THE NEPHRITIC SYNDROME

by Geoffrey K. Dube and Robert S. Brown

A 21 year-old woman presents with tea-colored urine

three weeks after being evaluated for a sore throat.
Physical examination is notable for a blood pressure
of 170/100 and 3+ pitting edema. Serum creatinine
is 2.1 mg/dl. Urine dipstick demonstrates 2+ protein,
large heme and large leukocyte esterase.

© 2004, Beth Israel Deaconess Medical Center, Inc.

A 21 year-old woman presents with tea-colored urine three weeks after
being evaluated for a sore throat. Physical examination is notable for a
blood pressure of 170/100 and 3+ pitting edema. Serum creatinine is 2.1
mg/dl. Urine dipstick demonstrates 2+ protein, large heme and large
leukocyte esterase.

Based on the results of the urine dipstick, which of

the following diagnoses is most unlikely?
a. The nephrotic syndrome.
b. The nephritic syndrome.
c. A combined nephrotic and nephritic syndrome.
d. Acute tubular necrosis.
In this case, the urine dipstick suggests the presence
of erythrocytes and leukocytes in the urine, as well as
proteinuria that probably does not reach the nephrotic
range. The urine dipstick measures mainly the
concentration of albumin in the urine, and thus, is
dependent on the total amount of protein in the urine
and the total urine volume. Thus, a reading of 4+
protein by dipstick does not guarantee the presence
of nephrotic-range proteinuria (if oliguria is present)
and a reading of 2+ does not rule out nephrotic-range
proteinuria (if urine volume is large). The findings in
this case are most consistent with a nephritic urine,
although they may also be seen in other conditions
such as acute pyelonephritis or acute tubular
necrosis.
The nephritic syndrome is characterized by the
appearance, at times sudden, of hematuria associated
with proteinuria. The nephritic syndrome may also be
associated with an elevated serum creatinine, oliguria
and hypertension. In the nephritic syndrome, breaks in
the glomerular basement membrane, mainly due to
immunologic phenomena, allow erythrocytes and
leukocytes to enter the urine. Damage to the glomerular
basement membrane also accounts for the presence of
abnormal amounts of protein in the urine.
In contrast to nephritic urine, nephrotic urine
typically contains at most a few erythrocytes
and leukocytes. The dipstick will often be
negative or show only trace amounts of heme
pigment and leukocyte esterase. The dipstick
will usually read 4+ protein, although a large
urine volume may cause the dipstick to be
less strongly positive.
Occasionally, the nephrotic syndrome and the
nephritic syndrome can coexist in a patient.
Examples include lupus nephritis, Henoch-
Shonlein purpura, membranoproliferative
glomerulonephritis and acute renal failure due
to non-steroidal anti-inflammatory drugs. In
these cases, the dipstick usually will be
strongly positive for heme pigment, leukocyte
esterase, and protein.
In acute tubular necrosis, large amounts of
hematuria, pyuria and proteinuria are typically
absent unless there is concurrent damage to
the glomeruli or interstitium. However, in
patients with preexisting intrinsic renal
disease, the dipstick may be positive for
heme, leukocyte esterase and/or protein even
in the absence of acute glomerular or
interstitial disease.
The urine sediment from the patient in the case is
shown above. What is demonstrated?
a. Acanthocytes and dysmorphic erythrocytes
b. Lipid droplets
c. Leukocytes
d. Renal tubular epithelial cells
In hematuria of glomerular origin, most erythrocytes have a
distorted appearance and many are smaller than usually. They
are referred to as dysmorphic erythrocytes. A subtype of
dysmorphic erythrocytes is referred to as acanthocytes.
Acanthocytes (arrow) are ring-shaped erythrocytes with one or
more vesicle-like protrusions. The etiology of dysmorphic
erythrocytes and acanthocytes is thought to be related to
membrane damage that occurs as the erythrocyte passes
through breaks in the glomerular basement membrane.
Acanthocytes (above, left) should be distinguished from
crenated red cells (above, right). Crenated erythrocytes form in
highly concentrated urine. In urine with a high osmolality, water
will pass out of the erythrocyte by osmosis, resulting in a
reduced cell diameter. Crenated erythrocytes have
characteristic spicules, as shown in the slide on the right. In
urine with a low osmolality, water will pass into the erythrocyte
by osmosis, resulting in an increased cell diameter. If enough
water enters the erythrocyte, the cell can lyse.
Lipid droplets (above) can be distinguished from
erythrocytes by their variable size and their color. Lipid
droplets are not found in nephritic urine unless there is a
concurrent nephrotic process, as can occur in
membranoproliferative glomerulonephritis and in some
types of lupus nephritis.
Leukocytes can be present in variable amounts in
nephritic sediment. Leukocytes are granular cells which
are larger than erythrocytes and contain a nucleus that
may be difficult to define. The slide on the right shows
both leukocytes (yellow arrows) and normal erythrocytes.
The slide on the left shows dysmorphic erythrocytes and
acanthocytes for comparison.
Renal tubular epithelial cells (above right, contained within a
cast) are typically seen in conditions which primarily involve
the tubules, such as ATN, interstitial nephritis and acute
allograft rejection. If the inflammation from acute
glomerulonephritis extends to the tubules, renal tubule
epithelial (RTE) cells can occasionally be seen in a nephritic
sediment. In some nephrotic sediments, RTE cells can be
seen due to tubular cell sloughing associated with damage
caused by heavy proteinuria and/or lipid droplet reabsorption.
Examination of our patient’s sediment also showed the two
formed elements shown above. What do they represent?
a. Erythrocyte casts
b. Leukocyte casts
c. Hemoglobin casts
d. Granular casts
Erythrocyte casts are formed in the tubule lumen as
erythrocytes complex with Tamm-Horsfall mucoprotein.
Erythrocyte casts are a marker of bleeding within the nephrons
of the kidney. They are most often seen in glomerulonephritis,
although they can also be seen in acute interstitial nephritis and
renal vasculitis. Although erythrocyte casts are an important
sign of acute glomerulonephritis, they are only variably present
in the nephritic sediment.
Leukocyte casts, as seen in the slide on the left, are seen in
upper urinary tract bacterial infection, although they can also
be seen with non-bacterial renal inflammation due to acute
interstitial nephritis and some forms of acute
glomerulonephritis. The slide on the right shows an
erythrocyte cast. Erythrocytes are smaller than leukocytes,
have a non-granular cytoplasm, and have no nucleus. In
contrast, leukocytes have a granular cytoplasm and have a
nucleus, although the nucleus may sometimes be difficult to
appreciate in an unstained sediment.
Hemoglobin casts are pigmented cellular casts that develop in
the presence of degenerated erythrocytes within the cast
matrix. They are typically brown in color and have a granular
appearance. Focusing up and down on the microscope may
reveal the presence of degenerated erythrocytes within the
hemoglobin cast. Rarely, hemoglobin casts develop in cases of
intravascular hemolysis. In these cases, the dipstick will be
positive for heme but there will be no evidence of microscopic
hematuria, and degenerated erythrocytes will not be present
within the hemoglobin cast.
Another example of a pigmented cast is a bilirubin
cast. Bilirubin in the urine can stain any type of cast,
causing the cast to take on the typical yellow
appearance of bilirubin.
Granular casts, like the one shown above, are a non-specific
finding which can be seen in numerous kidney disorders,
including ones which present with the nephritic syndrome. It is
thought that the granules are composed of degenerating cells
and filtered proteins that have subsequently aggregated within
the renal tubules. Although granular casts are a non-specific
finding, their presence in the sediment suggests the presence
of intrinsic renal disease.