Pediatric Steroid-Resistant Nephrotic Syndrome
Kevin D. McBryde, MD, David B. Kershaw, MD, and William E. Smoyer, MD
he term “nephrotic syndrome” describes the clini-
T cal state characterized by the presence of protein-
uria, hypoalbuminemia, and edema. Although
other clinicopathologic findings coexist with these 3,
they remain the central findings in nephrotic syndrome.
Both edema and proteinuria have been known clinically
for nearly 2000 years. Richard Bright first demonstrated
that edema and proteinuria were dependent on changes
in the kidney in 1827, and for the next 80 years, nephrot-
ic syndrome was known as “Bright’s disease.”1 In 1905
Friedrich von Muller further delineated kidney diseases
into “nephritis” and “nephrosis,” and finally in 1929
Henry Christian included the phrase “nephrotic syn-
drome” in his writings.1
Whereas the name “nephrotic syndrome” took mil-
lennia to emerge, its clinical course had been known
for some time. Although many patients died of their
disease, many physicians knew that edema might be
cured or even remit spontaneously.1 In the 18th and
19th centuries, treatments for nephrotic syndrome
included mercury-containing compounds, as well as
the induction of malaria or measles.1 The mortality
rate for children with nephrotic syndrome in this pre-
corticosteroid period was 67%.2 Then, in 1939 and
again in 1944, with the introduction of sulfonamides
and penicillin, respectively, patients with nephrotic
syndrome survived longer, and the mortality rate
declined to 42% and then 35%, respectively.2 After the
introduction of these antibiotics, the first reports of the
clinical courses of patients with nephrotic syndrome
began to appear. Finally, in the 1950s, adrenocorti-
cotropic hormone and cortisone became available and
were used to treat nephrotic syndrome. The use of cor-
ticosteroids in children with nephrotic syndrome
resulted in a dramatic resolution of proteinuria, and
the mortality rate decreased to around 9%.2
Curr Probl Pediatr 2001;31:275-307.
Copyright © 2001 by Mosby, Inc.
0045-9380/2001/35.00 + 0 53/1/119800
doi:10.1067/mps.2001.119800
280
Once effective treatment for the nephrotic syndrome
was available, it became apparent that not all patients
responded to therapy. Before proceeding, the defini-
tions involved in describing the response to therapy
must be delineated. Nephrotic syndrome requires the
presence of edema, hypoalbuminemia less than 2.5
g/dL, and proteinuria greater than 40 mg/m2/h (or a
protein/creatinine ratio of greater than 200 mg/mmol
or 2.0 mg/dL/mg/dL).3,4 Remission denotes a reduction
of the proteinuria to less than 4 mg/m2/h or a urinary
albumin dipstick of 0 or trace for 3 consecutive days.3,4
A relapse occurs with the recurrence of proteinuria of
greater than or equal to 40 mg/m2/h or a urinary albu-
min dipstick of 2+ or greater.3,4 Those patients who go
into remission with steroid therapy alone are called
steroid responsive, whereas those patients in whom
remission is not achieved after 8 weeks of steroid ther-
apy are labeled steroid resistant.3,4 This review will
examine those patients with steroid-resistant nephrotic
syndrome (SRNS) and what evidence is available to
aid in the management of these patients. One discrep-
ancy in the literature is the lack of a consistent defini-
tion of steroid resistance. Some authors define steroid
resistance as a failure to go into remission either (1)
after 4 weeks of enteral prednisone at a dose of 60
mg/m2/d; (2) after 4 weeks of the same dose of pred-
nisone plus 3 intravenous doses of methylprednisolone
1000 mg/1.73 m2/dose5; or (3) after 4 weeks of pred-
nisone for 4 weeks at the same dose followed by an
additional 4 weeks of alternate-day prednisone at a
dose of 40 mg/m2/dose.6 Patients with SRNS are at
risk for extrarenal complications of nephrotic syn-
drome, as well as the progression of their kidney dis-
ease to either chronic renal insufficiency (CRI) or end-
stage renal disease (ESRD).
Epidemiology
The prevalence of idiopathic nephrotic syndrome in
children is approximately 16 cases per 100,000 chil-
dren,3,7 with an annual incidence of 2 to 7 new cases per
Curr Probl Pediatr, October 2001
100,000 children.3,7-9 This prevalence translates to
approximately 1 in 6000 children who have develop-
ment of the nephrotic syndrome. The ratio of males to
females with nephrotic syndrome is approximately 2:1
in young children, but this male predilection disappears
in teenagers and adults.3,7 Sex-related differences also
exist according to the histologic diagnosis. In the
International Study of Kidney Disease in Children
(ISKDC) report, 39.9% of children with minimal-
change nephrotic syndrome (MCNS) were female,
compared with 30.6% of children with focal segmental
glomerulosclerosis (FSGS) and 64.1% of those with
membranoproliferative glomerulonephritis (MPGN).10
Age impacts on the diagnosis of nephrotic syndrome,
because two thirds to four fifths of pediatric patients are
less than 6 years of age.3,7 The underlying histologic
diagnosis affects the age at presentation of nephrotic
syndrome. Of children diagnosed with nephrotic syn-
drome, 79.6% of those with MCNS are less than 6 years
of age, whereas 50.0% of those with FSGS are less than
6 years of age.10 By comparison, only 2.6% of children
subsequently found to have MPGN are less than 6 years
of age at the time of diagnosis.10 The median ages at the
time of presentation in children according to their
histopathologic lesion is 3 years of age for MCNS, 6
years of age for FSGS, and 10 years of age for
MPGN.10 Thus the probability of having FSGS or
MPGN as the underlying cause of nephrotic syndrome
increases with increasing age, whereas the risk of hav-
ing MCNS is inversely related to the age at presentation
with nephrotic syndrome.10,11
Nephrotic syndrome affects persons of all races and
ethnic backgrounds. In a recent retrospective review of
pediatric patients in Houston, Texas, who were diagnosed
with nephrotic syndrome, 49% were white, 20% were
African American, and 24% were Hispanic.12 This distri-
bution of patients closely resembled the ethnic composi-
tion of the surrounding community.12 Ethnicity also
appears to have an effect on the risk for the various
histopathologic diagnoses. For biopsy-confirmed and
presumptive diagnoses, 53% of white patients and 73%
of Hispanic patients had MCNS, but only 36% of African
American patients had MCNS.12 In contrast, only 18% of
white patients and 11% of Hispanic patients diagnosed
with nephrotic syndrome were diagnosed with FSGS,
compared with 47% of African American patients.12 This
racial predisposition of African American patients to have
FSGS as the cause of their primary nephrotic syndrome
has been confirmed in other areas of the United States as
well. In the metropolitan Kansas City area, 44.0% of
Curr Probl Pediatr, October 2001
African American patients who underwent biopsy for
their nephrotic syndrome were diagnosed with FSGS
compared with just 16.7% of white patients.8
Most children diagnosed with nephrotic syndrome will
have a steroid-responsive form. The ISKDC found that
78.1% of children diagnosed with nephrotic syndrome
will respond to an initial course of prednisone adminis-
tered for 8 weeks.6 Of those patients who responded to
prednisone therapy in the ISKDC study, 91.8% of them
had MCNS and 8.2% had another histopathologic
lesion.6 Within the respective histopathologic categories,
93.1% of those with MCNS were steroid responsive,
whereas only 29.7% of those with FSGS and 6.9% of
those with MPGN responded to an initial course of pred-
nisone.6 The risks for those who have development of
SRNS are significant. In a report on the outcomes of 75
pediatric patients with FSGS who were followed up for
nearly 5 years, 37% had persistent proteinuria, 23% pro-
gressed to CRI, and 21% had development of ESRD.13
Clearly, for the 10% of pediatric patients with SRNS, the
risk of development of CRI or ESRD exceeds 40% in
just 5 years from the time of diagnosis. Although the
overall incidence of nephrotic syndrome has remained
rather constant, reports over the last 20 years have iden-
tified an increasing incidence of FSGS and a decreasing
incidence of MCNS.8,12 Thus an increasing proportion
of children diagnosed with nephrotic syndrome has
FSGS with its underlying tendency to be steroid resist-
ant. The remainder of this review will focus on SRNS.
Laboratory Evaluation
The laboratory evaluation of the pediatric patient with
SRNS begins with an examination of the urine for pro-
tein and of the serum for hypoalbuminemia. Other lab-
oratory abnormalities occur commonly in nephrotic
syndrome and contribute to the morbidity and mortality
rates of SRNS. As will be discussed later, the percuta-
neous native kidney biopsy is the most useful laborato-
ry study available for the diagnosis of the particular
histopathologic lesion causing the nephrotic syndrome.
Urinalysis
The routine urinalysis in the patient with nephrotic
syndrome demonstrates the presence of significant or
massive proteinuria, the primary abnormality. Although
SRNS may have a variable degree of proteinuria, its
presence is required for the diagnosis of nephrotic syn-
drome. The extent of the proteinuria may be measured
quantitatively, as well as qualitatively.
281
 Quantitation of the proteinuria is most accurately
accomplished by obtaining a 24-hour urine collection.
For a 24-hour urine collection, proteinuria ≥40
mg/m2/h or >50 mg/kg/24 h defines nephrotic syn-
drome proteinuria according to the ISKDC.3,14 In the
pediatric population, however, this poses certain logis-
tical and practical difficulties. Therefore a spot urine
sample often is obtained, and a urine protein/creatinine
ratio is calculated. On a first-morning spot urine sam-
ple, a urine protein/creatinine ratio of greater than 200
mg/mmol or 2.0 [(mg/dL)/(mg/dL)] indicates nephrot-
ic-range proteinuria.3 Semiquantitative measurement
of proteinuria can be accomplished with a urinary
albumin dipstick, with remission indicated with a 0 or
trace (≅15 mg/dL) measurement and a relapse indicat-
ed by a 2+ (≅100 mg/dL) to 3+ (≅300 mg/dL) or
greater measurement.3
In addition to quantitative urinary protein loss, pro-
teinuria represents variably abnormal selective perme-
ability (permselectivity) of the glomerular filtration bar-
rier (GFB). The typical proteins lost in the urine are the
intermediate-sized proteins with a molecular weight
(Mw) of approximately 40 to 200 kDa. The permselec-
tivity of the GFB is variable depending on the underly-
ing disorder responsible for the SRNS. In MCNS the
proteinuria is highly selective and comprised predomi-
nantly of albumin.3,7,15 The fractional clearances of
albumin (Mw of 66 kDa), transferrin (Mw of 77 kDa),
and immunoglobulin G (IgG) (Mw of 166 kDa) have
been shown to be greater in patients with nephrotic syn-
drome with FSGS than in those with MCNS who have
heavy proteinuria.15
In addition to proteinuria, the urinalysis in pediatric
patients with SRNS may demonstrate hematuria.
However, the degree of hematuria varies depending on
the underlying histopathologic diagnosis. With first
morning timed urine samples, the ISKDC reported that
hematuria of greater than 100,000 red blood cells/m2/h
occurred in 22.7% of those children with MCNS, 48.4%
of those with FSGS, and 58.8% of those with MPGN.10
Pediatric patients with diffuse mesangial hypercellulari-
ty have the highest reported incidence (89%) of micro-
scopic hematuria.16 Overall, the incidence of micro-
scopic hematuria was found to be 32% in a large
retrospective review.12
Other abnormalities seen in the urine of patients with
SRNS include the findings of hyaline casts and fat-
laden tubular epithelial cells.17 The fat-laden tubular
epithelial cells appear as the classic “Maltese cross”
under polarized light.1,17
282
Hypoalbuminemia
In nephrotic syndrome, both total protein and albumin
are decreased in the serum. Hypoalbuminemia results
from the inability of the liver to increase its synthesis of
albumin to offset the albuminuria.18 The liver increases
albumin synthesis 4-fold via increased transcription of
messenger RNA, and the absolute rate of albumin catab-
olism decreases throughout the body. However, the frac-
tion of the plasma pool of albumin catabolized per unit
of time increases as a result of the response of the renal
tubular epithelium to the albuminuria.18 As a result, the
excretion and catabolism of the albumin exceeds the
liver’s ability to maintain normal plasma albumin levels
and the intravascular oncotic pressure.
Other Plasma Proteins
Numerous other plasma proteins appear in the urine as
a result of the decreased permselectivity in SRNS.
Immunoglobulins and components of the complement
pathway are lost in the urine in nephrotic syndrome and
may give rise to infectious complications. Antithrombotic
proteins are of similar size to albumin and are lost in the
urine, resulting in low plasma levels. In contrast, many of
the prothrombotic proteins are too large to traverse the
GFB, and thus their levels increase in the plasma. These
hemostatic alterations, when combined with volume
depletion, contribute to the development of the thrombot-
ic complications seen in nephrotic syndrome. Anemia in
patients with nephrotic syndrome may be a complication
of erythropoietin and transferrin excretion in the urine,
resulting in an erythropoietin- or iron-deficient state.
Finally, several hormone binding-proteins are excreted in
the urine, although disturbances of these endocrinologic
pathways are not apparent clinically.
Serum Creatinine
The serum creatinine in the patient with nephrotic
syndrome may be low, normal, or elevated. A low
serum creatinine reflects hyperfiltration at the
glomerulus. In the ISKDC report, between one third
and one half of children diagnosed with idiopathic
nephrotic syndrome had a serum creatinine greater
than the 98th percentile for their age.10 The ISKDC
reported that 32.5% of patients with MCNS, 40.6% of
patients with FSGS, and 50.0% of patients with
MPGN had an elevated serum creatinine.10
Hyperlipidemia
Hyperlipidemia commonly occurs in patients with
nephrotic syndrome and results from a combination of
Curr Probl Pediatr, October 2001
increased hepatic synthesis and impaired catabolism.
Long-term elevated serum lipids and cholesterol are of
concern because they may be risk factors for cardio-
vascular disease later in life. The characteristic lipid
abnormalities seen in the nephrotic syndrome include
elevated very low–density lipoproteins (VLDL), low-
density lipoproteins (LDL), lipoprotein a [Lp(a)], cho-
lesterol, and triglycerides, as well as normal or
decreased serum levels of high-density lipoproteins
(HDL).7,18-20 The concern, though unproven, is that
the dyslipidemia associated with the nephrotic syn-
drome promotes accelerated atherosclerosis and
increases cardiovascular risk in patients with persistent
nephrotic syndrome.
VLDL levels increase as a result of decreased clear-
ance by lipoprotein lipase (LPL).18,20 LPL activity may
be reduced because of a depletion of endothelium-
expressed LPL, defects in LPL’s adherence to vascular
endothelium, or to inadequate availability of apolipopro-
tein C-II.18 Simultaneously, there is increased hepatic
conversion of VLDL to LDL, resulting in further eleva-
tion of serum LDL levels. The stimulus for increased
VLDL conversion to LDL may be either the decreased
serum oncotic pressure or the hypoalbuminemia result-
ing from the nephrotic syndrome. Lp(a) also increases,
but as a direct result of increased hepatic synthesis
alone.18 Lp(a) is known to be powerfully atherosclerotic
in genetically inherited syndromes of elevated Lp(a).18
Although the total serum cholesterol is increased as a
result of elevations of the various subtypes of choles-
terol, the triglycerides may be variably increased. The
severity of both the hypercholesterolemia and hyper-
triglyceridemia has been shown to be inversely related to
the serum albumin levels.17
Finally, there is delayed maturation of the HDL to the
more efficient HDL2 isoform, resulting in decreased
apolipoprotein C-II delivery and increased VLDL lev-
els.18 As a result, more of the HDL3 isoform is produced,
which favors reverse cholesterol transport and athero-
sclerosis.18 The dysregulation of HDL metabolism may
result in decreased inhibition of glomerular albumin per-
meability factors found in the serum of patients with
FSGS.21 Apolipoproteins E2 and E4, high-molecular
weight J and L, and a fragment of apolipoprotein A-IV
are all components of HDL and have recently been
shown to inhibit the activity of glomerular albumin per-
meability factors in the serum of patients with FSGS.21
Thus components of the HDLs may protect the glomeru-
lus from progressive renal injury in patients with FSGS,
but they may be inadequately synthesized because of the
Curr Probl Pediatr, October 2001
dysregulated maturation of HDL that occurs in the
nephrotic syndrome.
Pathophysiology
The basic functional defect in nephrotic syndrome is
an increased permselectivity of the GFB to molecules
that ordinarily would not be filtered. Numerous factors
affect the filtration of a molecule, such as the proper-
ties of the molecules themselves, the properties of the
filtration barrier, and hemodynamic factors. The prop-
erties of the molecules themselves include the size and
the charge of the molecules. Molecules greater than
approximately 40 Å in diameter or with a molecular
weight of greater than 200 kDa normally cannot tra-
verse the GFB.18,22 In addition to the size effect, the
charge of a molecule affects its transport across the
GFB. The GFB has a negative charge imparted to it by
a heparan sulfate proteoglycan that retards the trans-
port of negatively charged molecules across the GFB
while facilitating the passage of positively charged
molecules.22 Experimental data have shown that clear-
ances of neutral or positively charged molecules are
greater than for negatively charged molecules of com-
parable size. However, a recent study failed to demon-
strate any difference between the charge selectivity of
proteinuria in either MCNS or FSGS.23 Finally, the
blood flow to the kidneys affects the filtration by the
glomeruli. Both convection and diffusion are responsi-
ble for the clearance of intermediate size molecules,
although convection is responsible for the clearance of
both small and large molecules.22 As the glomerular
filtration rate increases, clearance resulting from diffu-
sion decreases whereas clearance caused by convec-
tion and solute drag increases. As a result, clearance of
many molecules increases with the increased blood
flow and glomerular filtration rate. The exact mecha-
nisms of alterations in the permselectivity of the GFB
or in the intrarenal hemodynamics remain unknown
for either MCNS or FSGS, although there are theories
for each.
Minimal Change Nephrotic Syndrome
The pathogenesis of MCNS remains elusive. MCNS
is believed to result from abnormalities of both the
humoral and cell-mediated immune system. Decreased
serum IgG and elevated serum immunoglobulin M
(IgM) are found in MCNS,3,7 although there is no evi-
dence of immune-complex mediated injury to the kid-
neys. However, in experimental models, antibodies
283
against components of the glomerular basement mem-
brane or against the podocytes can induce foot process
effacement and proteinuria.24 Some patients with Hodg-
kin’s disease and some other malignancies can have
development of MCNS, again suggesting a role for the
immune system in the cause of MCNS. Finally, there
is an increased incidence of atopic illnesses in children
with MCNS.3
Cell-mediated mechanisms also are hypothesized to
play a role in the development of MCNS. The pharma-
cologic agents used to treat MCNS, including glucocor-
ticoids, alkylating agents, and cyclosporine, are all
inhibitors of T lymphocytes. In addition, several lym-
phokines have been isolated that induce proteinuria
when administered to healthy rats.24 Soluble immune
response suppressor (SIRS) is a lymphokine produced
by T lymphocytes that appears to suppress T-cell response
to antigens, as well as B-cell production of immunoglob-
ulins.3 SIRS can be recovered from the urine of patients
with steroid-responsive nephrotic syndrome, although it
is absent in the urine of patients with SRNS. However,
SIRS is not believed to play a direct role in altering the
permselectivity of the GFB. Its exact role in SRNS is
unknown. Additionally, vascular permeability factor
may induce increased permeability of the GFB.3 Finally,
both interleukin-2 and interleukin-2–soluble receptor are
elevated in untreated MCNS and decrease in response to
medical therapy with corticosteroids, alkylating agents,
or cyclosporine.3,24 How these various abnormalities of
the humoral- and cell-mediated immune response con-
tribute to the development of MCNS is still uncertain.
Both SRNS and steroid-responsive nephrotic syn-
drome are associated with specific major histocompat-
ibility complex (MHC) markers. Certain MHC-class I
antigens appear to be more frequent in children with
SRNS, specifically HLA-B12.24,25 Among the MHC-
class II antigens, DR7+ appears to confer a markedly
increased risk for SRNS as well. Other MHC-class I
and II antigens are more frequent in children with
MCNS, although these appear to be associated with
steroid responsiveness.
FSGS
FSGS may be either a primary or secondary disorder.
Secondary causes include reflux nephropathy, renal dys-
plasia, morbid obesity, sickle cell disease, hereditary
nephropathies, human immunovirus–associated nephrop-
athy, and heroin-associated nephropathy. However, in
the pediatric population, these are relatively uncommon
causes. These secondary causes for the FSGS lesion
284
present similarly to primary FSGS, and thus they should
be carefully excluded before making the diagnosis of
primary FSGS. The hypothesized causes of primary
FSGS will be considered here.
The underlying mechanisms of FSGS fall into 4 main
categories: humoral factors, hemodynamic factors,
podocyte injury, and genetic predisposition. Humoral
mechanisms are suggested by the findings of IgM and C3
deposits in biopsy samples, as well as the decrease in pro-
teinuria with therapy by use of immunosuppressants or
plasmapheresis.24,25 Additionally, an “FSGS factor” has
been isolated from the serum of patients with FSGS that
can induce proteinuria when injected into rats.26
Hemodynamic factors that may contribute to the develop-
ment of FSGS include glomerular hypertension and
increased transmural pressure gradients.27 Although no
direct evidence demonstrates that mechanical forces are
directly damaging to podocytes, animal models of hyper-
tension-induced FSGS support this hypothesis.27
Increased transmural pressure gradients caused by
glomerular capillary hypertension may increase the
mechanical stress placed on the podocyte foot process-
glomerular basement membrane connection. This, in turn,
may cause a failure of adhesion of the podocyte and may
result in detachment of the podocyte.27 Podocyte injury
increasingly has been considered a possible cause of the
FSGS lesion. Toxic, immunologic, or inflammatory medi-
ators may cause direct injury to the podocyte, thereby
leading to effacement and partial detachment of the
podocyte foot process from the GFB. As the podocytes
undergo detachment, the glomerular basement membrane
is left exposed to the opposing parietal epithelial cells of
Bowman’s capsule and can form synechiae.27 Plasma pro-
teins begin to accumulate in the subendothelial region,
resulting in the characteristic hyalinosis found in the seg-
mental sclerosis of FSGS. Additionally, at the site of
attachment of the parietal epithelial cells to the exposed
glomerular basement membrane, a potential space arises
and fills with ultrafiltrate resulting in a periglomerular
space.27 These adhesions have a tendency to grow as a
result of ongoing accumulation of plasma proteins, as well
as the relative inability of podocytes to replicate postnatal-
ly and the resultant inability to replace damaged or
detached podocytes. Eventually, this process leads to seg-
mental sclerosis and can progress to global sclerosis.
Histopathology
Primary SRNS may be due to a variety of glomeru-
lonephropathies (Table 1) including MCNS, FSGS,
Curr Probl Pediatr, October 2001
 FIG 1. Histopathology of glomeruli in patients with nephrotic syndrome resulting from MCNS and FSGS. A, Normal-
appearing glomerulus by light microscopy, with normal capillary lumina and basement membranes, and without evi-
dence of sclerosis or a synechia. This is the appearance of a glomerulus in minimal-change nephrotic syndrome. B,
Electron micrograph of a patient with minimal change nephrotic syndrome demonstrates marked effacement of the
podocyte foot processes (Ep), a normal glomerular basement membrane (Bm), and the fenestrated capillary endothe-
lium (En). Insert demonstrates the normal appearance of the podocyte foot processes overlying the glomerular base-
ment membrane and the capillary endothelium. C, Light microscograph of a glomerulus from a patient with focal seg-
mental glomerulosclerosis demonstrates the segmental nature of the lesion (arrow). Notice the synechia at the location
of the sclerotic lesion, adhering the glomerular tuft to the epithelium of Bowman’s capsule. (Photomicrographs cour-
tesy of Dr. Kent J. Johnson, Department of Pathology, University of Michigan.)

MPGN, membranous glomerulonephritis (MGN), dif-
fuse mesangial proliferation, and proliferative glomeru-
lonephritis. Of these, more than 75% of cases of
nephrotic syndrome in children are due to either MCNS
or FSGS.8,10,12,22 However, MCNS and FSGS may not
represent distinct entities. Numerous reports document
patients with SRNS whose initial kidney biopsy speci-
mens demonstrated MCNS and subsequently had a fol-
low-up biopsy specimen that showed FSGS. This has
led to the conclusion that MCNS and FSGS may repre-
sent a continuum of the same process. The causes of
MPGN, MGN, diffuse mesangial proliferation, and
proliferative glomerulonephritis will not be discussed
here, because most cases of SRNS are due to MCNS or
FSGS. The following discussion of the pathology in
SRNS will be primarily focused on these 2 diagnoses.
MCNS
MCNS characteristically demonstrates little histopatho-
logic abnormality, as would be expected given its name.
The percutaneous kidney biopsy evaluation includes
light, immunofluorescent, and electron microscopy.
Each of these tests has characteristic findings in
MCNS. By light microscopic study, the glomeruli
appear normal and demonstrate minimal abnormalities
(Fig 1, A). The glomerular capillaries are widely patent,
and the glomerular basement membrane appears nor-
mal. There may be a slight increase in mesangial matrix
or hypercellularity, but there is no evidence of capillary
collapse or sclerosis. Globally sclerosed glomeruli may
be present in children and may be normal, depending
on the percentage of the total number of sampled
glomeruli. The tubules may demonstrate degenerative
and regenerative changes of acute tubular necrosis, par-
ticularly when the nephrotic syndrome is associated
with acute renal insufficiency. The interstitium shows
edema, and the blood vessels appear normal.
Immunofluorescent microscopy in MCNS generally
shows no evidence of immunoglobulin deposition in
the glomeruli. However, the mesangium may stain

Curr Probl Pediatr, October 2001 285

TABLE 1. Incidence of various histopathologic lesions in primary idiopathic nephrotic syndrome in children
White et al22 ISKDC10 Srivastava et al8 Bonilla-Felix et al12
Histologic lesion No. % No. % No. % No. %
Minimal change nephrotic syndrome 111 76.5 398 76.4 78 52.7 84* 55.3
Membranoproliferative glomerulonephritis 39 7.5 14 9.5 5 3.3
Focal and segmental glomerulosclerosis 12 8.3 36 6.9 34 23.0 33 21.7
Proliferative glomerulonephritis 20 13.8 12 2.3 18 12.2
Pure diffuse mesangial proliferation 12 2.3 26 17.1
Focal and global glomerulosclerosis 9 1.7 1 0.7
Membranous glomerulonephropathy 2 1.4 8 1.5 3 1.9
Chronic glomerulonephritis 3 0.6
Unclassified 4 0.8 2 1.3
Immunoglobulin A nephropathy 2 1.3
Total 145 100.0 521 100.0 148 100.0 152 100.0
*Thirty-seven (24.3%) patients with biopsy-confirmed MCNS and 47 (30.9%) patients with presumptive MCNS.

weakly positive for immunoglobulins or even comple-
ment (C3). Finally, electron microscopic study demon-
strates the only consistent abnormalities on the biopsy
specimens of patients with MCNS (Fig 1, B). By elec-
tron microscopic study, the visceral epithelial cells
(podocytes) show effacement of their foot processes,24
which is usually extensive. Podocyte hypertrophy,
microvillus transformation, and the presence of vac-
uoles containing lipids and proteins may accompany
foot process effacement.24 The glomerular basement
membrane appears normal in composition, as well as
thickness.
FSGS
The histologic diagnosis of FSGS requires the
demonstration of a portion of scarring occurring in
only some of the glomeruli, most commonly in the
juxtaglomerular region (Fig 1, C).28 Thus the lesion is
both focal (involving only some of the glomeruli) and
segmental (involving only a portion of the glomerular
tuft) in its distribution. The focal nature of this entity
may explain why it may not be seen on initial kidney
biopsy specimens that are interpreted as MCNS, only
to be diagnosed as FSGS on subsequent biopsy speci-
mens. The sclerosis is the consequence of an adhesion
between the glomerular filtration barrier and the pari-
etal epithelium of Bowman’s capsule. Given its
propensity for glomerular scarring, it is not surprising
that FSGS is responsible for 11.5% of children with
ESRD awaiting kidney transplantation.29
By light microscopic study the uninvolved areas of
the glomeruli appear to be normal in FSGS. In con-
trast, the involved areas demonstrate segmental
glomerular sclerosis. Other findings often observed in
FSGS include glomerular hypercellularity resulting
from hyperplasia and hypertrophy of the podocytes,24
as well as increased mean glomerular volume com-
pared with MCNS.30 Mesangial hypercellularity has
been reported and tends to occur more diffusely
throughout the kidney. Hyalinosis in FSGS appears as
a glassy and periodic acid-Schiff reaction positive
(magenta-colored) material localized to the inner
aspect of the glomerular capillary loop.24 The renal
tubules may show focal atrophy and depletion, where-
as the interstitium may demonstrate fibrosis. The pres-
ence of interstitial fibrosis, tubular atrophy, and tubu-
lar loss correlates with declining renal function.24
Finally, the blood vessels also may show hyalinosis of
their arteriolar walls. Immunofluorescent microscopic
study in FSGS often demonstrates both IgM and C3
deposits in areas of segmental sclerosis of the
glomerulus.24 The arterioles with hyaline changes fre-
quently demonstrate the IgM and C3 deposits as well.
On electron microscopic study, FSGS specimens
appear normal with the exception of podocyte foot
process effacement associated with focal areas of foot
process detachment from the glomerular basement
membrane.24
Treatment
Optimal treatment of SRNS has been hampered by a
lack of prospective, controlled trials. Additionally,
many of the patients begin empiric therapy for their
nephrotic syndrome before a histopathologic diagnosis
is established, and thus pretreatment may impact their
subsequent response to therapy. Much of the current
literature contains anecdotal or uncontrolled trials of
therapy, limiting the generalizability of the results to
pediatric patients diagnosed with SRNS. A recent sur-

286 Curr Probl Pediatr, October 2001

vey highlights the lack of consensus by pediatric
nephrologists with regard to the best treatment for
FSGS. This survey of pediatric nephrologists’ treat-
ment practices of FSGS reported their subjective
grading of their use of various agents as “often” or
“sometimes” versus “seldom” or “never.”31 Angio-
tensin-converting enzyme (ACE) inhibitors have
gained nearly universal acceptance in the treatment of
FSGS, being used either “often” or “sometimes” by
92.1% of pediatric nephrologists.31 There appears to
be a dramatic trend toward the use of cyclosporine to
treat FSGS, because 73.9% of respondents prescribe
it.31 For the cytotoxic agents, 60.1% of respondents
report using oral cyclophosphamide compared with
24.6% who prescribe chlorambucil, although only
44.3% use combination intravenous steroids plus oral
cytotoxic agents to treat FSGS.31 The use of corticos-
teroids to treat FSGS demonstrates the belief that
FSGS is a steroid-resistant disease. Only 50.3% of
those surveyed report using oral prednisone for greater
than 3 months, and 52.3% of those using intravenous
steroids do so without adding a cytotoxic agent.31
Finally, only 30.7% of pediatric nephrologists use
lipid-lowering agents to treat the dyslipidemia associ-
ated with refractory nephrotic syndrome.31
Supportive Measures
The general medical care of the child with SRNS is
very important. Careful history taking should focus on
symptoms of pulmonary edema or congestive heart fail-
ure resulting from volume overload, vomiting or diar-
rhea that may affect absorption of enteral medications,
abdominal pain caused by spontaneous bacterial peri-
tonitis, or oliguria suggestive of acute kidney failure. A
thorough physical examination should be performed
looking for signs of pulmonary edema, pleural effusions,
congestive heart failure, peritonitis, and edema sugges-
tive of a thrombotic event, erosions of edematous skin,
and hypertension. Attention should be paid to the main-
tenance of adequate intravascular volume, and volume
depletion should be corrected. Once the general care of
the patient has been addressed, attention may be turned
to the specific therapies for the underlying SRNS.
Diuretics
Diuretic therapy should be used judiciously in cases of
severe edema after intravascular volume depletion has
been excluded. In the patient with volume overload with
oliguria, diuretics may induce a diuresis and reestablish
urine output. The most commonly used diuretics are the
Curr Probl Pediatr, October 2001
loop diuretics, specifically furosemide. Loop diuretics
act by inhibiting the sodium-potassium-2 chloride trans-
porter located in the thick ascending limb of Henle. Loop
diuretics are highly protein bound, thus preventing their
clearance via glomerular filtration even in situations of
hypoalbuminemia.32 The protein-binding of furosemide
allows it to be delivered to the vasculature of the proxi-
mal tubule, where it subsequently is secreted into the
tubular lumen.32 From within the tubular lumen,
furosemide reaches its site of action.
In nephrotic syndrome, resistance to furosemide activ-
ity may be encountered clinically. Tubular resistance is
due to a combination of factors. Hypoalbuminemia may
result in decreased delivery of protein-bound furosemide
to the proximal tubules for secretion into the tubular
lumen.32 Additionally, hypoalbuminemia increases
furosemide’s volume of distribution due to diffusion of
free drug into the interstitial compartment.32 Finally, pro-
teinuria results in intraluminal binding of secreted
furosemide, resulting in a diminished amount of
unbound active drug to reach its site of action.32
Strategies to overcome the tubular resistance to
furosemide in the nephrotic syndrome include increased
doses, coadministration of furosemide with albumin, or
coadministration of furosemide with a distal tubular
diuretic. Increasing the dose of furosemide to 2 to 3
times the normal dose may overcome its decreased
delivery to the proximal tubules, thus allowing adequate
tubular secretion.32 Caution is necessary because high
doses with concurrent renal insufficiency will increase
the risk of furosemide toxicity.32,33 Next, the coadminis-
tration of furosemide with albumin has been shown to
increase both the natriuretic and diuretic response.33,34
The mechanism of action of the combined therapy is
believed to be a combination of increased intravascular
volume caused by increased oncotic pressure and
increased delivery of protein-bound furosemide to the
proximal tubules.33 Finally, administration of
furosemide with either metolazone or a thiazide diuretic
may increase the natriuretic and diuretic effect by
inhibiting distal tubular sodium resorption.32,35
Aggressive diuretic therapy should be avoided because it
can contribute to intravascular volume depletion and has
been identified as an independent risk factor for throm-
boembolic complications in nephrotic syndrome.36
Corticosteroids
Corticosteroids have been the mainstay of therapy for
nephrotic syndrome for nearly 50 years. The ISKDC
first recommended that the treatment of the nephrotic
287
TABLE 2. Dosing schedule for protocol of Mendoza and Tune with high-dose intravenous methylprednisolone
Week IVMP Dose* Schedule
1-2 30 mg/kg/dose 3 times per week
3-10 30 mg/kg/dose Weekly
11-18 30 mg/kg/dose Every 2 weeks
19-50 30 mg/kg/dose Every 4 weeks
51-82 30 mg/kg/dose Every 8 weeks
CYP, Cyclophosphamide; CHL, chlorambucil.
*Maximum methylprednisolone dose 1000 mg.
†Maximum prednisone dose 60 mg every other day.
‡Cyclophosphamide 2 to 2.5 mg/kg/dose (maximum 100 mg) for 8 to 12 weeks; chlorambucil 0.15-0.20 mg/kg/dose (maximum for 8 to 12 weeks).
syndrome begin with prednisone 60 mg/m2/d (or 2
mg/kg/d to a maximum of 80 mg/d) in divided doses for
4 weeks.6 The dose decreased to 40 mg/m2/d (or 1.5
mg/kg/d to a maximum of 60 mg/d) for 4 weeks on 3
consecutive days out of 7 for the next 4 weeks.6 The
Arbeitsgemeinschaft für Pädiatrische Nephrologie then
demonstrated that an alternate-day dosing schedule for
the second 4 weeks was more efficacious than the
ISKDC original regimen.37 As a result, the alternate-day
dosing schedule has become the standard of care for the
treatment of nephrotic syndrome with corticosteroids.
Failure to achieve a remission on completion of this reg-
imen defines “steroid resistance.”
Recent studies have challenged the appropriateness
of this dosing regimen for corticosteroids in the treat-
ment of nephrotic syndrome. The Arbeitsgemeinschaft
für Pädiatrische Nephrologie conducted a randomized,
prospective study to compare the efficacy of “short-
term” prednisone therapy (same initial dose as the
ISKDC recommendations until proteinuria was nega-
tive for 3 consecutive days and then reduce the pred-
nisone dose according to the ISKDC regimen) versus
the standard regimen advocated by the ISKDC. The
“short-term” therapy resulted in 50% fewer complete
remission at 2 years of follow-up and a 50% reduction
in the mean duration of clinical remissions compared
with the standard therapy.38 Since then, other studies
have concluded that the initial treatment for idiopathic
nephrotic syndrome should be a longer duration of cor-
ticosteroids lasting 12 to 16 weeks.39-43 These studies
found that the longer duration of corticosteroid treat-
ment for the initial episode results in higher remission
rates and in longer duration of remissions compared
with the standard regimen.39-43 Although these studies
were conducted primarily in patients whose conditions
responded to steroid treatment, they have impacted on
the treatment of the pediatric patients with SRNS. Pei
et al,44 in a retrospective study of patients with FSGS,
found that 44% of pediatric patients with FSGS could
288
No. of doses Prednisone Alkylating agent
6 None None
8 2 mg/kg/dose† CYP or CHL‡
4 ±Taper None
8 Slow taper None
4 Slow taper None
attain a complete remission with corticosteroids, and
that the mean and median times to remission were 3
months. All of the responders to corticosteroid therapy
had responded by 6 months.44 Thus more aggressive
treatment of idiopathic nephrotic syndrome with a
longer initial course of corticosteroids (12 to 16
weeks) may improve the steroid-responsiveness of
those patients with FSGS and thus decrease the popu-
lation of patients labeled as having SRNS.
Alkylating Agents
The alkylating agents cyclophosphamide and chlo-
rambucil have been used to treat both steroid-dependent
nephrotic syndrome and now SRNS. Early results from
the ISKDC and anecdotal reports indicated that neither
cyclophosphamide nor chlorambucil improved the out-
come of patients with SRNS.45,46 Approximately 25% of
both the steroid-alone and the steroid-plus-cyclophos-
phamide groups had a complete remission, but the
steroid-plus-cyclophosphamide group had more treat-
ment failures than those receiving just steroids.46 In con-
trast, a group in Canada found that cyclophosphamide
resulted in either a partial or complete remission in 48%
of study patients with SRNS.47 They also found that the
risk of CRI or ESRD decreased in patients whose SRNS
was cyclophosphamide sensitive. A study from
LeBonheur Children’s Medical Center in Memphis,
Tenn, found that those patients with SRNS who relapsed
after a second course of cyclophosphamide became
steroid sensitive again.48
A promising treatment for SRNS is the use of intra-
venous pulse cyclophosphamide infusions for 6 months.
In a prospective, randomized, and controlled trial com-
paring alternate-day oral steroids plus either oral or intra-
venous cyclophosphamide, it was found that 100% of
those patient in the SRNS group with MCNS who
received intravenous cyclophosphamide went into remis-
sion.49 Although 40% of these responders relapsed with
their nephrotic syndrome, all of them reverted to being
Curr Probl Pediatr, October 2001
steroid responders. A second prospective, randomized
controlled study in South Africa compared intravenous
cyclophosphamide and oral prednisone with prednisone
alone in patients with SRNS and with FSGS.50 These
authors found that 60% of patients in the primary
steroid-resistant group and 100% of patients in the sec-
ondary steroid-resistant group experienced either a com-
plete or partial remission.50 They, too, found that with
relapse, many of the patients with SRNS became steroid
sensitive.50
Chlorambucil also has been found to increase the
complete or partial remissions in patients with SRNS
caused by either FSGS or MPGN.51 Chlorambucil has
been successfully used to treat patients with both
steroid resistance and cyclophosphamide resistance,
resulting in an 80% remission rate and a 40% relapse
rate.51 Thus the alkylating agents should not be sum-
marily disregarded in the treatment of SRNS because
they may have a significant impact on the remission
rate, as well as reestablishing steroid responsiveness.
Combination Therapy
Recently, much attention has been directed to the
treatment of steroid-resistant FSGS with pulses of
intravenous methylprednisolone used with alternate-
day enteral prednisone, cyclosporine, or an alkylating
agent. These studies of combination regimens have, at
the core of the regimen, intravenous pulses of high
doses of methylprednisolone. French pediatric
nephrologists define steroid resistance as a failure to
achieve remission after 4 weeks of oral prednisone (60
mg/m2/d in divided doses), followed by 3 intravenous
methylprednisolone doses (1000 mg/1.73 m2/dose) on
alternating days.5 The most successful combination
regimen reported for the treatment of SRNS resulting
from FSGS comes from Mendoza et al52,53 and Tune et
al.54-56 They used an 18-month long course of treat-
ment with intravenous methylprednisolone at a dose of
30 mg/kg/dose administered every other day (3 days
per week) for 2 weeks.52-56 The frequency of doses
then decreases to weekly for 8 weeks, every 2 weeks
for 8 weeks, monthly for 8 months, and then every
other month for 6 months (Table 2).52-56 At the time of
initiation of the weekly doses of intravenous methyl-
prednisolone, the patients begin alternate-day oral
prednisone administration (2 mg/kg/dose to a maxi-
mum dose of 60 mg).52-56 With this regimen, Mendoza
et al52,53 and Tune et al54-56 reported that after an aver-
age follow-up of 6.33 years for 32 patients with SRNS
caused by FSGS, 21 (65.6%) were in remission, 3
Curr Probl Pediatr, October 2001
(9.4%) had mild proteinuria, 2 (6.3%) had moderate
proteinuria, and 6 (18.8%) continued to have nephrot-
ic syndrome. Of the 11 patients who did not have com-
plete remission, 3 (27.3%) had persistent proteinuria
but normal renal function, 5 (45.4%) had CRI, and 3
(27.3%) progressed to ESRD.54 Side effects of this
high-dose intravenous methylprednisolone therapy
included cataracts (22%), impaired growth (17%),
hypertension (17%), leukopenia (19%), and gastroin-
testinal distress (common).52,54
Although others have attempted to duplicate these
results, they have not been achieved because of differ-
ences in study design. However, several studies have
supported the response to intravenous methylpred-
nisolone results found by Mendoza and Tune, with
remission rates ranging from 53% to 82%, with simi-
lar side effects described previously.57-61 A study from
South Africa compared a 16-month regimen of intra-
venous methylprednisolone, oral cyclophosphamide,
and oral prednisone, with a short course of intravenous
methylprednisolone for 3 consecutive days followed
by 6 monthly doses of intravenous cyclophosphamide,
as well as administration of prednisone every other
day.62 They found that 86% of those treated with the
protocol used by Mendoza and Tune had either a com-
plete or partial remission, compared with 60% of those
treated with shorter course of therapy.62 However, the
shorter protocol cost one sixth that of the longer proto-
col, and it required 75% fewer hospital visits.62
Overall, the use of pulse intravenous methylpred-
nisolone offers the highest reported remission rate in
the treatment of SRNS caused by FSGS.
Cyclosporine
Because the causes of FSGS and MCNS are believed
to be immunologically mediated, cyclosporine repre-
sents a logical medical therapy for SRNS. Cyclosporine
causes immunosuppression primarily of the T lympho-
cytes through its inhibition of the production of inter-
leukin-2 and other lymphokines.63 However, there are
few well-designed trials to evaluate its efficacy in treat-
ing SRNS. Instead, its effectiveness in treating SRNS
has been extracted from numerous retrospective and
uncontrolled studies. The cumulative data from these
studies suggest an improvement in outcome of pediatric
patients with SRNS treated with cyclosporine.
Several uncontrolled, mostly retrospective, studies
have evaluated the efficacy of cyclosporine therapy for
the pediatric patients with SRNS (Table 3). Most of
these studies have had less than 20 subjects, although
289
TABLE 3. Uncontrolled trials of cyclosporine for the treatment of steroid-resistant nephrotic syndrome
No. of Complete Partial No
patients with remission remission response CRF ESRD Follow-
Authors Disorder Treatment SRNS No./% No./% No./% No./% No./% up (y)
Melocoton et al64 FSGS (n = 6), CSA, Pred 10 1/10 1/10 8/80 NR/NR 2/20 NR
MCNS (n = 4)
Niaudet et al65 MCNS (n = 19), CSA, Pred 31 14/42.5 3/9.7 14/45.2 0/0 1/3.2 NR
FSGS (n = 12)
Niaudet et al66 MCNS (n = 45), CSA, Pred 65 27/41.5 4/6.2 34/52.3 5/7.7 13/20 3.2
FSGS (n = 20)
Hymes et al67 MCNS (n = 7), CSA, Pred 18 9/50.0 5/27.8 4/22.2 2/11.1 2/11.1 NR
FSGS (n = 4),
MHC (n = 7)
Ingulli et al68 FSGS (n = 21) CSA, Pred 21 12/57.1 1/4.7 NR/NR 6/28.6 5/23.8 8.5
Gregory et al69 FSGS (n = 3), CSA, Pred 15 13/86.7 2/13.3 NR/NR NR/NR NR/NR NR/NR
MCNS (n = 3),
IgM (n = 9)
Garcia et al70 MCNS (n = 2), CSA, Pred 19 5/26.3 5/26.3 9/47.4 0/0 0/0 1.1
FSGS (n = 17)
Hino et al71 MCNS (n = 4), CSA, Pred 11 7/63.6 1/9.1 3/27.3 0/0 0/0 6.5
FSGS (n = 7)
Singh et al72 MCNS (n = 6), CSA 83 54/65.1 9/10.8 20/24.1 NR/NR 20/24.1 NR
FSGS (n = 42),
IgM (n = 17),
MPGN (n = 8),
SLE (n = 5),
HIV (n = 4),
MGN (n = 1)
Seikaly et al73 MCNS (n = 3) CSA, Pred 3 2/66.7 1/33.3 0/0 0/0 0/0 3.4
Total 276 144/52.1 32/11.6 92/33.3
SLE, Lupus nephritis; HIV, HIV nephropathy; CSA, cyclosporine; Pred, prednisone; NR, not reported.

one monitored 83 patients. The complete response to
therapy ranged from 10% to 86.7%.64-73 The mean
percentage of complete responders from these studies
is 52.1%, with an additional 11.6% of patients having
a partial remission. The complete failure to respond to
cyclosporine ranged from 0% to 80%, with a mean of
33.3%. The definitions of complete, partial, and no
response varied among studies, as did the duration of
follow-up and the documentation of progression of
renal disease in the study participants. Therefore it is
difficult to draw firm conclusions from these results.
Two randomized, placebo-controlled, prospective
trials have evaluated the efficacy of cyclosporine in the
treatment of SRNS. Lieberman and Tejani74 random-
ized 25 pediatric patients with biopsy-proven FSGS to
receive monotherapy with either cyclosporine or place-
bo for their glomerulonephritis. Of the 12 patients ran-
domized to receive cyclosporine, 4 (33.3%) experi-
enced a complete remission, and 8 (66.7%) had a
partial response.74 This is in contrast to the control
subjects, of whom only 2 (17%) had partial responses
and none had a complete response.74 In a second open,
prospective, randomized controlled study, Ponticelli et
al75 reported that 4 (40%) of 10 pediatric patients ran-
domized to receive cyclosporine experienced a com-
plete remission, and another 2 (20%) had partial remis-
sion.75 Those treated with cyclosporine also
experienced a decrease in their cholesterol and an
increase in their serum albumin and total proteins.75
Overall, it appears that nearly 60% of patients with
SRNS can be successfully treated with cyclosporine
therapy and achieve either a complete remission or at
least a partial remission. However, cyclosporine thera-
py is not a benign treatment. Minor side effects include
hypertrichosis, nausea, vomiting, headaches, and gin-
gival hyperplasia. More serious side effects include
hypertension, hyperkalemia, and usually reversible
acute renal insufficiency. In addition, cyclosporine is a
known nephrotoxin, and it has been associated with
progressive interstitial fibrosis and tubular atrophy not
resulting from the evolution of FSGS.71,73 Serum cre-
atinine, particularly in children, does not adequately
reflect the degree of interstitial fibrosis and tubular
atrophy that occurs during cyclosporine therapy.71-73,76
A final concern regarding the use of cyclosporine in
the treatment of SRNS is that relapse is very common

290 Curr Probl Pediatr, October 2001

after patients discontinue taking the cyclosporine.
Although not all of the studies published data on
relapse rates, those that did indicated a range of 10.0%
to 85.7% (mean of 41.9%) of patients with SRNS who
had a relapse on the discontinuation of cyclosporine.
ACE Inhibitors
ACE inhibitors decrease proteinuria, presumably as a
result of a combination of effects, including the reduc-
tion of intraglomerular capillary pressure by dilating the
efferent arteriole and by modifying glomerular permse-
lectivity.77 Several uncontrolled, prospective studies
have evaluated the effects of ACE inhibitors on protein-
uria in SRNS in children. All of these studies demon-
strated a nearly 50% reduction in urinary protein excre-
tion from baseline after the children were treated with
an ACE inhibitor.77-80 Unfortunately, in spite of the
marked decrease in proteinuria, many of these patients
continued to have a 24-hour urinary protein excretion in
excess of 1 g/d.78,80 Delucchi et al79 also described that
with the decrease in proteinuria following treatment
with an ACE inhibitor in the nephrotic patient, the qual-
ity of the proteinuria changes from a nonselective pro-
teinuria to a selective-albuminuria.79
In addition to their antiproteinuric effects, ACE
inhibitors can decrease serum lipid levels out of propor-
tion to the improved serum albumin and the decreased
proteinuria.77,80 Some of these studies also reported that
monotherapy with ACE inhibitors normalized the serum
total cholesterol level.78,80
Although these steroid-resistant patients with SRNS
experienced a decline in their proteinuria, as well as a
decline in their hyperlipidemia, no consistent finding
was identified with regard to the effect of ACE
inhibitors on serum albumin nor creatinine clearance.78
Because both of the proteinuric and hyperlipidemic
mechanisms are hypothesized to contribute to glomeru-
lar damage in nephrotic syndrome, their clinical
improvement may explain the renoprotective character-
istics of ACE inhibitors. As such, ACE inhibitors appear
to be of benefit in the treatment of SRNS resulting from
their renoprotective effects.
Treatment of Hyperlipidemia
Hyperlipidemia is a well-known consequence of the
nephrotic syndrome. Hyperlipidemia may contribute to
the permeability of the GFB, to the development of pro-
teinuria, and to the progression of glomerulosclerosis
and tubulointerstitial fibrosis.81-83 Therefore treatment of
hyperlipidemia may potentially reduce glomerular and
Curr Probl Pediatr, October 2001
tubular injury, as well as decrease the degree of protein-
uria associated with persistent SRNS.
Several uncontrolled trials of hydroxymethylglu-
taryl-CoA reductase inhibitors in children with
nephrotic syndrome have demonstrated significant
decreases in serum total cholesterol, LDL-cholesterol,
and triglycerides,81 as well as a decrease in total
lipids.83 Unfortunately, none of these studies has
shown a decrease in proteinuria or any change in the
rate of progression of the decline in renal function.
Whereas treated patients experienced a significant
decline in lipid and cholesterol levels from baseline,
the levels remained above normal in most patients.
Lack of significant improvement in proteinuria or renal
function with medical therapy alone may result from
an inability to normalize the serum values of total cho-
lesterol, LDL-cholesterol, or triglycerides.
LDL-apheresis therapy has been used to aggressive-
ly correct the hyperlipidemia associated with persistent
nephrotic syndrome. A retrospective preliminary study
demonstrated rapid amelioration of proteinuria with a
concomitant increase in serum protein levels and an
improvement in renal function in 5 of 8 patients
(62.5%) treated with LDL-apheresis therapy.82 In a
subsequent, prospective, uncontrolled trial of LDL-
apheresis therapy on 17 patients with FSGS, 12 of 17
(70.5%) patients experienced either complete [8 of 12
(66.7%)] or partial [4 of 12 (33.3%)] remissions.82
Those patients responding to LDL-apheresis also
experienced a significant decrease in their total serum
cholesterol and proteinuria, as well as an increase in
their serum albumin.82 However, no changes in serum
creatinine after therapy were observed. The average
duration of therapy necessary for improvement in pro-
teinuria was 14.7 days, with patients undergoing LDL-
apheresis 2 times a week for 3 weeks, followed by
weekly treatments for an additional 6 weeks.82
Mycophenolate Mofetil
Mycophenolate mofetil and mizoribine are new
immunosuppressant medications that prevent the de
novo purine synthesis pathway by inhibiting the
enzyme inosine monophosphate dehydrogenase. As a
result, these agents preferentially inhibit both T- and
B-lymphocyte proliferation. Other cells are protected
from these effects by their use of the purine salvage
pathway.83,84 They also interfere with activated lym-
phocyte adhesion to endothelial cells by inhibiting gly-
cosylation of adhesion molecules.84,85 Recently,
mycophenolate and mizoribine have been reported to
291
decrease proteinuria in adults with membranous
nephropathy by 50%86 and to decrease the relapse rate
in children with frequently relapsing nephrotic syn-
drome.87 Mycophenolate has undergone an uncon-
trolled prospective study in 8 selected adults with
SRNS or frequent relapsing nephrotic syndrome.84 The
glomerular diseases included MGN (n = 3 patients),
MCNS (n = 2), lupus nephritis (n = 2), and FSGS (n =
1). They found that mycophenolate therapy resulted in
significant reductions in proteinuria and stabilization of
the serum creatinine.84 Mycophenolate also had a
steroid-sparing effect allowing steroid withdrawal in all
of the patients except those with lupus nephritis.84
Two small prospective, uncontrolled trials of myco-
phenolate in steroid-resistant FSGS have been report-
ed. In the first report, 10 adolescent and adult patients
with FSGS and nephrotic-range proteinuria underwent
6 months of treatment with prednisone, an ACE
inhibitor, and mycophenolate. Four patients were
excluded from the analysis resulting from medical
noncompliance. There was no significant improvement
in either their 24-hour proteinuria or serum creatinine
in the remaining 6 patients.88 In a second report, 11
adult patients with FSGS and nephrotic-range protein-
uria were treated with either an ACE inhibitor or an
angiotensin-receptor antagonist plus mycophenolate
for a mean of 28 weeks. Although there was a statisti-
cally significant decrease in proteinuria after treatment
with mycophenolate, the actual decrease was from 6.8
g/24 h to 5.7 g/24 h, a difference that was not clinical-
ly important.89 No patient went into complete remis-
sion. At this time, mycophenolate does not appear to
decrease proteinuria to a clinically significant degree
in patients with SRNS resulting from FSGS.
Plasma Exchange and Immunoadsorption
Although the pathogenesis of SRNS and FSGS
remains elusive, it has been postulated that a circulat-
ing factor may be responsible for increased glomerular
permeability to albumin.21,90,91 Because of this possi-
bility, plasma exchange has been used in the treatment
of SRNS caused by FSGS in both primary disease and
in recurrent disease in renal allografts.
In a retrospective study, 7 pediatric patients with pri-
mary steroid- and cyclosporine-resistant FSGS under-
went plasma exchange therapy for their nephrotic syn-
drome. Two of the 7 patients (28.6%) went into
complete remission, and 2 (28.6%) more experienced
partial remission.91 All of the patients received intra-
venous methylprednisolone during their plasma
292
exchange therapies, and several of them continued to
receive ACE inhibitors, as well as cyclosporine, anti-
hypertensive, and antihyperlipidemia medications.
Two of the initial responders underwent plasma
immunoadsorption therapy with significant reductions
of their proteinuria.91 These authors concluded that the
responses to plasma exchange and plasma immunoad-
sorption therapies support the theory of a glomerular
permeability factor circulating in patients with FSGS,
and that these therapies improve proteinuria by remov-
ing these factors.91
Vitamin E
Vitamin E is a naturally occurring antioxidant that
may protect against kidney damage caused by reactive
oxygen molecules. A single prospective, uncontrolled
study of the effects of vitamin E on proteinuria in pedi-
atric patients with FSGS found a 58% reduction in pro-
teinuria in 10 of 11 participants (90.9%), although the
follow-up mean urine protein/creatinine ratio remained
markedly abnormal at 4.1.92 However, the duration of
treatment was only 2.9 months, which may have been
too short to demonstrate any further reduction in pro-
teinuria.92 Antioxidant therapy with vitamin E may
reduce the proteinuria associated with FSGS and retard
the progression of glomerular and tubulointerstitial
damage attributed to persistent proteinuria.
Tacrolimus
Tacrolimus has been used in the treatment of SRNS,
as well as in the treatment of nephrotic syndrome that
develops after kidney transplantation. Two uncon-
trolled trials and a case report of tacrolimus have
demonstrated that it successfully decreased protein-
uria.93-95 Seven pediatric and adult patients with SRNS
received tacrolimus monotherapy. All 7 patients had
significant decreases in proteinuria, although only 3
(42.8%) patients, including 2 children with FSGS,
demonstrated sustained improvement of their protein-
uria to subnephrotic ranges.93 Discontinuation of the
tacrolimus by 2 patients resulted in prompt relapse of
their proteinuria to the nephrotic range, with remission
again achieved with reinstitution of tacrolimus thera-
py.93 The most common side effect of tacrolimus ther-
apy was a decrease in the calculated creatinine clear-
ance that improved when the tacrolimus was decreased
or discontinued. A case report in an adult patient with
SRNS described remission of cyclosporine-resistant
and SRNS with a combined regimen of corticosteroids
and tacrolimus.94
Curr Probl Pediatr, October 2001
 Tacrolimus therapy for the treatment of nephrotic syn-
drome developing in 17 patients who had undergone
transplantation has been reported. Of these patients, 9
had development of nephrotic syndrome caused by
glomerulopathies not resulting from chronic allograft
nephropathy. Six patients (66.6%) had a decrease of
50% or greater in their proteinuria with the conversion
from cyclosporine to tacrolimus, although only 2
(22.2%) patients’ 24-hour urine calculations of protein-
uria were less than 1000 mg.95 Only one of the 3 pedi-
atric patients had a significant decrease in proteinuria.95
Tacrolimus is a potent immunosuppressive agent that
inhibits calcineurin and thus interleukin-2 production.
Its mechanism of action in treating SRNS is unclear.
Potential mechanisms for the antiproteinuric effects of
tacrolimus include the inhibition of T-cell lymphokine
production, the improvement in the permselectivity of
the glomerular basement membrane, a correction of an
underlying immunologic defect, or a reduction of the
glomerular filtration rate.93 Whatever the mechanism
of action of tacrolimus is, it appears to offer improve-
ment in the proteinuria of at least some patients with
SRNS.
Azathioprine
Azathioprine has long been regarded as having no
benefit in the treatment of SRNS. The ISKDC con-
ducted a prospective, double-blind, clinical trial to
compare azathioprine plus corticosteroids with corti-
costeroids alone for the treatment of the nephrotic syn-
drome. Of 197 children enrolled, 31 (15.7%) were
found to be steroid resistant.96 Of these 31 patients, 16
were randomized to receive azathioprine, and 15 were
randomized to placebo.96 Four (25.0%) of those
receiving azathioprine experienced a decrease in their
proteinuria (2 had complete remission [12.5%], and 2
had decreased proteinuria).96 In contrast, 2 of 15
(13.3%) of those treated with placebo had complete
remission, with an additional 2 who had development
of decreased proteinuria.96 They also found that 12 of
the 127 (9.4%) biopsy-confirmed diagnoses were
FSGS and that 10 of the patients (83.3%) were steroid
resistant.96 These authors concluded that azathioprine
offered no improvement in outcome compared with
placebo in the treatment of SRNS.96
In another prospective, uncontrolled study in pedi-
atric patients with nephrotic syndrome, 20 (55.6%) of
36 patients had SRNS.97 After combined treatment
with azathioprine and prednisone, 11 patients (55%)
had a decrease in their proteinuria.97 Only 2 of those
Curr Probl Pediatr, October 2001
with SRNS (10%) had sustained remission of their
proteinuria. Three patients (15%) received a renal
transplant, and 15 patients (75%) died.97
In contrast to these studies that found no significant
effect of azathioprine on proteinuria in SRNS, Cade et
al98 reported that 13 of 31 (41.9%) of adolescents and
adults with SRNS treated with azathioprine for 4 years
achieved complete remission after 1 to 3 years of ther-
apy. Three of the 13 (23.1%) patients were younger
than 21 years of age, and 2 of the 3 (66.7%) main-
tained complete remission after azathioprine treat-
ment.98 These results have not been reproduced and
are significantly out of agreement with the prior stud-
ies of azathioprine’s efficacy. No additional prospec-
tive, double-blind controlled studies with azathioprine
have been conducted to better define its role in the
treatment of SRNS.
Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs),
including indomethacin, ibuprofen, diclofenac, flur-
biprofen, and meclofenamate, have been used to
decrease the proteinuria associated with the nephrotic
syndrome.99 NSAIDs decrease proteinuria out of pro-
portion to the decrease in glomerular filtration rate, thus
they appear to have some additional effect on the
GFB.99,100 Proposed mechanisms of action include inhi-
bition of prostaglandin synthesis resulting in afferent
arteriolar vasoconstriction and a decrease in the
glomerular filtration rate,98 restoration of the permse-
lectivity of the glomerular filtration barrier,99 and atten-
uation of the inflammatory reaction.100 The exact mech-
anism responsible for the decrease in proteinuria
remains unknown.
The use of NSAIDs, however, entails certain risks.
Kidney failure, both reversible100 and irreversible,101
has been the most severe complication of NSAID ther-
apy. However, one group noted that the risk of kidney
failure or failure to achieve remission was increased in
those patients with diminished renal function at the
time of initiation of NSAID therapy.100 They recom-
mended that only patients with greater than 50% renal
function should be considered for NSAID therapy.
Other complications of NSAID therapy for nephrotic
syndrome include inducing a positive sodium balance
and exacerbating edema formation, interstitial nephri-
tis, and worsening of proteinuria.100 Additionally,
treatment failures are commonly reported for pediatric
patients,99 making them less than suitable candidates
for NSAID therapy.
293
Vincristine
Vincristine generally has been believed to be ineffec-
tive in the treatment of SRNS. Vincristine is a plant alka-
loid that blocks mitosis and metaphase arrest by binding
to the microtubular protein tubulin.102 It has been evalu-
ated in the treatment of SRNS in retrospective, uncon-
trolled studies. In one such study, 2 of 7 pediatric patients
(28.6%) had a complete and sustained remission of their
nephrotic syndrome after 8 weeks of treatment with daily
prednisone and weekly vincristine (1.5 mg/m2/dose).103
Five patients (71.4%) had no response to this regimen.103
In a second uncontrolled study, 2 of 8 patients (25%)
experienced remission of their nephrotic syndrome after
treatment with weekly vincristine monotherapy.102 One
of these 2 responders experienced several relapses during
follow-up, although each episode responded to reinitia-
tion of vincristine therapy.102 These authors found that
those patients who did not respond to vincristine had
moderate-to-severe renal impairment at the time of ther-
apy, whereas the responders had normal renal func-
tion.102 Thus they hypothesized that renal insufficiency
at the initiation of therapy explained the failure to
respond to vincristine.102
Mercaptopurine
Mercaptopurine is a potent antimetabolite that inter-
feres with the immune system by blocking purine metab-
olism. As a result of its immunosuppressive effects, it has
been used to treat adults with SRNS. We found no stud-
ies in the pediatric population with mercaptopurine used
to treat SRNS. In a prospective uncontrolled trial, 10
adults with SRNS caused by a variety of underlying dis-
orders were administered 14 courses of mercaptopurine
therapy. One patient (10%) had complete remission but
soon relapsed on withdrawal of the mercaptopurine.104
Four patients (40%) experienced partial remission, with
a significant decrease in their proteinuria associated with
an increase in serum albumin and a resolution of
edema.104 Unfortunately, 13 of the 14 (92.8%) courses of
mercaptopurine were complicated by leukopenia, and a
significant number of the patients experienced some
degree of anemia (n = 7), thrombocytopenia (n = 5),
mucosal lesions (n = 5), gastrointestinal symptoms (n =
3), and rashes (n = 1).104 Owing to its high incidence of
toxicity, mercaptopurine has not undergone any further
study in the treatment of SRNS.
Pefloxacin
Pefloxacin, a fluoroquinolone, has been reported to
successfully decrease proteinuria in SRNS. Pruna et
294
al105 first described remission of nephrotic syndrome in
a patient with MCNS who was treated with pefloxacin
for a bacterial infection. Two other patients with
nephrotic syndrome, one with MCNS and the other with
FSGS, received pefloxacin with a similar response.105
As a result of these observations, these authors recom-
mended pefloxacin as a first-line therapy for nephrotic
syndrome resulting from MCNS and FSGS.105
Since this initial report, other investigators have
questioned these results while raising concerns about
the safety of pefloxacin. No improvement was found
when pefloxacin was used to treat both MCNS and
FSGS SRNS in pediatric and adult patients.106-108
Adverse events associated with the pefloxacin therapy
included arthralgias with joint effusions, intracranial
hypertension, nausea, and acute kidney failure.106,107
Most recently, pefloxacin was studied in a rat model of
idiopathic nephrotic syndrome, adriamycin-induced
nephrotic syndrome.109 All of the rats developed
nephrotic syndrome after administration of doxoru-
bicin (Adriamycin). Pefloxacin-treated rats had a sta-
tistically significant decrease in their proteinuria by
day 7, but a sustained remission of their proteinuria
was not achieved.109
The mechanism of action of pefloxacin is unclear.
Pefloxacin has been reported to increase production of
interleukin-2 mRNA,105,107,109,110 to decrease inter-
leukin-2 receptor concentration,105,109 and to decrease
interleukin-1 production or release.110 Another mecha-
nism of action may be similar to the fluoroquinolone
flosequinan, which is a direct vasodilator, thereby
reducing glomerular hypertension and proteinuria.110
No controlled trials have been performed with
pefloxacin in human subjects to treat SRNS caused by
either MCNS or FSGS. The anecdotal reports present a
mixed picture of success and a relatively high incidence
of side effects. As a result, pefloxacin is not recom-
mended as a first-line therapy for SRNS.
Levamisole
Levamisole is an antihelminthic agent that has been
found to have immunostimulatory properties. Several
small studies have demonstrated significant antipro-
teinuric effects, as well as steroid-sparing effects in
frequently relapsing and steroid-responsive nephrotic
syndrome.111-116 Two small uncontrolled trials of le-
vamisole in the treatment of SRNS failed to achieve
remission in a single patient.115,116 Side effects of le-
vamisole include flulike symptoms, an erythematous
rash, vomiting, neurologic symptoms, and agranulocy-
Curr Probl Pediatr, October 2001
tosis. Thus, although levamisole may have a role in the
treatment of relapses of nephrotic syndrome in patients
with either steroid-dependent or frequently relapsing
nephrotic syndrome, it does not appear to have a role
in the treatment of SRNS.
Long-term Follow-up
As noted earlier, the outcome of children diagnosed
with SRNS is worse than for those who have a steroid-
responsive nephrotic syndrome. Most patients with SRNS
have FSGS as their histopathologic condition, and, as
noted previously, the incidence of FSGS has been increas-
ing over the past 20 years. Therefore the following data
presented on the outcome of long-term renal function is
taken from the follow-up of patients with FSGS.
The Southwest Pediatric Nephrology Study Group
prospectively monitored 75 pediatric patients with
FSGS, most of whom were treated with cortico-
steroids. After a mean follow-up of 57 months, 21% of
these patients had development of ESRD, with anoth-
er 23% having a decreased glomerular filtration rate by
calculation using the Schwartz equation.13 An addi-
tional 37% of this group of patients had persistent pro-
teinuria, and only 11% went into remission.13 A
Canadian study found similar results in a retrospective
review of 38 children with FSGS. In this study, 34%
had development of ESRD, 11% had development of
CRF, and 13% continued to have proteinuria or mildly
elevated serum creatinine.117 In this review, 42%
achieved remission after a mean of 12.5 years of fol-
low-up.117 Cumulatively, a review of 12 studies of
FSGS in 378 children with a mean follow-up of 5.8
years collected over 20 years revealed that 71% had no
response, 3% had a partial response, and 25% had a
complete remission in response to initial therapies with
corticosteroids as outlined by the ISKDC protocol.118
Two studies have examined the influence of race on
the prognosis in FSGS. FSGS is more common in
African American patients, and these studies demon-
strated that 32% to 45% of African American or
Hispanic patients had FSGS on kidney biopsy, com-
pared with only 20% to 22% of white patients.119,120
Ingulli et al119 found that 78% of their African
American and Hispanic population with FSGS pro-
gressed to ESRD compared with only 33% of white
patients.119 Sorof et al120 found an even worse progno-
sis for African American children with FSGS, because
they had a 5-year actuarial renal survival rate of only
8% as opposed to 31% for white patients.120 Thus, in
Curr Probl Pediatr, October 2001
spite of therapy, a very large majority of African
American children with FSGS will progress to ESRD.
Complications
Complications of SRNS may be a direct conse-
quence of the disease process itself or the result of
treatment of the underlying process. The most com-
mon complications of nephrotic syndrome include
edema, infections, thromboembolic events, malnutri-
tion, anemia, endocrine abnormalities, acute renal fail-
ure, hypertension, and impaired growth.
Edema
Edema formation in nephrotic syndrome may in-
volve 2 major mechanisms. The classical “underfill”
hypothesis states that the massive proteinuria results in
hypoalbuminemia and subsequently decreases the
intravascular oncotic pressure. As a result of decreased
intravascular oncotic pressure, fluid moves into the
interstitial compartment and causes intravascular vol-
ume depletion. The intravascular hypovolemia signals
the kidneys through the renin-angiotensin-aldosterone
system, which results in tubular retention of both salt
and water.18-20,121,122 This theory may be particularly
appropriate for patients with MCNS and normal renal
function.19,121,122
Alternatively, the “overfill” hypothesis states that
avid retention of both sodium and water by the renal
tubules occurs, resulting in increased intravascular vol-
ume. The increased intravascular hydrostatic pressure
favors the movement of fluid into the interstitium.
Recently, measurements of intravascular blood volume
in patients with nephrotic syndrome have found that
many are volume expanded.19 As hypoalbuminemia
develops, both the intravascular and interstitial com-
partments experience a decline in their respective
oncotic pressures, resulting in a constant transcapillary
oncotic pressure.18,19 As the fluid accumulates in the
interstitium, its hydrostatic pressure increases as a
result of the relative noncompliance of this compart-
ment.19 The increased interstitial hydrostatic pressure
should favor the reabsorption of edema. Lymphatic
flow also has been shown to increase up to 90-fold
above normal, allowing further rapid reabsorption of
the interstitial fluid.18 If hypoalbuminemia were the
only factor responsible for the formation of edema,
then these compensatory mechanisms would be
expected to promote the clearance of the edema.
However, the renal tubules appear to develop resist-
295
ance to atrial natriuretic peptides, resulting in an inabil-
ity to excrete sodium and water.18-20,121 The tubular
resistance to atrial natriuretic peptides, combined with a
decreased glomerular filtration rate, filtration fraction,
and glomerular capillary ultrafiltration coefficient,
results in expansion of the plasma volume with concur-
rent increased intravascular hydrostatic pressure.19 The
increased intravascular hydrostatic pressure overcomes
the increasing interstitial hydrostatic pressure, resulting
in the net movement of fluid into the interstitial com-
partment. The expanded plasma volume also suppresses
the renin-angiotensin-aldosterone system.
These two theories should not be thought of as mutu-
ally exclusive. Given the variety of primary and sec-
ondary disorders that can cause nephrotic syndrome, it
is reasonable to assume that different mechanisms of
edema formation may predominate in a particular case.
Infections
Infections represent one of the most serious complica-
tions of nephrotic syndrome. In the past, infections were
the leading cause of morbidity and death in patients with
nephrotic syndrome. Before 1948, as many as 75.1% of
children with nephrotic syndrome had development of a
serious infection, with a mortality rate of 59.6% (range
26.3% to 82.1%).123 Infection continues to be a problem
in patients with nephrotic syndrome, with 70% of the
deaths associated with nephrotic syndrome caused by
infections, and 50% of these being peritonitis.17
Peritonitis should be suspected in those patients with
complaints of abdominal pain, tenderness, fever, and
leukocytosis.7 Edematous skin may become a potential
site of cellulitis when skin breakdown occurs as a result
of the decreased tissue perfusion.19
Increased susceptibility to infections is related to the
proteinuria of nephrotic syndrome and possibly is due
to the immunosuppressive medications used to treat it.
One mechanism for increased susceptibility is the
hypogammaglobulinemia in nephrotic syndrome
caused by IgG being lost in the urine.7,18,19 In addition,
patients with nephrotic syndrome have diminished
opsonization of bacteria as a result of decreased serum
levels of factors B (C3 proactivator) and D necessary
for the alternative complement pathway.7,19 This
results in a particular susceptibility of patients with
nephrotic syndrome to infections by Streptococcus
pneumoniae. Although patients with nephrotic syn-
drome should receive the pneumococcal vaccine, up to
50% of children will have inadequate titers 1 year after
vaccination.7,19 Finally, the immunosuppressive med-
296
ications used to treat nephrotic syndrome are believed
to increase the patient’s risk of infectious complica-
tions, particularly with viruses such as varicella. As a
result, live-virus vaccines should not be administered
until the patient is receiving <2 mg/kg/day (or <20
mg/day) on a daily or alternate-day schedule.123a In
those patients receiving >2 mg/kg/day (or >20 mg/day)
on a daily or alternate-day schedule, live-virus vacci-
nations should be avoided until 2 to 4 weeks after the
discontinuation of corticosteroids.123a
Thromboembolic Events
Although thromboembolic complications occur less
commonly in pediatric than in adult patients with
nephrotic syndrome, they still constitute a serious and
potentially life-threatening complication. The overall
incidence of thromboembolic events in children with
nephrotic syndrome has been reported to be 3.3%, with
a range of 2%36 to 28%.124 This is in sharp contrast
from adults who have a nearly 20% to 50% risk of
thromboembolic events after the exclusion of renal
vein thromboses.19,20 In children with nephrotic syn-
drome, nearly 20% of the thromboembolic events are
arterial in nature, and the risk of a thromboembolic
event in a patient with SRNS is twice that of a patient
with steroid-responsive nephrotic syndrome.36 The
most commonly involved vessels are the deep veins of
the legs, followed by the inferior vena cava, with other
reported episodes of vascular thrombosis occurring in
the renal veins, superior vena cava, the mesenteric
artery, hepatic veins, and middle cerebral arter-
ies.19,36,124 A study in 16 children with steroid-respon-
sive MCNS by use of ventilation/perfusion scans
found a 28% incidence of changes consistent with a
pulmonary embolus, with 38% showing residual changes
and 35% with normal findings.125
Multiple abnormalities in the coagulation pathway
arise as a consequence of nephrotic syndrome. These
changes put the patients at risk for thromboembolic
events (Table 4). Procoagulant serum proteins, including
factors I, II, V, VII, VIII, X, and XIII, are increased as a
result of increased hepatic synthesis.7,17,20,124 Decreased
serum levels of the anticoagulant proteins, specifically
antithrombin III, is a direct result of proteinuria.7,18-20
Antithrombin III levels are lowest when the serum albu-
min level is less than 2.0 g/dL. Theoretically, low-dose
aspirin therapy should compensate for the low
antithrombin III levels, although controlled trials of
aspirin therapy in nephrotic syndrome have not been
performed. Paradoxically, the anticoagulant proteins S
Curr Probl Pediatr, October 2001
TABLE 4. Factors responsible for thromboembolic events in nephrotic syndrome
Proposed mechanisms Altered substance Comments
Increased procoagulant proteins7,17,20,124 Factors I, II, V, VII, VIII, X, and XIII increased Increased because of increased hepatic
synthesis
Decreased anticoagulant proteins7,18-20 Antithrombin III decreased Greatest when serum albumin < 2.0 g/dL
Protein S & C increased, though functionally Increased protein S and C binding pro-
deficient teins further decrease free levels
Altered platelet function7,17,19,20,124 Normal or increased platelet number Increased aggregation in response to colla-
Increased platelet reactivity gen, ADP, thrombin, arachidonic acid, and
epinephrine believed to be due to
increased thromboxane production
Hyperviscosity17,19,36 Volume depletion Caused by volume depletion as a result of
Hyperfibrinogenemia diuretics, and hyperfibrinogenemia

and C levels are increased in the serum in spite of their
urinary loss. However, these anticoagulants are func-
tionally deficient because binding proteins for both pro-
tein S and protein C are increased as a result of
increased hepatic synthesis and are not lost in the urine
because of their large molecular weights.18,19 As a result,
the free levels of these proteins are decreased.18,19
Platelets are dysfunctional in nephrotic syndrome and
are often increased in number. Increased platelet hyper-
aggregability in response to collagen, adenosine diphos-
phate, thrombin, arachidonic acid, and epineph-
rine7,17,19,20,124 appears to be due to increased platelet
synthesis of thromboxane in response to the hypoalbu-
minemia.7 Finally, the risks of thromboembolism in
nephrotic syndrome are increased by hyperviscosity of
the blood caused by hyperfibrinogenemia, as well as
intravascular volume depletion resulting from inappro-
priate use of diuretics.17,19,36
Malnutrition
Because of proteinuria and increased protein catabo-
lism, children with the nephrotic syndrome are in a
state of negative nitrogen balance when they relapse.
Although increasing dietary protein transiently in-
creases the serum total proteins, it also increases albu-
minuria and albumin catabolism.18 Protein restriction,
however, does not allow the patient with nephrotic syn-
drome to reach either a neutral or positive nitrogen bal-
ance. Therefore protein intake of approximately 130%
to 140% of the recommended daily allowance for
stature has been recommended.126
Anemia
Nephrotic syndrome affects hematopoiesis by affect-
ing serum levels of erythropoietin and transferrin.
Erythropoietin is a glycoprotein of intermediate mo-
lecular weight that is synthesized by the kidneys. In
some patients with nephrotic syndrome, erythropoietin
is lost in the urine,18,127 resulting in low plasma levels.
During a relapse of nephrotic syndrome, erythropoi-
etin is markedly reduced in both plasma level and plas-
ma half-life associated with an increase in urinary
excretion and clearance.127 These factors combine to
create an erythropoietin-deficient anemia that is best
treated with achieving remission of the nephrotic syn-
drome.127
In addition to erythropoietin deficiency, patients with
nephrotic syndrome lose transferrin into the urine.18,127
Transferrin is a glycoprotein of intermediate size that
is synthesized predominantly by the liver, which is
responsible for transporting ferric iron atoms to ery-
throid precursors. In a relapse of the nephrotic syn-
drome, it is lost through the nephrotic glomeruli.127
Because transferrin binds 2 ferric iron atoms, urinary
excretion of transferrin also results in iron deficiency.
Thus patients with nephrotic syndrome can have devel-
opment of iron deficiency anemia that can be treated
by both achieving remission of the nephrotic syndrome
and replacing the iron stores. A theoretical complica-
tion of transferrinuria involves iron dissociation in the
proximal tubular lumen. Free iron can generate free
radicals in the tubular lumen and thus contribute to
renal injury. Via this pathway, transferrinuria may lead
to further tubulointerstitial injury and promote pro-
gression of the renal disease.127
Endocrine Abnormalities
Many intermediate-sized binding proteins are lost in
the urine during relapses of nephrotic syndrome. As a
result, metabolism of certain hormonal and mineral
pathways may be disturbed.
Of the hormonal disturbances seen in the nephrotic
syndrome, the most obvious is the disturbance of the
calcium and vitamin D axis. Hypocalcemia has long

Curr Probl Pediatr, October 2001 297

been attributed to the hypoalbuminemia of the
nephrotic syndrome. However, the hypocalcemia
may represent a disturbance of vitamin D metabo-
lism in a subset of patients with nephrotic syndrome
who demonstrate hypocalcemia out of proportion to
the hypoalbuminemia. Vitamin D–binding protein,
which is an intermediate-sized protein, is easily fil-
tered by nephrotic glomeruli.19 The 25-hydroxy-
cholecalciferol [25-(OH)D3] circulates complexed
with vitamin D–binding protein and thus appears in
the urine as well.19 In addition to the urinary loss of
25-(OH)D3 associated with vitamin D–binding pro-
tein, serum levels of total 1,25-dihydroxycholecal-
ciferol [1,25-(OH)D3] are decreased in some patients
with nephrotic syndrome.7,17,19 The clinical impor-
tance of the diminished levels of 1,25-(OH)D3
remains uncertain because few patients have devel-
opment of secondary hyperparathyroidism. Thus the
replacement of vitamin D is only recommended for
those patients with persistent hypocalcemia, evi-
dence of secondary hyperparathyroidism, or those in
whom CRF develops.19
In addition to urinary loss of vitamin D–binding pro-
tein, nephrotic syndrome also results in urinary losses of
both thyroxin-binding globulin and corticosteroid-bind-
ing globulin.7,19 In spite of urinary losses of these two
binding proteins, symptomatic hypothyroidism and
hypocortisolism are not seen. Although some patients
with nephrotic syndrome will have low total T4 and T3
levels, free T4 and thyroid-stimulating hormone levels
are normal, and thus the patients are considered to have
normally functioning thyroid glands.7,19 Similarly,
patients with nephrotic syndrome have decreased total
serum 17-hydroxycorticosteroids, although the percent-
age of unbound cortisol is increased and thus the
patients do not have hypocortisolemia.19
Both zinc and copper deficiencies occur in relapsing
patients with nephrotic syndrome. Urinary loss of
ceruloplasmin in nephrotic syndrome results in low
levels of blood copper, as well as decreased red blood
cell copper levels.19 Zinc levels also are diminished in
patients with nephrotic syndrome because zinc nor-
mally is bound to serum albumin. As a result of albu-
minuria associated with the nephrotic syndrome,
reports have demonstrated a decrease in blood zinc and
an increase in urine zinc levels, respectively.19 The
associated zinc deficiency may have a role in the
growth retardation, ineffective immune responses, and
delayed wound healing that have been described in
pediatric patients with nephrotic syndrome.19
298
Acute Kidney Failure
Acute kidney failure may complicate the manage-
ment of the patient with nephrotic syndrome. Many of
the patients in whom acute kidney failure develops are
diagnosed with anasarca, massive proteinuria, and
oliguria.7,19 It is commonly believed that the cause of
acute kidney failure is hypovolemia or overdiuresis,
leading to diminished renal perfusion and acute tubu-
lar necrosis.17 However, some patients with nephrotic
syndrome have a low fractional excretion of sodium,
which does not support volume depletion as the cause
of acute renal failure in these patients.7 It has been pos-
tulated that acute kidney failure is the result of inter-
stitial edema, which may be visible on percutaneous
biopsy specimens in the absence of acute tubular
necrosis.7,19 Often, these patients have recovery of
their renal function after diuresis induced by either
aggressive diuretic therapy or hemodialysis.7,19
Hypertension
Significant hypertension increasingly is being recog-
nized as a complication of nephrotic syndrome.
Although hypertension has been considered to be a
side effect of corticosteroid therapy, approximately
20% of children with nephrotic syndrome continue to
have hypertension in spite of being in clinical remis-
sion.19 The cause of hypertension may be related to
impaired sodium hemostasis, resulting in sodium
retention and hypervolemia as outlined previously in
the discussion regarding edema formation. An addi-
tional cause may be urinary loss of an antihypertensive
agent, such as nitric oxide that circulates bound to
albumin, as a possible mechanism.19 Regardless of the
cause, sustained hypertension should be treated, with
either the ACE inhibitors or diuretics being the pre-
ferred long-term agents of choice.126
Impaired Growth
Impaired body growth of children with nephrotic
syndrome has long been assumed to be due to a com-
bination of corticosteroid therapy, persistent protein-
uria and malnutrition, and chronic renal insufficiency.
Although corticosteroids antagonize the effects of
endogenous growth hormone,7 studies have shown that
with remission of nephrotic syndrome, partial catch-up
growth occurs.128,129 Prepubertal children have better
final heights than children treated with corticosteroids
during puberty.128 Prepubertal children without renal
insufficiency experience a decrease in their height veloc-
ity during relapses and treatments with corticosteroids,
Curr Probl Pediatr, October 2001
TABLE 5. Known heritable forms of steroid-resistant nephrotic syndrome
Disease Histopathologic study
CNF Minimal Change
Disease
Familial FSGS Focal Segmental
Glomerulosclerosis
Familial FSGS Focal Segmental
Glomerulosclerosis
Familial FSGS Focal Segmental
Glomerulosclerosis
Denys-Drash syndrome Diffuse Mesangial
Hypercellularity
Frasier syndrome Focal and Segmental
Glomerulosclerosis
followed by partial catch-up growth after discontinua-
tion of the steroids during puberty.128 It has been
reported that the mean serum albumin concentrations
correlated with the improvement in height.128 Finally,
those patients with development of ESRD have the
greatest impairment of their final height.128 Thus, the
final height in children with nephrotic syndrome may
be determined by the cumulative dose of cortico-
steroids, the administration of corticosteroids during
the prepubertal versus the pubertal period, the preser-
vation of renal function, and the degree of hypoalbu-
minemia.
Genetic Forms of SRNS
Although most cases of nephrotic syndrome are spo-
radic, familial cases have been reported. Recent
advances in genetics and molecular biology have identi-
fied the genes responsible for several heritable forms of
SRNS. Histologically, these inherited forms of nephrot-
ic syndrome demonstrate either MCNS, FSGS, or dif-
fuse mesangial sclerosis. These recently identified genes
and their respective gene products have shed light on the
roles of the podocyte and the glomerular filtration barri-
er in the development of nephrotic syndrome (Table 5).
Congenital Nephrotic Syndrome of the Finnish
Type (NPHS1)
Congenital nephrotic syndrome of the Finnish Type
(CNF) is a steroid-resistant form of nephrotic syn-
drome characterized by massive proteinuria, hypoalbu-
minemia, and edema that develop shortly after birth.
CNF is inherited as an autosomal recessive disorder
with an incidence of 1:10,000 live births in Finland.130
CNF occurs in other ethnic groups, although at a
markedly lower incidence, with the exception of Old
Curr Probl Pediatr, October 2001
Inheritance pattern Gene locus Gene product
Autosomal Recessive 19q13.1 Nephrin (NPHS1)
Autosomal Recessive 1q25-31 Podocin (NPHS2)
Autosomal Dominant 19q13 Alpha-actinin 4 (ACTN4)
Autosomal Dominant 11q21-q22 Unknown
Sporadic 11p13, exons 8 & 9 Wilms tumor gene (WT1)
Unknown 11p13, intron 9 Wilms tumor gene (WT1)
Order Mennonites in Pennsylvania, who have an
unusually high incidence of 1:500 live births.131 The
natural course of CNF is that it progresses rapidly to
ESRD, and death by the second year of life used to be
the inevitable outcome. Now, bilateral nephrectomy,
optimal nutrition, renal replacement therapy, and kid-
ney transplantation are life-saving.
Recently, the gene responsible for CNF has been
localized to chromosome 19q13.1.130 The gene,
NPHS1, codes for the 1241–amino acid protein
nephrin, a member of the immunoglobulin superfami-
ly.130 Nephrin has been localized in the kidneys to the
podocytes, specifically in the slit diaphragms.132,133
Nephrin’s function remains elusive, although recent in
situ staining for nephrin mRNA and the gene product
shows diminution in animal models of MGN,134 as
well as in human beings with MCNS, FSGS, and
MGN.135 In a murine model, those homozygous for
inactivated NPHS1 had development of a congenital
nephrotic syndrome and died within 24 hours of birth
with massive proteinuria.136 These data suggest a piv-
otal role for the podocyte, as well as the slit
diaphragm, in the development of nephrotic syndrome.
Autosomal Recessive SRNS (NPHS2)
A familial SRNS has been described that is charac-
terized by an autosomal recessive inheritance pattern.
These patients also are characterized by steroid resis-
tance, onset between the ages of 3 months and 5 years,
absence of extrarenal disorders, and either MCNS or
FSGS on the biopsy specimen.137
With the genetic technique of positional cloning, the
gene responsible for autosomal recessive SRNS has
been identified as NPHS2 and has been localized to
chromosome 1q25-q31.137 NPHS2 codes for a
383–amino acid protein named podocin.137 Podocin is
299
expressed by podocytes and appears to be an integral
membrane protein of unknown function.137 Mutations
in NPHS2 may be responsible for sporadic cases of
steroid-resistant FSGS in children.
Autosomal Dominant SRNS (Alpha-actinin-4)
A second form of familial SRNS with an autosomal
dominant inheritance pattern has been reported. These
patients are characterized by an onset in adulthood, pro-
teinuria, progressive renal insufficiency, and focal seg-
mental glomerulosclerosis on histopathologic study.138
The identified candidate gene, ACTN4, had been
localized to chromosome 19q13, the same region as the
gene NPHS1.138 ACTN4 codes for alpha-actinin-4, an
actin-binding and cross-linking protein, found in the
podocyte.138 Alpha-actinin-4 is believed to be involved
in maintaining podocyte foot process architecture
through its presumed interactions with numerous
cytoskeletal, cell-surface, and signaling molecules.138
Autosomal Dominant Focal Segmental
Glomerulosclerosis
A second gene locus for autosomal dominant FSGS
has been identified in a large kindred from New
Zealand. Affected individuals were diagnosed in the
third to fourth decades of life with proteinuria. In those
patients who progressed to ESRD, the average time
between initial presentation and the development of
ESRD was 10 years.139
Using linkage analysis, the gene responsible for this
familial form of autosomal dominant FSGS was local-
ized to chromosome 11q21-q22.139 The affected gene
is currently unknown, although several candidate
genes for metalloproteinases, the interleukin-10 recep-
tor, and apoptosis genes 1 and 2 are known to lie in this
region.139 Of particular interest from this report is that
a second, large kindred of patients from North
Carolina with autosomal dominant FSGS was segre-
gated with neither this gene locus nor ACTN4.139
Denys-Drash Syndrome
An additional form of childhood SRNS occurs in
Denys-Drash syndrome. Denys-Drash syndrome con-
sists of the triad of male pseudohermaphroditism, the
development of Wilms’ tumor, and nephrotic syn-
drome.140,141 Affected children may have a wide variety
of genital abnormalities, ranging from normal genitalia
in patients with 46 XX to ambiguous genitalia or
pseudohermaphroditism in patients with 46 XY.140 The
incidence of Wilms’ tumor in children with Denys-
300
Drash syndrome is elevated, as is the risk for bilateral
tumors.140 Finally, nephrotic syndrome commonly
develops in the first year of life and histopathologically
is characterized by diffuse mesangial sclerosis.140,141
Denys-Drash syndrome now is known to result from
mutations in the Wilms’ tumor suppressor gene
WT1.140-145 WT1 localizes to chromosome 11p13 and is
encoded for by 10 exons, resulting in messenger RNA
subject to alternative splicing.142,146 The final gene
product is a complex protein containing 4 zinc finger
motifs, suggesting a role as a transcription factor.142 The
affected region responsible for Denys-Drash syndrome
lies in exon 9. Missense mutations within exon 9
account for the majority of WT1 mutations identified in
Denys-Drash syndrome.143 These mutations interrupt
the DNA binding capacity of WT1 in vitro by affecting
the amino acids responsible for the stability of the DNA
binding capacity of the zinc fingers.140 WT1 expression
occurs within the developing kidneys in utero, eventual-
ly localizing to the podocytes.143 Thus mutations within
exon 9 of WT1 produce this form of nephropathy,
although the mechanism remains unknown.
Frasier Syndrome
Frasier syndrome is characterized also by male
pseudohermaphroditism and nephropathy, although
Wilms’ tumors do not develop in affected children.
Instead, affected children often have development of
gonadoblastomas.140,141,147 In children affected by
Frasier syndrome, the onset of kidney disease is usual-
ly during the second decade, and the progression to
end-stage kidney failure is more gradual when com-
pared with those children with Denys-Drash syn-
drome. In Frasier syndrome, the renal histopathologic
condition is FSGS.140,141,147 In a recent study of non-
familial primary SRNS, only 1 of 37 patients was
found to have the genetic abnormality associated with
Frasier syndrome.147 This suggests that undetected
Frasier syndrome is unlikely to cause the development
of FSGS.
Frasier syndrome also is associated with mutations
in the WT1 gene, but mutations specifically occur in
intron 9.140,141,144,145 Mutations in the splice-site in
intron 9 result in either the presence or absence of
three amino acids, lysine-threonine-serine (KTS),
between zinc fingers numbers 3 and 4. Mutations
result in the loss of the splice-site and thus decrease the
production of KTS-positive transcripts, whereas the
wild-type allele continues to produce both KTS-posi-
tive and -negative transcripts.142 The altered ratio of
Curr Probl Pediatr, October 2001
TABLE 6. Recurrence rates of FSGS in renal allografts, and risk of allograft loss because of recurrence
Recurrence Recurrence
No. of patients/ Patients Grafts Immunosuppression Grafts lost to FSGS
Authors/Year no. of grafts No./% No./% regimen No./%
Striegel et al148 24/37 12/50% 16/43% P/Aza/ALG; P/Aza/CSA; 14/88%
P/CSA/ALG
Senggutuvan et al149 16/27 (children) 8/50% 10/37% P/Aza; P/CSA; P/Aza/CSA 6/60%
27/32 (adolescents & adults) 3/11% 3/9% P/Aza; P/CSA; P/Aza/CSA 3/100%
Ingulli et al150 28/42 6/21% 6/15% P/Aza; P/CSA 4/67%
Tejani et al151 127/132 26/20% 27/20% Not reported 10/37%
Wühl et al152 39/48 (included ages 4 to 12/31% 14/29% P/Aza/ATG or OKT3; Not reported
25 years old) P/Aza/CSA/ATG or OKT3
Dall’Amico et al153 29/32 15/52% 18/56% P/CSA; P/CSA/Aza; 10/56%
P/CSA/MMF
Butani et al154 20/27 8/40% 8/30% Not reported 3/38%
Kim et al155 22/22 9/41% 9/41% P/CSA; P/CSA/Aza 2/22%
P, Prednisone; Aza, azathioprine; ALG, antilymphocyte globulin; CSA, cyclosporine; ATG, antithymocyte globulin; OKT3, orthoclone; MMF, mycophenolate mofetil.

KTS-positive to KTS-negative transcripts appears to
play a role in the regulation of transcription142,147 and
in the development of Frasier syndrome. In patients
with Frasier syndrome, the ratio of KTS-positive to
KTS-negative isoforms is reversed from the normal
2:1 to 1:2.140,147 Because the WT1 gene product that is
produced is normal structurally, the manifestations of
Frasier syndrome result from the altered ratio of KTS-
positive to KTS-negative isoforms.140 As in Denys-
Drash syndrome, the exact mechanism in the develop-
ment of nephrotic syndrome from the altered ratio of
KTS-positive and KTS-negative isoforms is not
known.
Recurrence of Nephrotic Syndrome
After Transplantation
In those patients who progress to ESRD, kidney trans-
plantation is the desired renal replacement modality.
Unfortunately, several of the glomerulonephritides may
recur in the allograft, thus presenting with the develop-
ment of proteinuria or nephrotic syndrome. In many
optimal treatment for it. The most commonly reported
risk factors for recurrence of FSGS in the allograft
include the following: (1) a young age at the original
onset of nephrotic syndrome; (2) a short time between
onset of the original disease and development of
ESRD; (3) mesangial proliferation on the original
biopsy specimen; and (4) recurrence of FSGS in a
prior allograft. However, these risk factors are not con-
sistent from study to study. Several studies have
demonstrated that the risk of recurrence of FSGS in
allografts is greater in children with an older age of
onset (between 6 to 10 years) of their primary dis-
ease.149,152,153,156 However, other studies have con-
cluded that the risk of recurrence is greater in those
children with an age of onset of FSGS of less than 6
years of age.149 The data regarding duration of disease
before the development of ESRD similarly shows
mixed results. The majority of retrospective reviews
have demonstrated the increased risk for recurrence of
FSGS in patients with a short duration of disease from
presentation until the development of ESRD.148,151-
153,155,156 However, a large retrospective study of pedi-

cases, the recurrence of proteinuria or nephrotic syn-
drome is often steroid resistant. Thus treatment of the
recurrence presents a dilemma for the clinician.
FSGS can recur in the allograft, presenting with
either proteinuria or the nephrotic syndrome. Although
the pathogenesis of FSGS remains unknown, the recur-
rent proteinuria may be related to a circulating perme-
ability factor.90 The reported risk of recurrence of
FSGS in the renal allograft ranges from 15% to 56%,
with graft loss occurring in 37% to 88% of cases
(Table 6). Numerous reviews have sought to identify
risk factors for recurrence of FSGS, as well as the
atric patients with FSGS failed to predict recurrence of
disease on the basis of time to ESRD.149 The presence
of mesangial proliferation on the original biopsy sam-
ple has been shown to increase the risk of recurrence
of FSGS in the renal allograft.148,149 However, other
studies have not confirmed this finding.151,155 Finally,
subsequent allografts after loss of a previous graft to
FSGS have an increased risk of FSGS recur-
rence.148,149,152,153
Additional risk factors for recurrence of FSGS in the
renal allograft have been described. Acute renal failure
and acute tubular necrosis, combined with recurrence

Curr Probl Pediatr, October 2001 301

of FSGS, have been shown to increase the risk of los-
ing the allograft.148,157 The impact of a living donor
allograft compared with cadaveric donor allograft on
FSGS recurrence has been evaluated. Several studies
have shown recurrence rates for FSGS of 50% to 67%
in living donor allografts compared with 19% to 25%
in cadaveric donor allografts.151,154 This has led some
pediatric nephrologists to recommend not performing
living donor transplantation in patients with FSGS. A
single study found that hereditary FSGS does not
recur, as opposed to an increased risk of recurrence in
the patients with sporadic disease.158 Unfortunately,
this study occurred before the various genetic forms of
SRNS were identified, and thus the authors were not
able to identify the recurrence risk associated with
each of the individual genetic defects.
Race also has been identified as a risk factor for the
development of recurrent FSGS in renal allografts.
The recurrence risk for FSGS is 10% in African
American transplant recipients,151,154 compared with
20% in white and Hispanic patients.151 Recently, a
study of the recurrence of FSGS in a homogeneous
Korean population revealed a rate of 41%,155 which is
twice the recurrence risk in either white or Hispanic
patients.154
Treatment of recurrent FSGS has not undergone con-
trolled trials and is based on the belief that there may
be a circulating permeability factor that causes the
recurrence of proteinuria or nephrotic syndrome in
allografts. Cochat et al159 described the use of plasma-
pheresis followed by treatment with intravenous
immunoglobulins, methylprednisolone, and the substi-
tution of cyclophosphamide for azathioprine immuno-
suppression to treat the recurrence of FSGS in 3
patients. Plasmapheresis was begun with 10 sessions
over 2 weeks, with no more than 2 days in between
sessions, followed by 1 session per week for 2
months.159 Azathioprine was discontinued, and each
patient began to receive cyclophosphamide at a dose of
2 mg/kg/d for 2 months.159 All 3 patients experienced
improvement in their serum creatinine, as well as res-
olution of their proteinuria.159 Other nonrandomized
uncontrolled studies have applied variations of this
protocol, such as adding methylprednisolone,160 dis-
continuing mycophenolate mofetil and beginning
cyclophosphamide,153 or increasing the dosage and the
target trough levels of cyclosporine.150 These studies
demonstrated clinical improvement in the proteinuria,
as well as recovery of renal function in most patients.
However, one retrospective study found that resolution
302
of the proteinuria took a mean of 24 ± 17 sessions last-
ing a mean of 150 ± 88 days to accomplish.161
Recurrence of proteinuria and nephrotic syndrome not
resulting from acute cellular rejection also has been report-
ed in patients who underwent transplantation for CNF.
Treatment protocols have used increased prednisone and
cyclosporine doses, as well as switching from azathioprine
to cyclophosphamide.162 In 1993 a Finnish group report-
ed on 29 kidney transplantations performed in 28 patients
with CNF and found a recurrence risk of nephrotic syn-
drome in 7 grafts (24%) in 6 (21%) patients.163 Overall
response to therapy was poor, with only 2 patients (33%)
going into complete remission, 1 patient (16%) going into
partial remission, and 4 grafts (57%) being lost.163 This
group found little response to intravenous methylpred-
nisolone and oral cyclophosphamide.163 Finally, the North
American Pediatric Renal Transplant Cooperative Study
reviewed 132 transplant recipients whose ESRD was due
to CNF. They found 43 graft failures (33%) in this popu-
lation, which was statistically greater than the graft failure
rate (24%) for the patients with other primary kidney dis-
eases.164 Proportional hazards regression analyses
revealed that risk factors for graft loss included a cadaver-
ic source of the allograft and a recipient age less than 2
years of age.164 The leading cause of graft failure in the
recipients with congenital nephrotic syndrome was vascu-
lar thrombosis, occurring in 8.3% of patients with con-
genital nephrotic syndrome compared with 2.9% of other
recipients.164 Unfortunately, the North American Pediatric
Renal Transplant Cooperative Study addressed graft sur-
vival but did not evaluate the recurrence of nephrotic syn-
drome nor its response to therapy.
Conclusions
Steroid-resistant nephrotic syndrome is a relatively
uncommon kidney disease in children, comprising
approximately 20% of children diagnosed with nephrot-
ic syndrome. Of these, most will have FSGS on biopsy,
with a slightly smaller number having MCNS. Although
numerous treatment regimens have been used, approxi-
mately 70% of children with FSGS are nonresponsive to
corticosteroids, and no other treatment regimen has been
found that adequately treats SRNS and FSGS. Because
of the lack of effective treatment and the poor prognosis
with progression to CRI and ESRD, SRNS represents a
significant therapeutic dilemma for pediatricians and
pediatric nephrologists.
SRNS caused by FSGS represents a heterogeneous
group of disorders, and this diversity may explain its
Curr Probl Pediatr, October 2001
variability in response to treatment. This is highlighted
by new genetic research that has identified at least 4
different types of familial FSGS, inherited as autoso-
mal recessive, autosomal dominant, or an unknown
inheritance pattern. Of those forms of familial FSGS
with identified gene products, they appear to be due to
defects in key structural components of the podocyte
and the GFB. Additionally, there certainly are cases of
primary FSGS that involve mediators that alter
glomerular permselectivity. These different causes
may explain the variability of responses to the same
therapy seen in pediatric patients with FSGS.
Delineation of the various forms of FSGS on the basis
of genetic mutations may allow better classification of
primary FSGS and thus allow segregation of patients
to allow for more homogeneity of study populations.
With regard to treatment, both immunosuppressive
and nonimmunosuppressive therapies have been tried.
Corticosteroids remain the mainstay of therapy,
although there is indirect evidence that the course of
therapy is too short to be effective in FSGS. The roles
of intravenous methylprednisolone, cyclosporine,
intravenous cyclophosphamide, and alkylating agents
need to be studied further. The importance of ACE
inhibitors and antihyperlipidemic agents may increase,
given the emerging roles of proteinuria and hyperlip-
idemia on progressive nephropathy.
Thus the state of management of the pediatric patient
with SRNS remains less than ideal. Most importantly,
case-control, randomized prospective clinical trials are
needed to establish the efficacy of the various therapies
for SRNS. If these factors can be addressed, the care of
the pediatric patient with SRNS would be better
defined, with the ultimate benefit of improved health
for these children.
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