, 426
Retrograde pyelography
in hydronephrosis, 265
multiple obstructions on, 159f
Retroperitoneal hematoma, 728, 729f
S
Salicylate poisoning, 28
Sarcoma, clear cell, 667, 682
Sarcoma botryoides, 479f, 481, 685686, 685f. See also
Rhabdomyosarcoma
salt-wasting form of, 713
Scarring. See Renal scarring
Schinzel-Giedion syndrome, 4243
Schistosomiasis, 195
endoscopy in, 8586, 86f
Scintigraphy. See also at Radionuclide
cortical, static, 108111. See also DMSA (dimercaptosuccinic acid) scan
Sclerotherapy, in hydrocele, 582
Scrotoplasty, in penoscrotal transposition, 553, 554f
Scrotum
absence of, 552, 552f
acute, 556562
clinical presentation of, 557
differential diagnosis of, 557560, 558t
inflammatory causes of, 559560, 560561f
physical examination in, 557
traumatic causes of, 559, 560f
varicocele and, 559
vascular causes of, 557559, 558559f
811
Scrotum (Continued)
bifid, 554, 555f
ectopic, 553, 553f
enlargement of, in neonate, 711712, 711712f
hemangioma of, 554555, 555t, 556f
magnetic resonance imaging of, 561
radionuclide imaging of, 561
transposition of, 553554, 553554f
ultrasonography of, 561
Self-esteem, enuresis and, 381
Sertoli cell tumor, 699700
Sexual abuse, 379
enuresis and, 381
hymenal examination in, 476
labial adhesions and, 477
Sexual differentiation, 459, 460462f
disorders of, 459. See also Ambiguous genitalia
and specific disorders
classification of, 460
management of, 460461
nursing interventions for, 204
physiopathology of, 459460
male, 459460, 460462f
genetics of, 460, 463f
Sexual function
behavior interventions for, 517
after bladder exstrophy treatment, 405406
after feminizing genitoplasty, 506
micropenis and, 510
after rhabdomyosarcoma treatment, 692693
Shock wave lithotripsy, extracorporeal. See
Extracorporeal shock wave lithotripsy
Short gut syndrome, cloacal exstrophy and, 412
Sigmoid cystoplasty, 750, 752f
Silicone, injectable, 786
Silk glove sign, 579
Simpson-Golabi-Behmel syndrome, 41, 176177t,
664, 665t
prenatal diagnosis of, 41, 40t
Sleep
arousal from, 381
voiding during, 357. See also Enuresis
Sling. See Periurethral sling
Smith-Lemli-Opitz syndrome, 35t, 176177t, 469
Snodgrass procedure, 531, 535, 540
Society of Fetal Urology Grading System, in
hydronephrosis, 261, 261t
Sodium
abnormalities of, 2627
fractional excretion of, 11
in kidney failure, 597
renal handling of, 11
fetal, 13, 14f
neonatal, 15
in premature infant, 1720, 1820f
urinary, in kidney failure, 597
Sodium bicarbonate, in hyperkalemia, 602t
SOX9, 463
Spasms, bladder
after exstrophy treatment, 395397
after hypospadias surgery, 198199
after ureteral reimplantation, 334
Spinal cord
congenital abnormalities of, 363364. See also
Myelomeningocele
untethering of, 414
Spindle urethra, 448449, 452f
Spinning top urethra, 69, 72f
Splenogonadal fusion, 555556, 557f, 557t
Sports participation, after renal injury, 727728
SRD5A1, 472
SRD5A2, 472
SRY, 468, 463
Stabbing injury
renal, 726728
ureteral, 728
Static cortical scintigraphy, 108111. See also DMSA
(dimercaptosuccinic acid) scan
Stem cells, 209210
adult, 209
embryonic, 209210
Stenosis. See Meatal stenosis
Stones. See Urolithiasis
812
Index
T
Technetium 99m (Tc99m)-labeled diethylenetriamine
penta-acetic acid, in dynamic renography,
111112, 275
Technetium 99m (Tc99m)-labeled dimercaptosuccinic
acid scan. See DMSA (dimercaptosuccinic acid)
scan
Technetium 99m (Tc99m)-labeled ethylene-dicysteine,
in dynamic renography, 112
Technetium 99m (Tc99m)-labeled glucoheptonate, 108
Technetium 99m (Tc99m)-labeled mercaptoacetyltri
glycine, in dynamic renography, 111112. See
also Radionuclide dynamic renography
Teflon. See Polytetrafluoroethylene
Teratogens, 173177
Teratoma, 698699
Testicular artery ligation, varicocelectomy and,
591592
Testicular regression syndrome, 466, 467f
Testis (testes)
absence of, 566567
agenesis of, 567
anatomy of, 572
ascended, 568, 583584
blood supply to, 572, 585
cryptorchid. See Cryptorchidism
cystic dysplasia of, 221
descent of, 563564
androgen receptors in, 564
androgens in, 564
calcitonin generelated peptide in, 565
epidermal growth factor in, 565
estrogens in, 564565
hormonal factors in, 564565
insulin-like factor 3 in, 564
mechanical factors in, 565, 565f
mllerian inhibiting substance in, 565
processus vaginalis in, 564
transabdominal migration in, 563564
transinguinal, 564
development of, 89f
developmental abnormalities of, 469473
in androgen insensitivity syndrome, 472473,
473f
in 7-dehydrocholesterol reductase deficiency, 469
in 17,20-desmolase deficiency, 471
Index
Trauma (Continued)
blunt, 728729, 730f
contusion in, 729
penetrating, 728
treatment of, 729730, 730731f
Tricyclic antidepressants, in enuresis, 384385
Trigonal cyst, vs. ureterocele, 343
Trigone
agenesis of, 6
embryology of, 3f
Trimethoprim, prophylactic, 192, 192t
Trimethoprim-sulfamethoxazole, prophylactic,
192193, 192t
Trisomy 13, prenatal diagnosis of, 40t
Trisomy 18, horseshoe kidney in, 215
Tuberculosis, 195
Tumor lysis syndrome, 598
Tumor necrosis factor-
in renal cell apoptosis, 242243
in renal scarring, 311
Tunica vaginalis, 9f
Turner syndrome, horseshoe kidney in, 215
Twelve-hour pad test, 367368, 372f, 373t
Tyrosine kinase receptors, in neuroblastoma, 703
U
Ulcerative colitis, neovaginal, 486
Ultrasonography, 56. See also Prenatal diagnosis
in adrenal hemorrhage, 717
in adrenal tumor, 704, 704f
in anorectal malformation, 788
in appendix testis torsion, 558559
in bilateral hydrocele, 711f
of bladder, 5960, 6061f
in bladder septation, 424f
in blunt renal trauma, 720
color Doppler, 56
in congenital mesoblastic nephroma, 682f
duplex Doppler, 56
in dysplastic kidney, 61, 63f
fetal, 3132, 260261
gray-scale, 56, 57f
in hydronephrosis, 61, 61f, 65f, 142f, 161, 250
indications for, 6162
in inguinal hernia, 711f
of kidneys, 5759, 5758f
in megaureter, 274275, 275f, 282
in multicystic dysplastic kidney disease, 61, 62f,
222, 223224f
in nephrolithiasis, 81f
in neuroblastoma, 716f
in non-neuropathic bladder dysfunction, 372373
in penile/scrotal edema, 555
in pheochromocytoma, 707f
in posterior urethral valves, 443f
power Doppler, 5657
in prune-belly syndrome, 431
in renal agenesis, 61, 64f
in renal calculi, 81, 81f
in rhabdomyosarcoma, 688, 688f
screening, 6162, 65f
scrotal, 561
in syringocele, 452, 456f
in testicular rupture, 559, 560f
in testicular torsion, 558, 711712, 712f
transperitoneal, in posterior urethral valves, 441
in urachal cyst, 419421, 420f
in ureterocele, 341, 342f, 716f
in ureteropelvic junction obstruction, 714, 715f
of ureters, 5759
in urinary tract infection, 190
with uroflowmetry, 130
in urogenital sinus anomalies, 486
in urolithiasis, 634, 635f
in vesicoureteral reflux, 302304
in Wilms tumor, 6162, 65f, 81, 674
Umbilicus, drainage from, 713714
Underactive bladder 360361, 135, 358t. See also
Detrusor underactivity
Unstable bladder. See Detrusor overactivity;
Overactive bladder
UPK2, 179
UPK3A, 179
Urachal cyst, 419421, 420f
Urachal sinus, 419, 420f
Urachus
anatomy of, 417418
anomalies of, 417422
clinical presentation of, 418419
embryology of, 418, 419f
management of, 422
radiography of, 418419
type I, 418419, 419f
type II, 418421, 419f
type III, 418421, 419f
type IV, 418, 419f
embryology of, 418
histology of, 417418
patent, 420421f, 421
Urate, urinary, 637638, 638t
Uremia, adverse effects of, 608
Ureter(s)
adventitia of, 272
anatomy of, 272
arteries of, 272
biophysics of, 251252, 252f
bladder entry of, 284, 285f
development of, 5, 238239
diameter of, 272
dilatation of. See Megaureter
duplication of, 338341. See also Duplex kidney
complete, 339f, 340341
incomplete, 339340, 340f
ectopic, 337, 349352
cystoscopy in, 87, 88f
embryology of, 6, 7f, 337338
in female, 337338, 349351, 349351f, 379
golf-hole orifice and, 285, 286f
imaging of, 78, 78f
incidence of, 349
magnetic resonance urography in, 167, 168f, 169
in male, 337338, 349, 349f, 351352, 351f
single, bilateral, 6, 7f, 55, 352
sites of, 349, 349f
treatment of
in bilateral single ectopic ureters, 352
in female, 350351
in male, 352
edema of, postoperative, 280281
embryology of, 337338, 338339f
excisional tapering of, in megaureter, 279280,
281f
imbrication of, in megaureter, 278279, 278279f
layers of, 272
length of, 284285
magnetic resonance urography of, 169
muscularis of, 272, 274f
distention effects on, 240
neuronal input of, 272
obstruction of. See also Hydronephrosis
bladder diverticulum and, 416
periurethral slingrelated, 770
operative injury to, 270
postoperative edema of, 280281
in prune-belly syndrome, 427, 427f
reconstruction of. See also Ureteral reimplantation
in megaureter, 278280, 278279f, 281f
in prune-belly syndrome, 432433
reflux into. See Vesicoureteral reflux
reimplantation of. See Ureteral reimplantation
sheath of, 272
stenting of, in megaureter, 279280
tissue engineering of, 210211
trauma to, 728730
blunt, 728729, 730
contusion in, 729
penetrating, 728
treatment of, 729730, 730731f
ultrasonography of, 5759
urine propulsion in, 253254, 254f
Ureteral cone, 253
Ureteral opening pressure
in megaureter, 276
in pressure-flow study, 158, 159f
813
814
Index
Urethra (Continued)
tear of, 88, 90f
trauma to, 732736
hematoma with, 733, 733f
management of, 734735, 734f
posterior, 733
straddle, 733, 733f
urodynamic study of, 136137, 137f
voiding cystourethrography of, 6970, 73f
tissue engineering of, 211
Urethral catheter. See Catheterization
Urethral diverticulum, 451452
anterior, 91
after hypospadias surgery, 200
Urethral fistula
after bladder neck closure, 774
after hypospadias surgery, 199, 541, 541f
Urethral pressure profile, 137138
Urethral sphincter
anatomy of, 353, 446
artificial. See Incontinence, artificial urinary
sphincter for
development of, 353354, 446
inactivity of, in neuropathic bladder, 364
innervation of, 354, 354f
tissue engineering of, 210
urodynamic study of, 136137
Urethral valves
anterior, 451452
voiding cystourethrography in, 70, 74f, 9091,
90f
posterior. See Posterior urethral valves
Urethritis posterior, 455457
Urethrocele, after hypospadias surgery, 541, 542f
Urethrocutaneous fistula, after epispadias repair,
408
Urethrography, retrograde, in trauma, 720, 734, 734f
Urethroplasty
in bladder exstrophy, 395
in hypospadias, 531534, 532537f
Urethrorrhagia idiopathica, 455457
Urethrotomy, internal, in prune-belly syndrome, 433
Urge incontinence, 358360, 358t. See also Overactive
bladder
Urgency, definition of, 358359
Uric acid nephropathy, 598
Urinalysis
in non-neuropathic bladder dysfunction, 367
in urinary tract infection, 188, 188t
Urinary diversion, 737
continent, 740744
absorption-related complications of, 746
adenocarcinoma and, 746
in bladder exstrophy, 405
bowel dysfunction after, 746
catheterizable channels for, 734744, 743745f
complications of, 744746, 745t
evaluation for, 741
gastroileal pouch for, 741742
Indiana pouch for, 742
Kock pouch for, 741
MAINZ pouch for, 742
secretion-related complications of, 746
structural complications of, 745746
urinary reservoir for, 737, 741
incontinent, 737740
cutaneous ureterostomy for, 738
cutaneous vesicostomy for, 738, 739f
ileal conduit for, 739740, 740f
ileovesicostomy for, 740
percutaneous nephrostomy tube for, 738739
percutaneous suprapubic cystotomy for, 738
urethral catheter for, 737738
in posterior urethral valves, 438439, 609f,
628630
in prune-belly syndrome, 432
temporary, in megaureter, 278
urolithiasis and, 638
Urinary incontinence. See Incontinence
Urinary retention, 379
Urinary tract dilatation, 4247
lower tract, 4751. See also Megacystis
upper tract, 4247. See also Hydronephrosis
Index
Urinary tract dilatation (Continued)
neonatal, 5859
postnatal management of, 4445
prenatal diagnosis of, 4347, 43f, 44t, 4546f
Urinary tract infection, 180. See also Cystitis;
Pyelonephritis
age and, 181, 187
anatomic abnormalities and, 183
animal models of, 181
anticholinergic therapy and, 384
after artificial urinary sphincter placement,
779780, 780t
after augmentation cystoplasty, 741
bacteria in, 180181
bladder diverticulum and, 417, 419f
bladder dysfunction and, 290, 361
bowel dysfunction with, 185
circumcision and, 181182, 317
classification of, 180, 181t
clinical symptoms of, 187
computed tomography in, 190
continent urinary diversion and, 746
detrusor overactivity and, 288
diagnosis of, 187190
direct radioisotope cystography in, 126f
DMSA scan in, 110111, 110111f, 110t, 171,
188189
dysfunctional voiding and, 377
epidemiology of, 180
experimental studies of, 290
familial factors in, 182
fecal bacteria and, 182183
fungal, 194195
gender and, 181
hematogenous spread in, 180
host susceptibility factors in, 181183
after hypospadias surgery, 199
imaging in, 180, 181t, 188190, 189f
immune factors in, 182
incidence of, 180, 305
lymphatic spread in, 180
magnetic resonance imaging in, 190
magnetic resonance urography in, 171
management of, 190193, 191t
prophylactic, 192193, 192t
multicystic dysplastic kidney disease and, 222
myelomeningocele and, 364
natural history of, 183185
neuropathic bladder and, 183
P blood group and, 182, 291
pathogenesis of, 180183
periurethral colonization and, 181
physical examination in, 187
radionuclide renography in, 190
recurrent, 180, 185
classification of, 180
rate of, 305
treatment of, 193
renal scarring and, 184187, 184f, 295297, 296f,
298f, 305306. See also Renal scarring
treatment of, 376
ultrasonography in, 190, 302304
urinalysis in, 187188, 188t
urinary tract abnormalities and, 185
urine culture in, 187188, 189t
uroepithelial adherence and, 182
vesicoureteral reflux and, 182183, 185, 287288,
295297, 296f, 298f, 304307
voiding cystourethrography in, 189190
voiding dysfunction with, 185
Urine
acidifying capacity of
in neonate, 16
in premature infant, 2021, 21f
calcium in, fetal, 261
catheterized specimen of, 187188
collection of, in infection, 187188
concentration of
in fetus, 1314, 257
in neonate, 1516, 15f, 257
in premature infant, 20
dilution of
in fetus, 1314
Urine (Continued)
in neonate, 1516
in premature infant, 20
examination of. See Urinalysis
fetal, 3, 32
absence of, 5455
flow rate of 128, 129f. See also Uroflowmetry
fetal, 1314
neonatal, 1516
in non-neuropathic bladder dysfunction, 370
premature infant, 20
formation of
in fetus, 257
in neonate, 257
loss of. See Incontinence
mean voided volume of, 355
2-microglobulin in, 261
midstream voided specimen of, 187
plastic bag specimen of, 187
production of, 11
residual, 130, 358t
in non-neuropathic bladder dysfunction, 370
retrograde flow of, 301. See also Vesicoureteral
reflux
intrarenal, 294295, 294296f, 315
suprapubic aspirated specimen of, 187188
ureteral propulsion of, 253254, 254f
ureteral transport of, 253254, 254f
Urinoma, in blunt renal trauma, 724, 724f
Urodynamic study, 127, 370372. See also
Uroflowmetry
ambulatory, 138
bladder capacity and, 130
clinical implications of, 138, 140t
indications for, 138
in myelomeningocele, 363364
in non-neuropathic bladder dysfunction, 370372,
373t
in occult neuropathic bladder, 361
in prune-belly syndrome, 427428
terminology for, 127
upper tract, 141. See also percutaneous pressureflow stydy video. See video-urodynamic
study
Urofacial (Ochoa) syndrome, 176t, 179, 362
Uroflowmetry, 127130
definitions for, 127
flow patterns on, 128, 129f
flow rates on, 128, 129f
interpretation of, 130
in non-neuropathic bladder dysfunction, 370
postvoid residual volume on, 130
setup for, 127128, 128f
ultrasonography with, 130
Urogenital adysplasia syndrome, 176t
Urogenital folds, 2f
Urogenital mobilization
partial, 488, 491492f, 493494
total, 488, 491494f, 493494, 498
Urogenital sinus
anomalies of, 486495. See also Congenital adrenal
hyperplasia
endoscopy in, 486
evaluation of, 486
history in, 486
magnetic resonance imaging in, 486
physical examination in, 486
radiography in, 486
surgical reconstruction in, 486495
clitoroplasty for, 487, 488f, 490494
cut-back vaginoplasty in, 487
flap vaginoplasty in, 488, 489f
in high vaginal confluence, 489f, 490493
labioplasty for, 490494, 493f
in low vaginal confluence, 488, 489f,
490, 493f
partial urogenital mobilization in, 488, 490f,
493494
philosophical considerations in, 486487
preparation for, 488490, 493f
pull-through vaginoplasty in, 488, 489f
results of, 494495
techniques of, 487488, 488t
815
816
Index
Urolithiasis (Continued)
radiography in, 62, 66f, 634635, 634f, 636f
ultrasonography in, 81, 81f, 634
site of, 631
staghorn, 646, 647f
stone analysis in, 637
stone composition in, 631, 632f, 633t
struvite, 631, 632f, 633t, 635, 636f, 637t
ultrasonography in, 634635, 635f
urethral, 657, 660661
uric acid, 632f, 633t, 635, 636f, 637t, 640
management of, 641
urinary diversion and, 638
urinary stasis and, 638
Uroplakin, 290291
Urothelium, in tissue engineering, 209
Urotherapy
in dysfunctional voiding, 377
in enuresis, 384
in non-neuropathic bladder dysfunction, 373375,
374f
in overactive bladder, 376
in voiding postponement, 377
Uterus
abnormalities of, 483, 483f
bicornuate, 503
duplication of, 503
cloacal exstrophy and, 412
fixation of, in bladder exstrophy patient, 406
septate, 503
Uterus didelphys, 483, 483f
Utricle, prostatic, 102103, 102f
laparoscopic excision of, 103, 103f
V
VACTERL association, 176t
abdominal radiography in, 66f
megalourethra in, 457458, 458f
Vagina
agenesis of, 500501
in androgen insensitivity syndrome, 500
in Mayer-Rokitansky-Kster-Hauser syndrome,
481482, 482f, 500501
nonsurgical treatment of, 501
atresia of, 482
bladder exstrophyrelated defects in, 389
construction/reconstruction of, 483486, 484t
Abbe-McIndoe procedure for, 484, 484f, 502
amnion for, 502
in bladder exstrophy, 406
carcinoma after, 485486
in cloacal exstrophy, 414
contracture after, 485
cut-back vaginoplasty in, 487, 488t
fasciocutaneous flaps for, 485
flap vaginoplasty in, 488, 488t, 489f, 490
Fogarty balloon catheterization in, 88, 89f
inflammation after, 486
intestine for, 484485, 485f, 502
laparoscopic, 102
long-term considerations in, 485486
myocutaneous flaps for, 485
outcomes of, 494495, 504506, 505f
parturition after, 485
peritoneum for, 502
progressive dilatation for, 484
pull-through vaginoplasty in, 488, 489f
Vecchietti operation for, 484, 501502
vulvovaginoplasty for, 484, 501, 501f
dilators for, 501
duplication of, 495496, 498, 503
Fogarty balloon catheterization of, 88, 89f
transverse septum of, 482483, 482f, 503504
Vaginal reflux, 69, 72f, 378
Vaginoplasty. See Vagina, construction/
reconstruction of
Vaginoscopy
in ambiguous genitalia, 88, 89f
in ectopic ureter, 350
Vanishing testis, 547, 567
Varicella-zoster infection, neurogenic bladder and, 173
Index
Vesicoureteral reflux (Continued)
pathophysiology of, 284291
in children, 290
genetic factors in, 285286
immature voiding dynamics and, 288, 288f
in infant, 288290, 288289f
infection and, 290
molecular aspects of, 290291
ureteric bud anomalies in, 285, 286f
urinary proteins in, 291
persistent
in peripubertal girls, 183
after ureteral reimplantation, 335336
urinary tract infection and, 183
PIC cystography in, 304
posterior urethral valves and, 438, 444, 444f
pregnancy and, 318
prenatal diagnosis of, 4647, 47f, 315316
prevalence of, 283284, 284285t
primary, 286
protein markers in, 304, 304t
in prune-belly syndrome, 427
race and, 306307
radionuclide cystography in, 301302, 303304f
renal agenesis and, 307
renal scarring and, 111, 184185, 291299, 291f,
305306. See also Renal scarring
secondary, 286
spontaneous resolution of, 286, 322323
sterile, 297
summary of, 299300
surgical treatment of, 322, 330
American Urological Association guidelines for,
318320, 319320t
complications of, 335336
cystoscopy before, 330
duplex ureters and, 334335
early obstruction after, 335
extravesical, 333334
exposure for, 333334, 333f
sutures for, 334, 334f
indications for, 330
intravesical, 330333
closure for, 333
Cohen cross-trigonal technique for, 331333,
332f
drainage after, 333
exposure for, 330331, 331f
Politano-Leadbetter technique for, 331
ureteral dissection for, 331, 331f
laparoscopic, 9798
extravesical, 97
intravesical, 9697f, 9899
robot-assisted, 107
management after, 334
vs. medical management, 308309
neocontralateral reflux after, 329
nursing interventions in, 200201
paraureteral diverticulum and, 335
persistent obstruction after, 335
persistent reflux after, 328329, 335336
positioning for, 330
reoperative, 335
results of, 322
into transplanted kidney, 318
ultrasonography in, 302304
prenatal, 4546, 46f, 315316
upper tract urodynamics in, 154155, 155f
ureterovesical junction in, 284286, 286f
urinary tract infection and, 182183, 185, 287, 290,
304307
experimental study of, 290
voiding cystourethrography in 302f, 63, 71f, 155f,
189190, 286287, 287f, 301. See also Voiding
cystourethrography
voiding dysfunction and, 185, 316317, 316f
voiding urosonography in, 67
Vesicourethral canal, 4
VHL, 667
Video-urodynamic study, 131137
abdominal pressure in, 132
in anorectal malformation, 788
bladder capacity in, 132
817
W
WAGR (Wilms tumor, aniridia, genitourinary
abnormalities, and mental retardation)
syndrome, 176177t, 462, 664, 665t, 671, 672t,
681682
Warts, 479f, 480
Water. See also Fluid(s); Fluid therapy
body, 24
Wegener granulomatosis, 235
Weigert-Meyer rule, 313314, 314f, 338, 339f
Weight, neonatal loss of, 24
Whitaker test, 149, 149f, 150t. See also Percutaneous
pressure
flow study
in megaureter, 276
White blood cell(s), urinary, in infection,
188, 188t
Williams-Beuren syndrome, 176177t
Williams syndrome, voiding cystourethrography
in, 68, 68f
Williams vulvovaginoplasty, 501, 501f
Wilms tumor, 663667, 671
adult, 682
age and, 665
anaplastic, 673, 673f
in Beckwith-Wiedemann syndrome, 671
bilateral, 674
imaging of, 674
treatment of, 679680, 680f
bone metastasis in, 679
bone scan in, 674
brain metastasis in, 679
-catenins in, 664
caval thrombus in, 673, 676677
chest radiography in, 674
chromosome 1p in, 663665, 664f
chromosome 16q in, 663665, 664f
clinical presentation of, 673, 673f
computed tomography in, 81, 82f, 674, 674675f,
680f
diagnosis of, 674, 674t
Doppler ultrasonography in, 6162, 65f
echocardiography in, 674
epidemiology of, 671
extrarenal, 673674
familial, 665
hepatic metastasis in, 679
in high-risk patient, 681682
histology of, 665
magnetic resonance imaging in, 81, 674, 675f
metastatic, 678679
molecular biology of, 663664
multicystic dysplastic kidney disease and, 223
pathogenesis of, 672, 673f
pathology of, 672673, 673f
positron emission tomography in, 674
prenatal diagnosis of, 682
prognosis for, 665, 680
pulmonary metastasis in, 678679
screening for, 681682
staging of, 665, 674675, 675t
survival rate in, 680
syndromic associations with, 664665, 665t, 671,
672f, 672t
818
Index
X
X-linked adrenal hypoplasia congenita, 464
Xanthine dehydrogenase deficiency, 640642
Xenobiotics, sex differentiation disorders and, 473
Y
Yolk sac, 1, 2f
Yolk sac tumor, 695698
Young-Dees-Leadbetter procedure, 398, 399f,
404405, 760763
modifications of, 763
results of, 762763
sugical technique for, 762
Z
Zellweger (cerebro-hepato-renal) syndrome, 43
Zipper injury, of foreskin, 522
Zygote, 1
P A R T
XI
Appendix
STANDARDS
David B. Joseph
e
STANDARDS
Name
Record number
Age (months)
36
35
34
33
32
31
30
Length
29
28
27
26
18
21
24
27
30
33
105
95
90
75
100
50
95
cm
90
25
10
5
18
80
17
75
16
90
70
15
75
37
in.
40
39
65
14
50
35
33
13
25
31
30
29
28
27
55
12
10
26
25
5
11
50
24
23
10
45
22
21
40
cm
20
19
18
17
16
15
kg
15
14
13
12
Weight
11
Mothers stature
Fathers stature
Date Age
Birth
10
9
8
7
6
5
4
lb
18
3
2
kg
B
12
Length
21
24
27
Age (months)
30
33
36
Gestational
age
weeks
Weight Head circ.
Comment
lb
Weight
60
37
32
15
in.
38
34
17
16
39
36
95
19
18
40
38
21
20
41
41
85
23
22
100
95
25
24
36
105
37
15
38
12
Length
39
*Adapted from Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: National
Center for Health Statistics percentiles. Am J Clin Nutr. 1979;32:607-629. Data from the Fels
Longitudinal Study, Wright State University School of Medicine, Yellow Springs, Ohio.
40
41
part
Name
XI: Appendix
e
Record number
Age (months)
B
21
12
15
18
21
24
27
30
33
54
53
53
95
90
51
50
75
50
25
10
5
49
19
48
47
18
46
51
20
50
49
48
19
47
in.
43
21
46
42
20
44
41
19
42
40
18
40
17
38
16
36
15
95
90
75
50
25
10
5
38
37
14
12
35
14
13
34
32
30
28
34
12
33
11
32
10
22
20
18
16
31
in. cm
26
24
14
lb
kg
kg
lb
12
10
8
6
cm
50
55
60
65
70
75
80
85
90
95
100
in. 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
Length
Date
Age
Birth
Length
Weight
Head circ.
Comment
12
10
8
6
Weight
13
36
15
39
16
*Adapted from Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth:
ational Center for Health Statistics percentiles. Am J Clin Nutr. 1979;32:
N
607-629. Data from the Fels Longitudinal Study, Wright State University School
of Medicine, Yellow Springs, Ohio.
44
17
Head circumference
52
46
cm
45
Weight
21
Head circumference
54
52
20
36
e
part
XI: Appendix
Name
Record number
Age (years)
15
16
17
18
160
10
5
155
cm
in.
145
95
210
140
90
135
85
Length
Stature
190
Comment
185
180
175
95
90
75
170
165
63
62
61
60
59
58
57
56
55
54
53
52
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
29
in.
160
10
155
150
95
130
80
125
75
lb
190
180
170
160
90
120
70
115
65
75
110
50
105
25
100
10
5
95
150
140
60
130
55
120
50
110
45
100
90
40
85
35
80
30
75
25
90
80
70
60
50
cm
20
40
30
200
15
15
kg
kg
18
10
Age (years)
11
12
13
14
15
16
17
40
30
lb
Weight
Weight
Stature
50
Stature
25
76
75
74
73
72
71
70
69
68
67
66
65
64
63
62
61
Date Age
14
13
*Adapted from Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: National Center
for Health Statistics percentiles. Am J Clin Nutr. 1979;32:607-629. Data from the National
Center for Health Statistics (NCHS), Hyattsville, Maryland.
12
11
Mothers stature
Fathers stature
part
XI: Appendix
e
Name
Record number
Date Age
51
Stature
Weight
50
Comment
110
49
48
105
47
46
45
100
44
43
95
42
41
90
40
95
39
85
38
37
90
36
80
33
65
30
29
28
60
27
27
10
Weight
50
45
40
35
30
25
lb
25
24
24
23
23
22
22
21
21
20
20
19
19
18
18
17
17
16
16
15
15
14
14
13
13
12
12
kg
kg
cm
in.
85
90
95
100
105
110
115
120
125
130
135
60
26
25
65
28
25
26
55
30
50
29
140
145
33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
Stature
55
50
45
40
35
30
25
lb
70
31
Weight
32
75
75
34
*Adapted from Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: National Center
for Health Statistics percentiles. Am J Clin Nutr. 1979;32:607-629. Data from the National
Center for Health Statistics (NCHS), Hyattsville, Maryland.
35
e
part
XI: Appendix
Name
Record number
Age (months)
36
35
34
33
32
31
30
Length
29
28
27
26
18
21
24
27
30
33
105
95
90
100
50
95
95
25
10
5
90
cm
18
85
17
16
75
15
70
37
in.
40
39
14
65
35
33
13
60
10
5
31
30
29
28
27
12
26
25
11
50
24
23
10
45
22
21
40
cm
20
19
18
17
16
15
kg
15
14
13
12
Weight
11
Mothers stature
Fathers stature
Date Age
Birth
10
9
8
7
6
5
4
lb
18
3
2
kg
B
12
Length
21
24
27
Age (months)
30
33
36
Gestational
Age
weeks
Weight Head circ.
Comment
lb
Weight
25
55
37
32
50
15
in.
38
34
75
17
16
39
36
90
19
18
40
38
95
80
21
20
41
41
23
22
100
75
25
24
36
105
37
15
38
12
Length
39
*Adapted from Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: National
enter for Health Statistics percentiles. Am J Clin Nutr. 1979;32:607-629. Data from the Fels
C
Longitudinal Study, Wright State University School of Medicine, Yellow Springs, Ohio.
40
41
part
Name
XI: Appendix
e
Record number
Age (months)
12
15
18
21
24
27
30
33
36
54
54
21
95
90
75
52
20
51
50
25
10
5
50
49
19
18
48
51
20
50
49
48
19
47
46
46
cm
in.
43
21
46
42
20
44
41
19
42
40
18
40
17
38
16
36
39
15
95
90
75
50
25
10
5
38
37
14
12
35
14
13
34
32
30
28
34
12
33
11
32
10
22
31
20
18
16
in. cm
26
24
14
lb
kg
kg
lb
12
10
8
6
cm
50
55
60
65
70
75
80
85
90
95
100
in. 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
Length
Date
Age
Birth
Length
Weight
Head circ.
Comment
12
10
8
6
Weight
13
36
15
*Adapted from Hamill PVV, Drizd TA, Johnson CL, et al. Physical
growth: National Center for Health Statistics percentiles. Am J
Clin Nutr. 1979;32:607-629. Data from the Fels Longitudinal Study,
Wright State University School of Medicine, Yellow Springs, Ohio.
16
44
17
Head circumference
52
47
45
Weight
21
Head circumference
53
53
e
part
XI: Appendix
Name
Record number
Age (years)
11
Mothers stature
Fathers stature
Date Age
Length
Stature
12
13
14
15
16
17
18
cm
in.
95
210
190
Comment
95
90
185
75
180
50
175
25
170
10
160
10
160
155
150
145
95
140
135
90
130
90
85
80
180
160
70
50
115
65
150
140
110
25
60
130
105
10
55
120
50
110
95
45
100
90
40
85
35
80
30
75
25
100
90
80
70
60
50
cm
20
15
15
kg
kg
18
10
Age (years)
11
12
13
14
15
16
17
40
30
lb
120
75
75
Center for Health Statistics percentiles. Am J Clin Nutr. 1979;32:607-629. Data from the
National Center for Health Statistics (NCHS), Hyattsville, Maryland.
lb
190
170
125
40
30
200
63
62
61
60
59
58
57
56
55
54
53
52
51
50
49
48
47
46
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
29
in.
165
Weight
Weight
Stature
Stature
155
76
75
74
73
72
71
70
69
68
67
66
65
64
63
62
61
part
XI: Appendix
e
Name
Record number
Date Age
51
Stature
Weight
50
Comment
110
49
Birth
48
105
47
46
95
45
100
44
43
95
42
90
41
90
40
39
85
38
75
37
36
80
35
50
34
75
33
55
Weight
50
45
40
35
30
25
lb
10
30
29
29
28
28
27
27
26
26
25
25
24
24
23
23
22
22
21
21
20
20
19
19
18
18
17
17
16
16
15
15
14
14
13
13
12
12
kg
kg
cm
in.
85
90
95
100
105
110
115
120
125
130
135
140
145
33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
Stature
65
60
55
50
45
40
35
30
25
lb
60
30
*Adapted from Hamill PVV, Drizd TA, Johnson CL, et al. Physical growth: National
enter for Health Statistics percentiles. Am J Clin Nutr. 1979;32:607-629. Data from the
C
National Center for Health Statistics (NCHS), Hyattsville, Maryland.
65
70
31
Weight
32
25
e10
part
XI: Appendix
STANDARDS
Hypertension Definitions
Age (yr)
0.5
6.15 0.67
Term
Definition
6.65 0.54
Normal BP
7.36 0.54
High normal
BP*
7.36 0.64
7.87 0.50
8.09 0.54
7.83 0.72
High BP
Average systolic or average diastolic BP (or
(hypertension)
both) >95th percentile for age and sex with
measurements obtained on at least 3 occasions
*If
the BP reading is high normal for age, but can be accounted for by
e xcess height for age or excess lean body mass for age, such children are
considered to have normal BP.
BP, blood pressure.
From Report of the Second Task Force on Blood Pressure Control in
Children1987. Pediatrics. 1987;79:1.
8.33 0.51
8.90 0.88
9.20 0.90
10
9.17 0.82
11
9.60 0.64
12
10.42 0.87
13
9.79 0.75
14
10.05 0.62
15
10.93 0.76
16
10.04 0.86
17
10.53 0.29
18
10.81 1.13
Mean (cm)/SD
0.5
5.63 0.42
6.26 0.63
Severe
Hypertension
(mm Hg)
6.65 0.55
Age Group
Significant
Hypertension
(mm Hg)
6.97 0.64
Newborn7 days
Systolic BP >96
Systolic BP >106
7.22 0.66
7.63 0.53
8-30 days
Systolic BP >104
Systolic BP >110
Infants <2 yr
Systolic BP >112
Systolic BP >118
8.11 0.52
Diastolic BP >74
Diastolic BP >82
8.14 0.76
Systolic BP >116
Systolic BP >124
8.23 0.76
Diastolic BP >76
Diastolic BP >84
8.95 0.90
Systolic BP >122
Systolic BP >130
10
9.09 0.73
Diastolic BP >78
Diastolic BP >86
11
9.34 1.30
Systolic BP >126
Systolic BP >134
12
9.64 0.90
Diastolic BP >82
Diastolic BP >90
13
9.83 0.66
Systolic BP >136
Systolic BP >144
14
10.09 1.10
Diastolic BP >86
Diastolic BP >92
15
9.71 0.86
Systolic BP >142
Systolic BP >150
16
10.21 0.93
Diastolic BP >92
Diastolic BP >98
17
10.04 1.02
18
10.28 1.13
19
10.23 1.00
Children 3-5 yr
Children 6-9 yr
Children 10-12 yr
Adolescents 13-15 yr
Adolescents 16-18 yr
From Gross GW, Boal DK. Sonographic assessment of normal renal size in
children with myelodysplasia. J Urol. 1988;140:784.
part
XI: Appendix
e11
Ureter only
Grade II
Grade III
Grade IV
Grade V
Gross dilation and tortuosity of ureter; gross dilation of renal pelvis and calyces; papillary impressions are no longer visible in most calyces
Description
Image
Further dilation of pelvis and calyces; calyces may appear convex; thin
renal parenchyma
From Maizels M, Reisman ME, Flom S, et al. Grading nephroureteral dilatation detected in the first year of life: correlation with obstruction. J Urol. 1992;148:609-614.
Ureteral Diameter
<7 mm
7 10 mm
>10 mm
e12
part
XI: Appendix
Genitals
Pubic Hair
Stage
Breast
Pubic Hair
None
Elevation of papilla
None
II
II
III
III
Further development of
breast and areola, no
separation of their contours
IV
IV
Adult quality,
distribution inverse,
triangular spread to
medial thighs
Penile Length
Stretched penile
length (cm)
Mean
2.5 SD
10
8
6
4
2
0
10
12
Age (yr)
14
16
18
20
Testicular Size
Age (yr)
Tanner Stage
Volume (mL)
Length (cm)
1.4 0.4
1.4 0.4
1.5 0.6
1.8 0.3
2 0.5
10
II
2.7 0.7
12
III
3.4 0.8
10
14
IV
4.1 1
20
16
5 0.5
29
5 0.5
29
18
Based on Keefer JR. Endocrinology. In: Siberry GK, Iannone R, eds. The
Harriet Lane Handbook. St. Louis: Mosby; 2000.
part
EQUATIONS
XI: Appendix
e13
Water
Electrolytes
First 10 kg
100 mL/kg/24 hr =
4 mL/kg/hr
Second 10 kg
50 mL/kg/24 hr = 2 Cl 2
mg/kg/hr
Additional kg
20 mL/kg/24 hr = 1 K+ 2
mg/kg/hr
*>14
days of age.
From Choukair MK. Fluids and electrolytes. In: Siberry GK, Iannone R, eds.
The Harriet Lane Handbook. St. Louis: Mosby; 2000.
Creatinine Clearance
Creatinine clearance = Ccr
Ccr (mL/min/1.73 m2) = (U V/P) 1.73/BSA
U (mg/dL) = urinary creatinine concentration
V (mL/min) = total urine (mL) time collected (min)
P (mg/dL) = serum creatinine concentration
BSA (m2) = body surface area
Mean (mL/
min/1.73 m2)
Age
Range (mL/
min/1.73 m2)
Neonates <34 wk
gestational Age
2-8 days
11
11-15
4-28 days
20
15-28
30-90 days
50
40-65
2-8 days
39
17-60
4-28 days
47
26-68
30-90 days
58
30-86
1-6 mo
77
39-114
6-12 mo
103
49-157
12-19 mo
127
62-191
2 yradult
127
89-165
Neonates >34 wk
gestational Age
Bladder Capacity
Age + 2 = oz ( 30) = mL*
<2 yr
>2 yr
From Barratt TM, Auner ED, Harmon WE. Pediatric Nephrology. 4th Ed.
Philadelphia: Lippincott Williams & Wilkins; 1999.
K = constant
K Values
Low-birth-weight infants: 0.33
Full-term infants: 0.45
Children: 0.55
-Fetoprotein
Synonyms: AFP
Reference Range: <8.5 ng/mL
From Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and
adolescents. Pediatr Clin North Am. 1987;34:571.
e14
part
XI: Appendix
Androstenedione
Reference Range: See the following table
Use: Evaluation of hirsutism or virilization, evaluation of androgen
production and metabolism
Androstenedione, Serum
Age
Premature infants
Full-term infants
1-7 days
1-12 mo
6-68 (mean 23); androstenedione gradually decreases during the first 6 mo to prepubertal levels
Puberty
Male
Female
Tanner Stage
Age (yr)
ng/dL
Age (yr)
ng/dL
<9.8
<9.2
II
9.8-14.5
9.2-13.7
III
10.7-15.4
10-14.4
IV
11.8-16.2
10.7-15.6
12.8-17.3
11.8-18.6
Creatinine, Blood
Reference Range: 0-2 yr, 0.2-0.6 mg/dL; 8 yr, 0.3-0.7 mg/dL; 11-13
yr, 0.4-0.8 mg/dL; 14-17 yr, 0.4-0.9 mg/dL; >16 yr, 0.7-1.5 mg/dL
Age
1-7 days
1-5 yr
Male (g/dL)
Female (g/dL)
184-305
133-394
0-36
0-57
6-10 yr
13-83
19-114
11-15 yr
32-305
32-229
16-20 yr
121-368
44-248
part
Deoxycorticosterone
XI: Appendix
e15
Dihydrotestosterone
Synonyms: DOC
Estradiol, Serum
Deoxycorticosterone, Serum
Age
ng/dL
Cord blood
Newborns
Prepubertal children
(2-10 yr)
Estradiol, Serum
Age
ng/dL
Cord blood
Estradiol levels markedly elevated at birth and decrease rapidly during the first week to prepubertal values
1-6 mo
Male
Female
Prepubertal children
(1-10 yr)
<1.5
Puberty
Male
Female
Tanner Stage
Age (yr)
ng/dL
Age (yr)
ng/dL
<9.8
<9.2
II
9.8-14.5
9.2-13.7
III
10.7-15.4
10-14.4
IV
11.8-16.2
10.7-15.6
12.8-17.3
11.8-18.6
Adults
0.8-3.5 (mean 2)
e16
part
XI: Appendix
Estrogens, Serum
Reference Range: See the following table
Use: Evaluation of ovarian estrogen-producing tumors, evaluation
of estrogen excess in males
Estrogens, Serum
Age
ng/dL
Cord blood
Estrogens markedly elevated at birth and decrease rapidly during first week to reach prepubertal
levels by 7 days
1-6 mo
Levels increase in early infancy to a range of 1-4 ng/dL in males and 1-6 ng/dL in females between
30-60 days
<2.5
Puberty
Male
Female
Tanner Stage
Age (yr)
ng/dL
Age (yr)
ng/dL
<9.8
1-3.8 (mean 2)
<9.2
II
9.8-14.5
1.7-4.5 (mean 3)
9.2-13.7
III
10.7-15.4
10-14.4
IV
11.8-16.2
10.7-15.6
12.8-17.3
2.5-8 (mean 5)
11.8-18.6
Adults
Follicle-Stimulating Hormone
Synonyms: FSH
Reference Range: See the following table
Use: Evaluation of neuroendocrine gonadal function
Additional Information: Low or normal in hyperpituitarism,
Kallmanns syndrome, isolated gonadotropin deficiency,
delayed puberty, and Stein-Leventhal syndrome. Normal or
increased in cryptorchidism, azoospermia and oligospermia,
and complete testicular feminization. High in primary testicular
failure, anorchia, Klinefelters syndrome, Turner syndrome, and
idiopathic or central nervous system lesions causing precocious
puberty. Low in precocious puberty related to adrenal tumors or
congenital adrenal hyperplasia.
part
XI: Appendix
e17
mIU/mL
Cord blood
<1
2 wk2 yr
Male
Female
Prepubertal children
Puberty
Male
Female
Tanner Stage
Age (yr)
ng/dL
Age (yr)
ng/dL
<9.8
<9.2
II
9.8-14.5
9.2-13.7
III
10.7-15.4
10-14.4
1.5-9 (mean 5)
IV
11.8-16.2
2-8 (mean 6)
10.7-15.6
12.8-17.3
11.8-18.6
Adults
Growth Hormone
Synonyms: Arginine stimulation; HGH; human growth hormone;
levodopa stimulation
Reference Range: Children (overnight fast), <16 ng/mL; newborns,
<140 ng/mL
Additional Information: Marked fluctuations in HGH
concentration occur in normal individuals; random sampling
does not give useful information
17-Hydroxycorticosteroids, Urine
Synonyms: 17-OHCS
Reference Range: Male, 3-12 mg/24 hr; female, 2-8 mg/24 hr
Use: Evaluation of glucocorticoid production
17-Hydroxypregnenolone
Synonyms: 17-OH Preg
Reference Range: See the following table
Use: Evaluation of adrenal function, especially 17-desmolase deficiency in congenital adrenal hyperplasia
17-Hydroxypregnenolone
Human Chorionic Gonadotropin, Beta Subunit
Age
ng/dL
Cord blood
50-2121
Premature infants
64-2380
3 days
10-829
Use: Detection of early pregnancy, ectopic pregnancy, or a threatened abortion. Elevated levels are found in choriocarcinoma and
embryonal cell carcinoma.
1-6 mo
36-763
6-12 mo
42-540
Additional Information: Various poorly differentiated or undifferentiated neoplasms produce ectopic chorionic gonadotropin,
including choriocarcinoma, hydatidiform mole, and germinal
testicular tumors.
15-221
44-235
Adults
53-357
Full-term infants
e18
part
XI: Appendix
17-Hydroxyprogesterone
Synonyms: 17-OHP
Reference Range: See the following table
Use: Assess congenital adrenal hyperplasia caused by inadequate
levels of 21-hydroxylase or 11--hydroxysteroid dehydrogenase
or both
17-Hydroxyprogesterone
Age
ng/dL
Cord blood
Premature infants
1-12 mo
Male
Female
Levels increase after the first week to peak values 40200 ng/dL between 30-60 days. Values then decline
to prepubertal range before 1 yr
Puberty
Male
Female
Tanner Stage
Age (yr)
ng/dL
Age (yr)
ng/dL
<9.8
<9.2
II
9.8-14.5
9.2-13.7
III
10.7-15.4
10-14.4
IV
11.8-16.2
10.7-15.6
12.8-17.3
11.8-18.6
Adults
17-Ketosteroids (17-KS)
Age (yr)
mg/24 hr
mg/g Creatinine
Children
1-4
<1-2
5-9
10-12
12-14
Male (15-25)
Female (15-25)
Not determined
Adults
Male
Female
part
XI: Appendix
e19
mIU/mL
Newborns (1 wk)
2 wk1 yr
Male
Female
Prepubertal children
Puberty
Male
Tanner Stage
Female
Age (yr)
ng/dL
Age (yr)
ng/dL
<9.8
<9.2
II
9.8-14.5
9.2-13.7
<1-5 (mean 3)
III
10.7-15.4
2-10 (mean 4)
10-14.4
IV
11.8-16.2
10.7-15.6
12.8-17.3
11.8-18.6
Adults
Pregnenolone
Reference Range: See the following table
Use: Evaluation of adrenal function, particularly in
17-hydroxylase deficiency in congenital adrenal hyperplasia
Pregnenolone
Age
ng/dL
150-2000 (mean 650); levels decrease after birth and are within
prepubertal range by 3 mo
Adults
e20
part
XI: Appendix
Progesterone, Serum
Reference Range: See the following table
Use: Evaluation of ovarian function
Additional Information: Increased in choriocarcinomas, ovarian Sertoli-Leydig cell tumors, adrenal cortical hyperfunction,
ovarial (luteal) cysts, hydatidiform mole, and pregnancy
Progesterone, Serum
Age
ng/dL
Premature infants
Progesterone levels markedly elevated in neonates, but decrease rapidly to reach prepubertal
levels by 7 days and remain steady until puberty
Puberty
Male
Female
Tanner Stage
Age (yr)
ng/dL
Age (yr)
ng/dL
<9.8
<9.2
II
9.8-14.5
9.2-13.7
III
10.7-15.4
10-14.4
IV
11.8-16.2
10.7-15.6
12.8-17.3
11.8-18.6
Adults
Testosterone, Free
Reference Range: See the following table
Use: Evaluation of hirsutism and masculinization in females;
evaluation of testicular function
Additional Information: Free testosterone is usually increased in
hirsute women.
Testosterone, Free
Male
Age
Female
% Free
pg/mL
% Free
pg/mL
1-15 days
0.9-1.7
1.5-31
0.8-1.5
0.5-2.5
1-3 mo
0.4-0.8
3.3-18
0.4-1.1
0.1-0.3
3-5 mo
0.4-1.1
0.7-14
0.5-1
0.2-1.1
5-7 mo
0.4-1
0.4-4.8
0.5-0.8
0.2-0.6
Prepubertal children
0.4-0.9
0.15-0.6
0.4-0.9
0.15-0.6
Adults
1.5-3.2
52-280
0.8-1.4
1.1-6.3
Infants
part
XI: Appendix
e21
Testosterone, Serum
Reference Range: See the following table
Use: A reliable indicator of luteinizing hormone secretion and
Leydig cell function; evaluation of gonadal and adrenal function; diagnosis of hypogonadism in males and hirsutism and
virilization in females
Additional Information: Testosterone level is normal or decreased in hypopituitarism, Kallmanns syndrome, isolated
gonadotropin deficiency, and Klinefelters syndrome. Normal
in cryptorchidism, azoospermia, and oligospermia. Decreased
in delayed puberty, primary testicular failure, and anorchia.
Normal or increased in testicular feminization. Increased in precocious puberty related to idiopathic or central nervous system
lesions, adrenal tumors, or congenital adrenal hyperplasia.
Testosterone, Serum
Age
Male (ng/dL)
Female (ng/dL)
Premature infants
Full-term newborns
1-7 mo
Puberty
Male
Female
Tanner Stage
Age (yr)
ng/dL
Age (yr)
ng/dL
<9.8
<9.2
II
9.8-14.5
9.2-13.7
III
10.7-15.4
10-14.4
IV
11.8-16.2
10.7-15.6
12.8-17.3
11.8-18.6
Adults
Synonyms: BUN
Synonyms: VMA
e22
part
XI: Appendix
Pathologic
Nonpathologic
Color
Pathologic
Nonpathologic
White
Bacteria
Phosphates
Pyridium
Chyle
Urates
Senna
Pus
Colorless to pale
yellow
Port wine
Chronic nephritis
Decreased normal
pigment
Diabetes
Dilute urine
Diuresis
Yellow to amber
Bilirubin
Porphobilinogen
Uroporphyrin
Brown to black
Normal pigments
Urobilin
Orange
Acriflavine
Azo Gantrisin
Carrots or vitamin A
Bilirubin
Chloroquine
Homogentisic acid
Hydroquinone
Indican
Iron compounds
Melanin
Levodopa
Methemoglobin
Methyldopa
Myoglobin
Metronidazole
Food color
p-Hydroxyphenylpy- Nitrofurantoin
ruvic acid
Nitrofurantoin
Phenol
Pyridium
Serotonin
Sulfasalazine
Pink to red
Porphobilin
Hemoglobin
Aminopyrine
Myoglobin
Antipyrine
Porphobilin
Beets (anthocyanin)
Porphyrins
Bromosulfophthalein
Cascara
Phenytoin
Food color
Methyldopa
Blue to green
Quinine
Porphyrins
Resorcinol
Biliverdin
Acriflavine
Pseudomonas infection
Amitriptyline
Azure A
Creosote
Evans blue
Indigo pigment
Methylene blue
Phenylsalicylate
Thymol
Phenacetin
Tolonium
Phenolphthalein
Triamterene
Phenolsulfophthalein
Vitamin B complex
Phenothiazine
part
FORMULARY
Generic Name: Acetaminophen
Trade Name: Tylenol, Tempra, Panadol, Feverall
Drug Class: Analgesic, antipyretic
Use: Control of fever and pain
Cautions: Renal
Dosing: Pediatric: 10-15 mg/kg/dose q 4-6 hr PO/PR
Forms: Infant drops: 80 mg/0.8 mL
Childrens solution/suspension: 160 mg/5 mL
Elixir: 80, 120, 160, 325 mg/5 mL
Sprinkle capsules: 80, 160 mg
Suppositories: 80, 120, 125, 325, 650 mg
Chewable tabs: 80, 160 mg; tabs: 160, 325, 500,
650 mg
Generic Name: Amikacin sulfate
Trade Name: Amikin (Amiklin [France]; Amikin [UK])
Drug Class: Aminoglycoside
Use: Antibiotic
Cautions: Renal, pregnancy
Dosing: Infants and children: 15-22.5 mg/kg/24 hr q 8 hr
IV/IM
Initial maximum dose: 1.5 g/24 hr
Therapeutic levels: peak 20-30 mg/L; trough 5-10
mg/L
Neonates: 30-36 wk gestational age: 10 mg/kg/dose
q 24 hr
Neonates: >37 wk gestational age, <7 days: 7.5 mg/
kg/dose q 12 hr
Neonates: >7 days: 7.5 mg/kg/dose q 8 hr
Generic Name: Amoxicillin
Trade Name: Amoxil, Trimox, Wymox, Polymox (A-Gram,
Amodex [France]; Amoxil, Almodon [UK])
Drug Class: Aminopenicillins
Use: Antibiotic
Cautions: Renal
Dosing: 20-50 mg/kg/24 hr tid PO
Forms: Drops: 50 mg/kg/mL
Suspension: 125, 250 mg/5 mL
Caps: 250, 500 mg
Chewable tabs: 125, 250 mg
Generic Name: Amoxicillin-clavulanic acid
Trade Name: Augmentin (Augmentin [France]; Augmentin
[UK])
Drug Class: Aminopenicillins, -lactamase inhibitor
Use: Antibiotic
Cautions: Renal
Dosing: <3 mo: 30 mg/kg/24 hr bid PO
>3 mo: 20-40 mg/kg/24 hr tid PO
Forms: Tabs: 250, 500 mg (with 125 mg clavulanate)
Chewable tabs: 125, 250 mg amoxicillin (31.25 and 62.5
mg clavulanate)
Suspension: tid dose 125, 250 mg amoxicillin/5 mL
(31.25 and 62.5 mg clavulanate)
Suspension: bid dose 200, 400 mg amoxicillin/5 mL
(28.5 and 57 mg clavulanate)
Generic Name: Amphotericin B
Trade Name: Fungizone, Amphocin (Fungizone [France];
Abelcet, Ambisome, Fungizone [UK])
Drug Class: Antifungal
Use: Intravesical irrigation
Dosing: 50 mg amphotericin B in 1 L sterile water for urinary
irrigation only
XI: Appendix
e23
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XI: Appendix
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XI: Appendix
e25
e26
part
XI: Appendix
part
XI: Appendix
e27
e28
part
XI: Appendix
part
XI: Appendix
e29