Core Concepts: Neonatal Glomerular Filtration Rate

Sharon W. Su and Barbara S. Stonestreet

NeoReviews 2010;11;e714-e721
DOI: 10.1542/neo.11-12-e714

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Article core concepts

Core Concepts: Neonatal Glomerular Filtration Rate

Sharon W. Su, MD,*
Barbara S. Stonestreet, MD† Abstract
Although the placenta is the primary organ responsible for fetal clearance and electrolyte
homeostasis, fetal kidneys contribute to amniotic fluid production and fetal hemodynam-
Author Dislosure
ics. Maternal factors can significantly influence fetal urinary output and blood pressure.
Drs Su and Maturation of neonatal glomerular filtration rate (GFR) depends on the development of
Stonestreet have renal blood flow (RBF). After birth, a marked increase in systemic blood pressure and
disclosed no financial decrease in renal vascular resistance results in elevated RBF and consequent increases in
relationships relevant GFR. Vasoactive factors, including renin, angiotensin II, glucocorticoids, nonsteroidal
anti-inflammatory drugs, nitric oxide, prostaglandins, bradykinin, and endothelin, each
to this article. This
play vital roles in the regulation and development of neonatal GFR. Prematurity and
commentary does
intrauterine growth restriction (IUGR) may affect renal endowment and place infants at
contain a discussion risk for hypertension and accelerated loss of renal function later in life.
of an unapproved/
investigative use of a
commercial product/ Objectives After completing this article, readers should be able to:
device.
1. Describe renal development and the changes in GFR and RBF from in utero to birth.
2. Recognize the differences in the rate of GFR maturation between preterm and term
infants.
3. Review the concept of single-nephron GFR.
4. Identify factors that regulate GFR and RBF in neonates.
5. Explain how medications such as angiotensin-converting enzyme (ACE) inhibitors,
glucocorticoids, and indomethacin alter neonatal GFR.
6. Discuss the long-term prognosis of GFR in infants born preterm or with IUGR.

Renal Development
Human kidneys are derived from three embryologic units: pronephros, mesonephros, and
metanephros. The first two eventually involute; the latter leads to the development of the
mature kidney. The formation of the pronephros occurs at 2 to 3 weeks of gestation,
followed by the mesonephros, which appears at 4 to 5 weeks of gestation. However, the
first glomeruli do not develop until 9 weeks’ gestation. The metanephros consists of two
portions: the metanephric blastema and the ureteric bud. The glomeruli, proximal tubules,
loop of Henle, and the early part of the distal tubule arise from the metanephric blastema
(Fig. 1). The calyces, pelvis, and collecting ducts arise from the ureteric buds. Nephro-
genesis is complete by 34 to 36 weeks’ gestation, resulting in 0.7 to 1 million nephrons per
kidney. Maturation of the nephrons begins in the juxtaglomerular region, extending
outward toward the renal cortex. (1)(2)
Urine production begins at 10 to 12 weeks’ gestation. A total of 5 mL/hour of urine is
produced by 20 weeks’ gestation, which comprises 90% of the amniotic fluid volume by
this gestational age. The urine production rate continues to increase with gestational age,
reaching 50 mL/hour by 40 weeks of gestation. Thus, fetal oliguria during the second
trimester can lead to pulmonary hypoplasia and oligohydramnios sequence. (3)

*Division of Pediatric Nephrology, Department of Pediatrics, Hasbro Children’s Hospital, The Warren Alpert Medical School of
Brown University, Providence, RI.
†
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Women and Infants Hospital of Rhode Island, The Warren
Alpert Medical School of Brown University, Providence, RI.

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 core concepts glomerular filtration rate

Renal Blood Flow

The maturational increases in RBF contribute to the
maturation of neonatal GFR. Although adult kidneys
receive 20% to 25% of cardiac output, kidneys in the fetus
receive 3% to 4% and in 1-week-old infants receive 8% to
10% of cardiac output. The developmental increase in
the proportion of cardiac output distributed to the kid-
neys correlates with the growth-related redistribution of
RBF from the medulla (deepest portion of kidney) to the
outer cortex because renal growth occurs centrifugally.
RBF is 20 mL/min at 25 weeks and increases to 50 to
60 mL/min by 40 weeks of gestation. These findings
were based on measurements of para-aminohippurate
clearance, which traditionally has been used as a marker
to measure effective RBF because such clearance is clin-
ically feasible to use in humans. RBF doubles by 2 weeks Figure 1. Renal morphogenesis. The metanephric blastema
of age and reaches mature levels by 2 years of age. RBF is develops into the glomeruli, proximal tubules, loop of Henle,
dependent on two major factors: 1) renal perfusion pres- and the early part of the distal tubule. The ureteric bud
develops into the calyces, pelvis, and collecting ducts. Re-
printed with permission from Dressler GR. The cellular basis
of kidney development. Annu Rev Cell Dev Biol. 2006;22:
509 –529.
Abbreviations
ACE: angiotensin-converting enzyme
AII: angiotensin II sure, which is approximately equal to systemic arterial
AT1: angiotensin type-1 blood pressure; and 2) renal vascular resistance (RVR),
AT2: angiotensin type-2 which is regulated by renal afferent and efferent arte-
BK: bradykinin rioles. (4)(5)(6)(7)
COX-2: cyclooxygenase-2 In neonates, renal perfusion pressure is low and RVR
D1: dopamine receptor 1 is high, resulting in low RBF. Fetal RBF can be affected
D2: dopamine receptor 2 by several maternal factors, such as maternal hydration
ET: endothelin status, maternal medications, and vasoactive substances
GFR: glomerular filtration rate that cross the placenta. For example, when hypotonic
IUGR: intrauterine growth restriction fluids were given to pregnant women, maternal serum
K f: glomerular capillary ultrafiltration coefficient osmolality decreased and fetal urinary output conse-
NO: nitric oxide quently increased. (8) When pregnant sheep were given
PBS: Bowman space or proximal tubule hydraulic pressure intravenous indomethacin, fetal RBF, GFR, and urine
PGC: glomerular capillary hydraulic pressure production decreased. (9) Basal production of nitric
PG: prostaglandin oxide (NO) in third-trimester fetal sheep maintained
Q A: glomerular plasma flow rate RBF by inducing renal vasodilation. Blockade of NO
RAS: renin-angiotensin system
production increased fetal RVR by 50%. (10)
RBF: renal blood flow
After birth, RBF progressively increases as renal per-
RVR: renal vascular resistance
fusion pressure increases and RVR decreases. The larger
SCr: serum creatinine
fraction of cardiac output distributed to the kidneys
SNGFR: single-nephron glomerular filtration rate
contributes to the higher renal perfusion pressures. The
TGF: tubuloglomerular feedback
decline in RVR can be attributed to increases in both the
⌬P: mean glomerular transcapillary hydraulic
pressure difference
diameter and the total number of renal blood vessels and
⌬␲: mean oncotic pressure difference
to the production of vasoactive factors, such as angio-
␲A: afferent arteriolar plasma oncotic pressure tensin II (AII), catecholamines, prostaglandins (PGs),
and NO. (5)(6)(7)

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core concepts glomerular filtration rate
Glomerular Filtration Rate
A nephron is comprised of the glomerulus (filtration) and
the tubules (secretion and reabsorption). Each nephron has
its own GFR, known as the single-nephron glomerular
filtration rate (SNGFR). Multiplying SNGFR by the total
number of nephrons determines overall GFR. SNGFR is
dependent on four factors:
1. Mean glomerular transcapillary hydraulic pressure
difference [⌬P⫽(PGC) ⫺ (PBS)]
2. Afferent arteriolar plasma oncotic pressure (␲A)
3. Glomerular plasma flow rate (QA)
4. Glomerular capillary ultrafiltration coefficient
(Kf⫽k ⫻ S)
where PGC⫽glomerular capillary hydraulic pressure,
PBS⫽Bowman space or proximal tubule hydraulic pres-
sure, k⫽permeability of glomerular capillary to water,
and S⫽total surface area available for filtration.
Therefore, SNGFR can be mathematically expressed
as:
SNGFR⫽Kf ⫻ (⌬P ⫺ ⌬␲)⫽Kf ⫻ PUF
where ⌬P⫽mean glomerular transcapillary hydraulic
pressure difference, ⌬␲⫽mean oncotic pressure differ-
ence, Kf⫽glomerular capillary ultrafiltration coefficient,
and PUF⫽glomerular capillary ultrafiltration pressure.
Increases in ⌬P, QA, and Kf increase GFR; increases in
␲A decrease GFR. In young developing rats, marked
increases in QA and Kf were associated with increases in
SNGFR. Furthermore, increases in QA correlated with a
60% reduction in afferent and efferent arteriolar resis-
tances. (11) In other animal studies, QA increased three-
fold and significantly contributed to GFR maturation.
Both PGC and PBS increase with age, with an overall net
effect of increasing ⌬P. However, the contribution of
⌬P to increasing GFR is only about 10% to 15%. Kf may
play a greater role in GFR development; one study
demonstrated a 57% increase in Kf when comparing fetal
sheep to young lambs. The increase in Kf is postulated to
result from greater glomerular surface area and not from
increased permeability. The glomerular surface area is
increased by the recruitment of glomeruli located in the
outer cortex of fetal kidneys. (12) Therefore, the post-
natal combination of increases in systemic arterial blood
pressure and reductions in RVR alters factors involved in
the regulation of SNGFR. These changes in SNGFR
then result in increased GFR.
GFR in the fetus correlates with both gestational age
and body weight and parallels the increase in renal mass.
Fetal GFR is low, even when corrected for body size.
Three- to fivefold increases in GFR occur around 34 weeks
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of gestation, coinciding with the completion of nephro-
genesis by 36 weeks. Neonates born before 34 weeks of
gestation experience this same phenomenon when they
reach the corrected age of 34 weeks of gestation. (1)(6)
After birth, GFR continues to correlate directly with
gestational age and postnatal age. (13)(14)(15) In term
infants, GFR doubles after 2 weeks of age, reaching adult
levels by 2 years of age. (5) This rate of GFR maturation
is markedly diminished in preterm infants. (13)(16) GFR
in preterm infants eventually achieves adult levels, but
the interval to reach the mature GFR remains uncertain
because limited comparative studies exist. In one study,
Vanpee and colleagues (16) demonstrated that GFR in
preterm babies remained lower at 9 months corrected
age than in term infants of the same postconceptual age
(82⫾23 mL/min/1.73m2 and 125⫾18 mL/min/1.73m2,
respectively). GFR in preterm infants did not reach nor-
mal mature levels until 8 years of age.
Although GFR rapidly increases after birth, serum
creatinine (SCr) concentrations in the newborn peak
during the first few postnatal days. Miall and associates
(17) demonstrated increasing SCr concentrations in the
first 48 hours after birth, especially in neonates born
before 30 weeks’ gestation. The peak and prolonged
increases and subsequent decreases in SCr were pro-
portional to the degree of prematurity. Gallini and col-
leagues (14) observed a similar inverse correlation be-
tween SCr concentration and gestational age of neonates.
In their study, SCr values increased during the first 36 to
96 hours after birth. Bueva and Guignard (13) reported
elevated SCr concentrations in 66 infants born at 28 to
40 weeks of gestation, with preterm infants having sig-
nificantly higher values compared with term infants. The
differences in SCr concentrations were not apparent by
3 weeks of age in the preterm and term infants. Among
neonates of lower gestational ages, the increases in SCr
were higher and the decreases more gradual. The initial
increases in SCr are a reflection of maternal SCr concen-
trations, reduced neonatal clearance resulting from im-
mature glomerular filtration, and reabsorption of filtered
creatinine in the leaky renal tubules of the neonates.
(17)(18) Thayyil and associates (19) recently published
reference ranges for SCr in preterm infants ages 25 to
28 weeks’ gestation. Stabilization of SCr occurred by
5 weeks of age.
Inulin clearance is the gold standard marker for assess-
ing GFR in children and adults because it is freely filtered
and not secreted or reabsorbed. However, measurement
of inulin clearance is tedious because a constant intrave-
nous infusion is required over 3 to 4 hours to maintain
constant inulin concentrations. Timed urinary and plasma
 core concepts glomerular filtration rate

Cystatin C is synthesized by all nucleated cells, freely

filtered through the glomerulus, and completely reab-
sorbed and catabolized by tubular cells. Serum concen-
trations obtained in preterm infants, children, or adults
are not affected by sex, height, or muscle mass. (5)
Reference ranges for plasma cystatin C measurements in
preterm infants, neonates, and older children were pub-
lished in 2000. (22)
In 1976, Schwartz and associates (23) derived and vali-
dated an uncomplicated formula to estimate GFR in chil-
dren by means of SCr and height measurements. Ten years
later, this group expanded this sentinel discovery to include
Figure 2. Serum creatinine values (mg/dL) during the first
3 postnatal months in preterm, low-birthweight infants (ges- preterm infants (Tables 1 and 2). (24) To this day, the
tational age range, 26 to 36 weeks; birthweight range, 515 to Schwartz equation remains the most widely used method
2,080 g). Reprinted with permission from Stonestreet and Oh. for assessing GFR by clinicians throughout the world:
(21)
GFR (mL/min/1.73m2)⫽(k ⫻ Ht) ⫼ SCr
samples are collected every 30 minutes. For younger
infants who cannot void on command, catheterization is where k⫽constant proportional to age and sex*,
necessary. In contrast, measuring SCr requires a simple Ht⫽height (cm), and SCr⫽serum creatinine (mg/dL)
blood sample determination, an easier, faster, and more
*Age k
cost-effective process. Consequently, it remains the pre-
ferred method for estimating GFR in the clinical setting. Low-birthweight infants ⱕ1 year 0.33
However, clinicians should note that when neonatal Term to 1 year 0.45
GFR is calculated from SCr, initial values reflect a com- 2 to 12 years 0.55
Female 13 to 21 years 0.55
bination of maternal SCr concentrations and neonatal Male 13 to 21 years 0.70
tubular reabsorption from leaky, immature tubules.
Stonestreet and colleagues (20) compared endogenous
creatinine clearance to inulin clearance in neonates born Renal Autoregulation
at 30 to 36 weeks of gestation. They demonstrated that Adult human kidneys possess the ability to maintain
endogenous creatinine clearance was a good estimation constant RBF and GFR during changes in renal perfu-
of inulin clearance, but there was overestimation of this sion pressures. Two mechanisms are postulated to par-
correlation at low GFR ranges and underestimation at ticipate in renal autoregulation: myogenic reflex and
high GFR ranges. These investigators also published the tubuloglomerular feedback (TGF). The myogenic reflex
first measured values of SCr in neonates born at 26 to involves changes in renal arteriolar vascular tone, which
36 weeks’ gestation. (21) SCr values in the first 10 occurs in response to changes in transmural pressure. For
postnatal days ranged from 0.1 to 1.8 mg/dL (8.8 to example, if systemic blood pressure increases, renal per-
159.1 mcmol/L), with a mean of 1.3⫾0.07 mg/dL fusion and transmural pressures also increase, resulting in
(114.9⫾6.2 mcmol/L). They discovered a negative cor- afferent arteriolar vasoconstriction and consequent pres-
relation between SCr concentra-
tion and increasing postnatal age in
preterm infants. During the first Table 1. Serum Creatinine (mg/dL) Values Based
postnatal month, SCr was inversely
related to postnatal age (Fig. 2). In
Upon Gestational Age (24)
the second and third months, SCr Postnatal Age 25 to 28 Weeks 29 to 34 Weeks 38 to 42 Weeks
did not vary with age.
Week 1 1.4ⴞ0.8 0.9ⴞ0.3 0.5ⴞ0.1
Newer methods of measuring
Weeks 2 through 8 0.9ⴞ0.5 0.7ⴞ0.3 0.4ⴞ0.1
GFR in neonates are being investi- >Week 8 0.4ⴞ0.2 0.35* 0.4ⴞ0.1
gated using cystatin C, a low-
Values represent mean ⫾ SD.
molecular weight protein from the *n⫽1, therefore no SD.
cysteine protease inhibitors family.

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core concepts glomerular filtration rate
Glomerular Filtration Rate (mL/min/
Table 2.
1.73m2) Based Upon Gestational Age (24)
Postnatal Age 25 to 28 Weeks 29 to 34 Weeks
Week 1 11.0ⴞ5.4 15.3ⴞ5.6
Weeks 2 through 8 15.5ⴞ6.2 28.7ⴞ13.8
>Week 8 47.4ⴞ21.5 51.4*
Values represent mean ⫾ SD.
*n⫽1, therefore no SD.
ervation of RBF and GFR. This reflex is believed to be
an inherent characteristic of the vessel, although the
mechanism has not been fully elucidated. TGF involves
a feedback system by which the macula densa senses the
rate of distal tubular flow. The vascular tone in the
adjacent afferent arterioles then is altered and GFR is
stabilized. An inverse relationship exists between tubular
flow rate and GFR, with increased tubular flow resulting
in decreased GFR and vice versa. This mechanism main-
tains the constancy of solute and water delivery to the
distal tubule. Several vasoactive substances, including
endothelin, AII, NO, adenosine, and thromboxane A2,
are considered to play important roles in the TGF path-
way. Both autoregulatory processes function early in life
and maintain renal function by preventing pressure-
induced fluctuations in RBF and GFR. Renal autoregu-
lation in neonates is highly dependent on the balance of
vasoconstrictive and vasoactive factors. Therefore, neo-
natal GFR is more susceptible to fluctuations when ex-
posed to insults such as hypoxemia, nonsteroidal anti-
inflammatory drugs, and ACE inhibitors. (4)(5)(7)
Effects of the Renin-Angiotensin System
on GFR
The renin-angiotensin system (RAS) (Fig. 3) plays a vital
role in the regulation of RBF and GFR and in the
development of renal vascular and tubular structures.
The RAS is upregulated during fetal life and in the
newborn period. Renin, ACE, and AII concentrations all
are elevated during the neonatal period. Plasma renin
activity correlates inversely with gestational and postnatal
age. In term infants, a slight increase occurs at 3 to 5 days
after birth, with activity decreasing over the next 1 to
6 weeks. By 3 to 5 years of age, plasma renin activity is
similar to adults. In humans, most renin is contained in
cells located at the juxtaglomerular apparatus, irrespec-
tive of gestational or postnatal age. Fetal kidneys also
contain renin in the interlobular arteries and glomeruli.
(3)(4) ACE values increase during late gestation and
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peak after birth. (3)(25) In the de-
veloping kidney, ACE expression
has been localized to the endothe-
lium of arterioles, glomerular capil-
38 to 42 Weeks
laries, descending vasa rectae, and
40.6ⴞ14.8 epithelium of proximal tubular
65.8ⴞ24.8
cells. (25) AII causes vasoconstric-
95.7ⴞ21.7
tion of both afferent and efferent
arterioles. However, because effer-
ent arterioles are smaller in diame-
ter, the net effect is potent vasocon-
striction of efferent arterioles and
resultant increases in PGC and GFR. Numerous animal
studies have demonstrated that in utero exposure to ACE
inhibitors affects renal hemodynamic function and
growth in the fetus and newborn. For example, systemic
administration of ACE inhibitors resulted in decreased
arterial blood pressure and RVR in newborn lambs and
near-term fetuses (⬎130 days of gestation). (26) In fetal
sheep, arterial pressure, GFR, and urine production de-
creased when ewes were exposed to captopril. (27)
Fetal kidneys also express only angiotensin type-2
(AT2) receptors, but after birth, expression is downregu-
lated and angiotensin type-1 (AT1) receptors begin to
predominate. The reason for these changes and the rela-
tionship between AT1 and AT2 receptors is currently
under investigation. Although the RAS is highly active
throughout fetal development, the mechanism of how
renin, ACE, AII, and AT receptors interact with each
other and with other vasoactive factors, such as brady-
kinin and PGs, during various stages of fetal develop-
ment and postnatally remains to be determined. (28)
Effects of Glucocorticoids on GFR
Glucocorticoids accelerate maturation of neonatal GFR.
Injection of betamethasone in preterm lambs resulted
Figure 3. The renin-angiotensin system and bradykinin path-
way. ATⴝangiotensin, ACEⴝangiotensin-converting enzyme.
From Yosipiv and El-Dahr. (25)

in significantly higher GFRs compared with near-term
lambs receiving placebo and term nontreated controls.
(29) Pharmacologic doses of methylprednisolone given
to rats resulted in an increase in QA but no difference
in Kf, ⌬P, or ␲A. (30) How glucocorticoids alter GFR
remains unclear, but a link may exist between gluco-
corticoids, RAS, and PG, a vasodilatory substance.
Antenatal betamethasone administration to fetal sheep
resulted in decreases in plasma renin, renin mRNA, and
renal cyclooxygenase-2 (COX-2) mRNA compared with
ewes until 1 year postnatal age. (31) The researchers
postulated that betamethasone suppressed COX-2 ex-
pression and, thus, may affect PG synthesis. Another
mechanism by which glucocorticoids could affect GFR is
through glucocorticoid-mediated increases in Na-K-
ATPase activity in the renal cortex, with consequent
increases in urinary sodium reabsorption and increases in
systemic blood pressure. (29)(32)(33) Increases in sys-
temic blood pressure are known to alter RBF and GFR.
Effects of Hypoxemia on GFR
Neonatal renal function is highly dependent on adequate
oxygenation. Numerous studies have shown renal com-
plications after perinatal asphyxia or hypoxemia in new-
borns. However, data are conflicting regarding changes
in GFR after a hypoxic event. The effects of hypoxia and
asphyxia on the GFR most likely relate to several factors,
including the duration of hypoxemia, severity of acidosis,
presence and severity of concomitant hypotension, and
the severity of insults to other organs. Stonestreet and
associates (34) exposed newborn lambs to 25 minutes of
asphyxia and did not see significant changes in GFR.
GFR did decrease after 1 hour of severe hypoxia in both
newborn and intrauterine growth-restricted piglets. (35)
In a prospective study of 87 term neonates suffering from
hypoxic-ischemic encephalopathy, 17% demonstrated
decreases in GFR, as defined by significant increases in
SCr. (36) Neonates who had reduced GFR also tended
to have more severe neurologic outcomes.
Effects of Other Vasoactive Factors on GFR
Vasodilation
PGs are potent vasodilators that increase RBF by stimu-
lating vasodilation of afferent arterioles. (9)(30) PG syn-
thesis inhibitors, such as indomethacin, can cause severe
vasoconstriction in immature kidneys, leading to re-
duced RBF, GFR, and urine output. Long-term mater-
nal indomethacin treatment may decrease fetal urine
output enough to alter amniotic fluid production. For-
tunately, GFR reduction is often reversible once the drug
has been discontinued. (3)(9)
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core concepts glomerular filtration rate
NO maintains RBF and GFR via its vasodilatory ef-
fects on the developing kidney. Blockade of NO synthe-
sis in third-trimester fetal sheep resulted in significant
increases in RVR and decreases in RBF. (10) NO may
serve to offset the high level of RAS activity by modu-
lating renin release and the effects of AII on vascular
vasoconstriction and GFR. NO also may aid in pro-
tecting the immature kidney from hypoxemic insults.
Changes in GFR were significantly greater in newborn
rabbits exposed to both hypoxemia and NO synthesis
inhibition compared with hypoxemia alone. (37)
Bradykinin (BK) stimulates NO and PG production,
resulting in vasodilation and natriuresis. BK production,
via kallikrein, is markedly upregulated in the developing
kidney. Increased expression of the kallikrein-kinin sys-
tem correlates with maturation of RBF. Blockade of BK
receptors in newborn rabbits resulted in increases in RVR
and consequent decreases in RBF. (38)
Dopamine can alter renal function by binding to re-
ceptors (D1 and D2) located in the renal vessels, glomer-
uli, renal tubule, and cortical and medullary collecting
ducts. Stimulation of D1 increases RBF, whereas activa-
tion of both D1 and D2 may increase GFR. (39) Dopa-
mine infusion rates of 2.5 mcg/kg per minute resulted in
increases in GFR and urine output, without changes in
blood pressure or heart rate, in normotensive preterm
infants whose mean gestational age was 34⫾2 weeks.
(40) However, these changes were not observed at do-
pamine infusion rates of 0.5 or 7.5 mcg/kg per minute.
Other studies have described the efficacy of dopamine in
regulating renal hemodynamics at doses ranging from
0.5 to 4 mcg/kg per minute. (41)(42) Fenoldopam, a
selective D1 agonist, was recently used off-label in 22
neonates ages 24 to 39 weeks of gestation. This retro-
spective study showed no significant improvement in SCr
or urine output. (43) Although animal models demon-
strated evidence of dopamine’s effect on modulating
renal hemodynamics, the previously cited studies dem-
onstrate conflicting results regarding the clinical efficacy
of dopamine receptor agonists in improving neonatal
GFR.
Vasoconstriction
Endothelin (ET) is a potent vasoconstrictor expressed by
endothelial cells in renal vessels, mesangial cells, and
distal tubular cells. AII, BK, epinephrine, and shear stress
regulate ET production. ET causes constriction of renal
arterioles (afferent greater than efferent), resulting in
increased RVR and subsequent reductions in GFR. ET
may also stimulate a counterregulatory mechanism of
NeoReviews Vol.11 No.12 December 2010 e719
core concepts glomerular filtration rate
vasodilation, possibly via NO secretion. The modulation
of neonatal renal hemodynamics by ET may not be as
straightforward as a direct vasoconstrictive response but
instead may involve a complex balance between vasodi-
latation and vasoconstriction via interactions with other
vasoactive substances. (3)
Long-term Prognosis of GFR in
Preterm Neonates
Recent studies have emerged suggesting that preterm
infants may be at risk for developing long-term renal
sequelae such as hypertension, proteinuria, glomerulo-
sclerosis, and decline in GFR during childhood or adult-
hood. Brenner and colleagues (44) first proposed this
theory when they postulated that preterm infants, partic-
ularly those who had IUGR, are born with a decreased
number of nephrons and, thus, reduced glomerular fil-
tration surface area. To maintain GFR, the remaining
glomeruli are required to hyperfilter to compensate for
the loss of renal endowment. Chronic hyperfiltration
subsequently causes glomerular and systemic hyperten-
sion, proteinuria, and glomerulosclerosis, ultimately lead-
ing to worsening renal function. Ultrasonography has
demonstrated reduced renal volume and size in small-
for-gestational age fetuses and low-birthweight infants.
(45)(46) In kidneys examined at autopsy, total glomer-
ular number correlated directly with birthweight. Mean
glomerular volume also demonstrated an inverse rela-
tionship with total glomerular number. (47) Preterm
birth also was associated independently with lower kid-
ney length and volume. (48) Children born preterm or
with IUGR had slightly but significantly lower GFR,
although GFR remained in the normal range for their
ages. (49) These studies can only suggest an association
between renal endowment and birthweight and age of
gestation. They do not clearly explain or prove how
changes in nephron number regulate long-term renal
function in fetuses and newborns born preterm or with
IUGR. (50)(51) Therefore, the association of nephron
endowment with glomerular size and GFR in hyperten-
sive children or hypertensive adults, born either preterm
or with IUGR, requires further investigation. The clini-
cal implications are of the highest importance.
Conclusion
The development and maturation of neonatal GFR in-
volves a complex, multifactorial process consisting of
fetal and newborn hemodynamics, renal nephron en-
dowment, birthweight, gestational age at birth, vaso-
active substances, and maternal factors. Various endoge-
nous and exogenous insults and therapeutic agents can
e720 NeoReviews Vol.11 No.12 December 2010
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disrupt this highly regulated system and lead to progres-
sive decline in renal function long term.
American Board of Pediatrics Neonatal-Perinatal
Medicine Content Specifications
• Know the production sites and actions of
various types of vasoactive substances that
affect renal function.
• Know the production pathway and the
actions of the components of the renin-
angiotensin system.
• Know the effects of prostanoids, and their inhibitors, on renal
function.
• Know how to interpret various renal function tests (eg,
creatinine clearance).
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NeoReviews Vol.11 No.12 December 2010 e721
 Core Concepts: Neonatal Glomerular Filtration Rate
Sharon W. Su and Barbara S. Stonestreet
NeoReviews 2010;11;e714-e721
DOI: 10.1542/neo.11-12-e714

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