Article renal disease

Nephrotic Syndrome:
Pathogenesis and Management
Karl S. Roth, MD,*
Objectives After completing this article, readers should be able to:
Barbara H. Amaker, MD,*
James C.M. Chan, MD† 1. Describe the signs and symptoms of minimal-change nephrotic syndrome.
2. Characterize the laboratory findings in children who have minimal-change nephrotic
syndrome.
3. Plan a treatment program for a young child who has an initial episode of minimal-
change nephrosis.
4. Recognize the major complications of minimal-change nephrotic syndrome.

Introduction
The estimated annual incidence of nephrotic syndrome in healthy children is 2 to 7 new
cases per 100,000 children younger than 18 years of age, making it a relatively common
major disease in pediatrics. The peak age of onset occurs at 2 to 3 years except for the rare,
congenital type of nephrosis. Approximately 50% of affected children are ages 1 to 4 years;
75% are younger than age 10 years. In addition, even the most benign form of the
nephrotic syndrome is, by nature, a recurrent disorder, so each new-onset case likely will
continue to manifest disease for some time. Nephrotic syndrome is one of the most
frequent reasons for referral to a pediatric nephrologist for evaluation, although its
insidious onset frequently causes delay in diagnosis.
Careful examination of the anatomy of a nephron permits characterization of the
glomerular basement membrane as the barrier between the circulation and the external
environment. Thus, the glomerular membrane, which permits passage in an adult of
approximately 180 L/d of fluid, is the final determinant of how much of the solute
originally contained in this volume enters the tubular lumen. The normal glomerular
membrane is remarkably selective for protein compared with other solutes (Table 1). Once
this selectivity is lost, the ensuing proteinuria defines not only the diagnosis of nephrotic
syndrome, but many pathophysiologic consequences as well. It is the purpose of this article
to discuss the definition, causes, pathophysiologic consequences, and management of
nephrotic syndrome. The emphasis is on the idiopathic form, which most often occurs in
children as minimal-change nephrotic syndrome; other types of the nephrotic syndrome
are mentioned briefly.

Definition
As anticipated from the name, the composite of clinical findings can be found either alone
or in association with a number of systemic disorders, including toxicities. The sine qua non
of the diagnosis of nephrotic syndrome is the presence of urinary protein, with the albumin
disproportionately greater than the globulin, deriving from a loss of glomerular membrane
selectivity. In the pediatric age group, urinary protein loss of 50 mg/kg per 24 hours or
greater is a firm diagnostic criterion. It is imperative to recognize the distinctive origin of
the proteinuria in the glomerulus rather than the tubule; nephrotic syndrome may be seen
as exclusively glomerular in origin without any associated tubular dysfunction. Addition-
ally, as a syndrome, the clinical picture may be either primary or secondary, and underlying
causes must be excluded.

*Departments of Pediatrics and Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond,
VA.
†
Department of Pediatrics, The Barbara Bush Children’s Hospital at Maine Medical Center, Portland, ME.

Pediatrics in Review Vol.23 No.7 July 2002 237

renal disease nephrotic syndrome

Selected Materials in
Table 1. (VLDL and LDL, respectively) cholesterol are character-
istic findings. VLDL-cholesterol is increased as a conse-
Glomerular Filtrate Versus Urine* quence of decreased hepatic catabolism, thus increasing
circulating triglyceride and cholesterol. LDL-cholesterol
24-hour
Glomerular is increased due to an enhanced synthetic rate. What
Material Filtrate Urine (24 hour) remains to be elucidated is the cause for these distur-
bances in hepatic lipid metabolism.
Sodium 24,000 mEq 50 to 200 mEq
Potassium 680 mEq 10 to 100 mEq Primary nephrotic syndrome may occur at any age,
Calcium 7 to 10,000 mg Approximately 200 mg from the neonate to the adult. The neonatal or congen-
Glucose 200 g <50 mg ital nephrotic syndrome, also called Finnish congenital
Amino Acids 10 g 50 to 150 mg nephrosis, is clearly defined as a genetic mutation in the
Protein ** <150 mg/L nephrin gene and has been mapped to chromosome
Water 180 L 1.5 L
19q13.1. Nephrin is a glomerular basement membrane
*Data are presented for a “standard adult male”; values for infants and protein that participates in formation of anionic-rich
children vary with gestational age, age in years, and stage of renal
tubular development. sites, causing electrochemical repulsion of plasma pro-
**Data are lacking in the literature. teins. The mutation also has been reported in a Menno-
nite group in Pennsylvania who have no Finnish heritage
and is believed to have arisen independent of the Finnish
Clinical Diagnostic Criteria type. Primary childhood nephrotic syndrome rarely ap-
The diagnostic criteria are: 1) generalized edema; 2) hy- pears before 18 months to 2 years of age and peaks in
poproteinemia (⬍2 g/dL [20 g/L]), with dispropor- incidence at about 3 years of age.
tionately low albumin in relation to globulin; 3) urine
protein (mg/dL) to urine creatinine (mg/dL) ratio in Laboratory Findings
excess of 2 in a first morning void or a 24-hour urine The primary laboratory feature of the nephrotic syn-
protein that exceeds 50 mg/kg body weight; and 4) hy- drome is a marked proteinuria, in excess of 50 mg/kg per
percholesterolemia (⬎200 mg/dL [5.17 mmol/L]). 24 hours (Table 2). The excreted protein is predomi-
The reduced serum albumin, which can fall to as low nantly albumin, although immunoglobulins (Igs) also
as 0.5 g/dL (5 g/L), causes a marked reduction in are lost. In uncomplicated cases of idiopathic nephrotic
plasma oncotic pressure. Consequently, circulatory vol- syndrome, it is unusual to see gross hematuria in the
ume is lost to the interstitial spaces, resulting in general- presence of proteinuria, although microscopic hematuria
ized edema. Often, the initial swelling is observed as occurs in a sizeable proportion of cases. For patients who
facial (especially periorbital) and pretibial edema, with have gross hematuria and proteinuria, IgA nephropathy
prominent swelling of the scrotum or labia also seen. An always must be a diagnostic consideration.
additional consequence of the lowered oncotic pressure In the presence of clinical edema, measurement of
is reduced perfusion of the splanch-
nic capillary bed, which can cause
abdominal pain. Pleural effusions Table 2. Laboratory Findings in the Nephrotic
may form, and frank pulmonary
edema also may occur, with either
Syndrome
or both resulting in tachypnea and Primary Finding Diagnostic Concentration
chest pain.
Levels of serum cholesterol, Proteinuria >50 mg/kg per 24 h
triglyceride, and lipoprotein cho- Hypoproteinemia <2.0 g/dL (20 g/L)
Cholesterolemia >200 mg/dL (5.17 mmol/L) (frequently
lesterol are consistently elevated. >500 mg/dL [12.9 mmol/L])
The mechanism(s) underlying
these changes are not understood Secondary Finding Frequently Found Values
completely, in part due to the com- Hypocalcemia (ionized <9.0 mg/dL (2.25 mmol/L)
plexity of lipid transport and the fraction normal)
Hyperkalemia >5.0 mEq/L (5.0 mmol/L)
difficulties inherent in human clini-
Hyponatremia <136 mEq/L (136 mmol/L)
cal studies. Increases in very-low Hypercoaguability 2partial thromboplastin time (PTT)
density and low-density lipoprotein

238 Pediatrics in Review Vol.23 No.7 July 2002

 renal disease nephrotic syndrome

serum protein will yield low values; the serum albumin is

likely to be 2.0 g/dL (20 g/L) or lower. Albumin Primary and Secondary
Table 3.
concentrations as low as 0.5 g/100 mL can be seen, and
the albumin/globulin ratio is commonly less than 1.0.
Glomerulopathies
Concomitantly, and directly related to the reduced se- Idiopathic Minimal-change Nephrosis
rum protein, hypocalcemia is found frequently, as re-
flected in reduced total and ionized fractions. However, Focal Segmental Glomerulosclerosis
hypocalcemia rarely is manifested clinically. Idiopathic
Of much greater significance than hypocalcemia to Obesity
patients who have nephrotic syndrome is the increased Unilateral renal agenesis
concentrations of coagulation factors, especially those of Glycogen storage disease
Postinfectious glomerulonephritis
high molecular weight. Thrombin also is increased, while Obstructive uropathy
fibrinolytic activity and circulating quantities of platelet Lupus nephropathy
adhesion inhibitors are decreased. As a consequence of Sickle cell disease
these changes, as well as the intravascular hypovolemia, Alport syndrome
affected patients are at greatly increased risk of thrombo- Membranous Glomerulonephritis
sis. In addition, IgG in plasma is reduced, which in Idiopathic
combination with large steroid doses, may predispose to Lupus nephropathy
infection. Sickle cell disease
Children who become oliguric from diminished intra- Sarcoidosis
vascular volume have a tendency to develop hyperkale- Hashimoto thyroiditis
Heavy metal toxicity
mia. The use of diuretics may complicate the electrolyte Captopril
disturbances further, necessitating close monitoring of Penicillamine
serum electrolyte levels during treatment. Nonsteroidal anti-inflammatory drugs
Syphilis
Hepatitis B and C
The Need for a Renal Biopsy Membranoproliferative Glomerulonephritis
In the acute stage of childhood nephrotic syndrome, Chronic bacterial infection
especially during the initial episode, renal biopsy usually Chronic viral infection
is unnecessary. The key indications for biopsy in any renal Lupus nephropathy
disorder are the need to make a specific diagnosis for Rheumatoid arthritis
Chronic liver disease
therapeutic reasons or to provide a prognosis. The treat- Sickle cell disease
ment of initial-onset nephrotic syndrome is the same, Renal transplant
irrespective of cause, and the need for determining a Bone marrow transplant
prognosis never can outweigh the risks of thrombosis,
bleeding, and infection due to a biopsy in the acute stage
of the disorder. family’s anxieties over the immediate medical problems
The subsequent disease course in a patient can help to have dissipated.
determine the timing of a renal biopsy. In an uncompli- In contrast, when there is poor or no response of the
cated case in which proteinuria clears within a few weeks initial episode after 4 to 6 weeks of standard treatment
in response to orally administered corticosteroids and (defined as steroid-resistance disease), biopsy should be
normal renal function, the diagnosis is presumed to be considered as soon as the patient is medically stable. In
minimal-change nephrotic syndrome. If there is no sig- such cases, the biopsy is essential to distinguish the
nificant proteinuria between relapses that continue to nature and severity of the glomerular process, which may
respond promptly to corticosteroids, this diagnosis is be primary or secondary (Table 3). It should be clear
strengthened. If the child is younger than 10 years of age from the plethora of types and causes of glomerular
at the initial presentation, no renal biopsy need be con- nephropathy that treatments and prognoses vary consid-
sidered. At age 10 years or older, the increasing risk of erably, making specific diagnosis imperative. Because
underlying primary disease compels the need to obtain a proteinuria and microscopic hematuria are injury re-
biopsy for histologic diagnosis. In such cases, renal bi- sponses of the glomerulus, the need for clarification
opsy can be deferred until the child is stable and the through renal biopsy is plain. The underlying pathology

Pediatrics in Review Vol.23 No.7 July 2002 239

renal disease nephrotic syndrome
Figure 1. A. Light microscopic view of a normal glomerulus
(Jones silver stain). B. Electron micrograph showing normal
glomerulus with well-defined epithelial cell foot processes.
(Figs. 1 to 5) varies with age; the incidence is summa-
rized in Table 4. The indications for initial kidney biop-
sies in the nephrotic syndrome are summarized in Table
5.
Beyond the issue of renal biopsy for initial diagnosis,
there are circumstances in which a subsequent biopsy
may be considered. Glomerular injury may evolve over
time such that the clinical findings (eg, increasing pro-
teinuria, development of chronic renal insufficiency)
change significantly. Such cases may represent progres-
sion of a disease that initially was diagnosed as minimal-
change nephrosis by biopsy or progressive injury to the
kidney by an underlying disease such as lupus nephrop-
athy. In these situations, a second renal biopsy should be
considered for evaluation of progressive renal disease.
Technological developments in ultrasonography have
reduced significantly the risk associated with percutane-
ous renal biopsy in children. Moreover, the improve-
ments in electron microscopy equipment and technique,
coupled with decades of observation, have enhanced the
ability of the histopathologist to interpret the specimen
accurately. Nonetheless, a renal biopsy is not always
240 Pediatrics in Review Vol.23 No.7 July 2002
Figure 2. A. Light microscopic view of minimal-change dis-
ease. The glomerulus is normal at the light microscopic level
(PAS stain). B. Diffuse epithelial cell foot process effacement
is seen, and lipid droplets are present in the cytoplasm of the
visceral epithelial cell.
essential to good medical care, and its use should be
viewed judiciously in all patients.
Treatment
The treatment of primary childhood nephrotic syndrome
is supportive and will be determined largely by the pa-
tient’s clinical status. Boys can experience scrotal edema,
which may cause testicular torsion. Other children may
become short of breath due to pulmonary edema; still
others may become oliguric and develop a functional
azotemia. The latter is due to reduced circulating volume
in the vascular space that results in temporary renal
insufficiency. Any of these presentations, alone or in
combination, demands immediate attention to symp-
tomatic treatment.
Treatment of Acute-onset Disease
The unifying factor in this disease is depleted blood
volume as a consequence of low oncotic pressure. There-
fore, treatment should be directed at returning fluid to

Figure 3. A. Segmental sclerosis of the glomerular tuft as seen with light microscopy (PAS stain). B. Immunofluorescence
demonstrates the presence of IgM in the segmentally sclerotic portion of the glomerulus. C. The visceral epithelial cell contains
vacuoles, and focal foot process effacement is seen.
the vascular space and encouraging diuresis to avoid
volume overload (Table 6). The intuitive solution to the
diminished oncotic pressure is to restore serum albumin
concentration to better than 2 g/dL (20 g/L) by intra-
venous infusion. However, the effectiveness of this mea-
sure is reduced considerably because of the hypoalbu-
minemia resulting from glomerular leakage of serum
protein. The degree of urinary loss can be illustrated by
the hepatic rate of albumin synthesis, which in adults can
be as high as 12 to 14 g/d. If a patient becomes hy-
poalbuminemic at such endogenous rates of replace-
ment, it is apparent that replacement by infusion can only
be a temporary remedy. Nonetheless, for a patient who
has pulmonary edema or renal shutdown, intravenous
albumin (1 g/kg of a 25% solution) can be very effective
in mobilizing fluid into the vascular space. The rate of
increase in oncotic pressure is directly proportional to the
rate of expansion of intravascular volume. Thus, too
rapid an infusion will place the child at risk for congestive
renal disease nephrotic syndrome
heart failure. Accordingly, intravenous albumin should
be infused continuously over 8 to 12 hours under close
supervision.
As intravascular space expands, renal perfusion im-
proves, and with it, the opportunity to reduce accumu-
lated fluid volume is enhanced. Administration of a di-
uretic is the obvious means by which to maximize this
opportunity. Keeping in mind that a normal or low
serum sodium concentration is likely to represent the
result of a dilutional effect, the choice of diuretic should
be directed at sodium as well as at water excretion. An
ideal choice is a loop diuretic such as furosemide, which
can be administered at a dose of 1 to 2 mg/kg intrave-
nously and acts within 15 minutes. Furosemide-induced
inhibition of active chloride reabsorption in the ascend-
ing loop of Henle results in urinary excretion of sodium,
chloride, and water. A portion of the calculated furo-
semide dose can be administered during the albumin
infusion or it all can be administered at the end of the
Pediatrics in Review Vol.23 No.7 July 2002 241
renal disease nephrotic syndrome
Figure 4. A. Hypercellularity and lobulation is seen in this
glomerulus (PAS stain). B. Broad granular staining for com-
plement 3 is present along glomerular capillary walls. C.
Electron micrograph showing a large, discrete, electron-dense
subendothelial deposit and “reduplication” of the glomerular
basement membrane.
infusion, depending on the volume of urine output and
the degree of edema.
Debate continues over the true benefit of albumin
infusion, and no resolution is in sight. Nonetheless, it is
difficult to argue against its use in the clinical settings of
pleural effusion, pulmonary edema, or impending renal
shutdown due to depleted intravascular volume.
242 Pediatrics in Review Vol.23 No.7 July 2002
Figure 5. A. Diffuse uniform thickening of the capillary walls
is seen (PAS stain). B. Finely granular staining with IgG is seen
along the capillary walls. C. Electron micrograph showing
idiopathic membranous glomerulonephropathy, stage II to III.
Columns (“spikes”) of basement membrane-like material pro-
trude between the subepithelial electron-dense deposits.
Some of the deposits are embedded in the glomerular base-
ment membrane.
The child should be started on oral corticosteroid
therapy after a negative tuberculosis skin test result has
been determined. Prednisone is the usual drug of choice,
and the recommended maximum daily dose is 60 mg/m2

Underlying Renal Pathology in Nephrotic
Table 4.
Syndrome in Childhood
Minimal-change nephrotic syndrome
Focal segmental glomerulonephropathy (FSGS)
Membranoproliferative glomerulonephropathy
Membranous nephropathy
Others
*In Asian and African-American children, the risk of FSGS is 14%.
or 2 mg/kg. The daily dose should be maintained for
4 to 6 weeks. Opinion varies regarding this recommen-
dation, ranging from daily treatment administered just
long enough to achieve remission to 6 weeks of daily
treatment. Following remission, the dose should be kept
constant while changing to an alternate-day schedule for
an additional 6 weeks. A measurable decrease in urine
Indications for Initial
Table 5.
Kidney Biopsies in Nephrotic
Syndrome
1. Patients who have steroid-resistant nephrotic
syndrome and continue to have proteinuria and
edema despite a full course of prednisone.
2. Patients who have steroid-responsive nephrotic
syndrome and have more than two relapses in a 6-
month period (the so-called “frequent relapsers”)
3. Patients who have low serum complement at the
time of initial presentation of nephrotic syndrome
not related to acute postinfectious
glomerulonephritis. A biopsy is indicated to rule out
hypocomplementemic membranoproliferative
glomerulonephropathies.
4. Nephrotic syndrome with hypertension at
presentation. The risk of focal segmental
glomerulonephropathy (FSGS) is higher.
5. Patients younger than 1 year of age at presentation.
Biopsy is indicated because of a high likelihood of
congenital nephrotic syndrome.
6. Patients older than 10 years of age at presentation.
Biopsy is indicated to rule out more serious renal
pathology than minimal-change disease.
7. Systemic lupus erythematosus with proteinuria or
nephrotic syndrome.
8. Evidence of chronic renal insufficiency with
persistent elevation of serum urea nitrogen and
creatinine.
renal disease nephrotic syndrome
protein excretion should not be an-
ticipated for at least 7 to 10 days
following the initiation of treat-
ment, so the patient’s degree of
1 to 12 Years 13 to 19 Years
of Age of Age proteinuria should not determine
the length of a hospital stay. Chil-
76% 43% dren who have mild-to-moderate
7%* 13%
7% 14% edema, no pulmonary edema, and a
2% 22% good diuretic response generally re-
8% 8% quire a hospital stay of no more
than 2 to 3 days.
Fluid balance must be moni-
tored closely in the early stages of
treatment. Optimal nutrition, in-
cluding high-quality protein in amounts required for
growth, is essential because the demand for albumin
replacement is increased. The child should follow a “no
salt-added” diet, with maintenance sodium provided for
replacement during diuresis. Daily weights are key to
assessing the therapeutic progress. Other adjunctive
treatment, such as anticoagulation therapy, should be
used judiciously. If laboratory evidence is sufficient to
consider coagulopathy, heparin may be used at a dose of
Treatment of Acute-
Table 6.
onset Nephrotic Syndrome
Steroids (a negative tuberculosis skin test result must
be determined before starting steroid medications)
Prednisone
60 mg/m2 or 2 mg/kg daily for 6 weeks
60 mg/m2 or 2 mg/kg every other day for 6 weeks
Diuretics
Furosemide
0.5 to 2.0 mg/kg per dose intravenously
Protein Replacement*
Salt-free albumin
1.0 g/kg infused intravenously over 8 to 12 hours
Additional Measures
Heparin if sufficient hypercoagulability is
demonstrated
Adequate protein in diet for endogenous synthesis of
albumin
No salt-added diet to reduce fluid retention
*Many authorities dispute the need for or safety of this measure. The
degree of urinary protein loss makes any long-term improvement of
serum albumin concentrations unlikely. Such a measure is indicated
only when edema is sufficiently severe to cause potential compromise to
pulmonary function or integumental integrity.
Pediatrics in Review Vol.23 No.7 July 2002 243
renal disease nephrotic syndrome

Table 7. Steroidal and Nonsteroidal Treatment

Medication Dosage
Steroidal Agents
Prednisone 2 mg/kg per day orally
(maximum, 60 mg/d)
Methylprednisolone 30 mg/kg per week intravenously;
sodium succinate combined with prednisone
2 mg/kg on alternate days for
variable duration according to
underlying diseases
Nonsteroidal Agents
Cyclophosphamide 2 mg/kg per day for 8 wk;
prednisone 60 mg/m2 on
alternate days
Chlorambucil 0.2 mg/kg per day for 8 to 12 wk
Cyclosporine 5 mg/kg per day to maximum
20 mg/kg per day for up to 4 y
Levamisole 2.5 mg/kg per day during
remissions
Angiotensin-converting 5 to 10 mg/kg per day chronically
Enzyme Inhibitors
Indomethacin 50 kg/day for short term (<3
mo)
Mizoribine 2 to 5 mg/kg per day for 24 wk
Mycophenolate mofetil 25 mg/kg per day in two divided
doses for up to 1 y
Comments
Daily for 6 wk, followed by alternate-day dosing for 6 wk.
This 12-wk regimen is more effective than an 8-wk
regimen in reducing relapse. Adverse effects: growth
retardation, cataracts, osteoporosis
In partial steroid-resistant cases, this relatively high-dose
regimen may aid in moderating development of FSGS
May induce steroid sensitivity in later relapses. Adverse
effects: sterility, bone marrow depression, sepsis,
alopecia. To avoid hemorrhagic cystitis, administer
medication early in the day and encourage oral fluid
intake
Same as for cyclophosphamide. Adverse effects as for
cyclophosphamide; risk of marrow depression may be
higher
Effectively maintains remission, but relapses occur on
discontinuation. Adverse effect: nephrotoxicity
May help to maintain remission in steroid-dependent
disease
Renoprotective by reducing glomerular hyperfiltration.
Adverse effects: hypotension, cough
Reduces glomerular hyperfiltration. Adverse effect:
hepatorenal toxicity
Reduces relapsing nephrotic syndrome. Blocks purine
biosynthesis, inhibits mitogen-stimulated T- and B-cell
proliferation. Adverse effect: hyperuricemia
Effective in conjunction with prednisone to control diffuse
proliferative lupus nephropathy. Primary adverse effects
are gastrointestinal. Generally well tolerated

50 U/kg intravenously and 100 U/kg every 4 hours
intravenously for maintenance.
Using the treatment outlined previously, 85% to 90%
of children who have an initial onset of minimal-change
nephrotic syndrome will achieve satisfactory therapeutic
responses. For the few who do not experience a remission
with absence of proteinuria within the first 2 to 3 months
after onset, alternative therapies are available.
Chronic and Outpatient Treatment
For most children who have minimal-change nephrotic
syndrome, the proteinuria will clear by the third week of
oral prednisone treatment. This is a sufficient diagnostic
criterion to confirm the diagnosis. The small percentage
of children who are not completely free of proteinuria for
at least 3 to 5 days or those whose proteinuria continues
beyond 3 months are classified as frequent relapsing/
steroid-dependent or steroid-resistant patients, respec-
tively. For many such patients, different steroid-based
strategies or alternative treatments may be required
(Table 7).
Long-term maintenance on daily or alternate-day
low-dose oral prednisone may be appropriate for patients
who experience frequent relapses. Many children remain
in long-term remission on such a regimen with few, if
any, adverse effects. If the child can be kept in remission
with relatively low steroid doses in the absence of adverse
effects, this approach is optimal because it is the least
harmful of the available choices. On the other hand,
when high steroid doses are required for maintenance or
when steroid-related adverse effects supervene, alterna-
tive medications are required because the child clearly has
a steroid-resistant nephrotic syndrome.
Among the alternative medications are several immu-
nosuppressive agents as well as an antihelminthic and
certain nonsteroidal medications (Table 7). The usual

244 Pediatrics in Review Vol.23 No.7 July 2002


choices are cyclophosphamide and chlorambucil, each of
which can be used to achieve an initial remission or to
render the steroid-resistant child relatively more steroid-
responsive. The recommended dose of each is listed in
Table 7. However, each is associated with a rather im-
pressive list of systemic and specific organ toxicities,
which is the key reason for their general use as alternative
modalities. Either may be used over 2 to 3 months to
induce a complete remission, but after completion of
treatment, more than 50% of patients experience a re-
lapse, usually within 2 years. Moreover, in many such
relapses, the degree of steroid resistance is greater than
prior to the use of the immunosuppressive agent. Cyclo-
sporine also has been used for induction of a remission in
steroid-resistant patients. Although effective in this re-
spect, relapse occurs on drug discontinuation, unlike
chlorambucil and cyclophosphamide. Thus, the primary
advantage of all three drugs in steroid-resistant nephrotic
syndrome is to permit use of smaller doses of steroids,
thereby minimizing steroid-related adverse effects.
Recently, the results of a clinical trial have been pub-
lished for a new agent for induction of remission in
relapsing nephrotic syndrome. The double-blind,
placebo-controlled, multicenter trial examined the im-
munosuppressive drug mizoribine (Table 7). The agent
decreased the relapse rate and prolonged remission in
children 10 years of age and older, with relatively few
adverse effects. However, additional experience with this
drug must be acquired before it can be considered for
routine use. A clinical trial of the drug mycophenolate
mofetil in treatment of diffuse proliferative lupus nephri-
tis documented equivalent efficacy to cyclophosphamide
with far fewer adverse effects. Its use in treatment of
idiopathic nephrotic syndrome has not yet been re-
ported, nor can its safety for use in children be assumed at
this time.
Nonsteroidal agents (Table 7), such as anti-
inflammatory drugs and angiotensin-converting enzyme
inhibitors, may be of limited use as alternative therapeu-
tic agents in those very few patients who are refractory to
steroids. A combination of captopril and indomethacin
has been reported as effective for treatment of early-onset
(within the first several months of life) nephrotic syn-
drome. The mechanism of action is related to effects on
renal blood flow and glomerular filtration rather than to
immunosuppression, so the decrease in proteinuria
achieved is not a result of alterations in the basic disease
mechanism. Secondary effects of altered renal perfusion
may predispose the already intravascularly depleted pa-
tient to acute renal failure, requiring careful monitoring
when using these agents.
renal disease nephrotic syndrome
Because minimal-change nephrosis occurs most com-
monly in young children, there may be problems related
to routine childhood immunizations. It is clear that no
child should receive immunizations during treatment
with high-dose steroids to gain remission or with immu-
nosuppressive agents to address frequent relapses. How-
ever, because relapses often are related to viral illness, use
of live virus vaccines during remissions are viewed with
disfavor by some nephrologists. A recent study suggested
no unanimity of opinion among pediatric nephrologists
with respect to immunization practices for children who
have nephrotic syndrome. Because affected patients are
prone to pneumococcal infection, the American Acad-
emy of Pediatrics recommends use of the polyvalent
vaccine (Pneumovax威) in children older than 2 years and
prophylactic penicillin in those younger than 2 years.
Complications
Because minimal-change nephrotic syndrome is a self-
limited disease in the majority of affected children, a clear
distinction should be made between complications of the
disease and those that more likely are related to the
treatment. For example, a patient treated with high-dose
prednisone is at greater risk for the development of many
steroid-related disorders (eg, gastrointestinal ulcer, insu-
lin resistance), which are not among the known compli-
cations of nephrotic syndrome (Table 8).
One true complication of nephrotic syndrome is the
tendency to develop infections (eg, peritonitis, cellulitis,
sepsis). A major source of morbidity from infection in
those who have nephrosis is peritonitis, which results
from multiple abnormalities of the humoral antibody
system. IgG antibody is lost in the urine, and comple-
ment activation is impaired by concomitant loss of factor
B. Other events in the bowel may contribute to the
tendency. Marked intravascular depletion causes dimin-
ished splanchnic blood flow and hypoxia, and a marked
tendency to thrombosis may cause microinfarctions, low-
ering resistance of the bowel wall to bacterial passage.
The organisms causing peritonitis include Streptococcus
pneumoniae and Escherichia coli. Peritonitis is a major
contributor to the 1% to 2% mortality in nephrotic syn-
drome and always should be considered in an affected
patient who complains of abdominal pain. Abdominal
paracentesis then should be performed. Bacterial inva-
sion of the skin, usually by gram-positive organisms,
appears as erysipelas, with sharply demarcated borders
and associated lymphangitis.
The second major contributor to both mortality and
morbidity in this disease is thromboembolism. There is a
real risk of thrombosis in children experiencing an initial
Pediatrics in Review Vol.23 No.7 July 2002 245
renal disease nephrotic syndrome
Table 8. Complications of Nephrotic Syndrome
Complications Cause
Infection
Superficial peritonitis Edema
2Serum IgG
2Factor B
2Mesenteric blood flow
1Coagulability
Thromboembolus
Generally venous 1Platelet aggregation
1[Fibrinogen]
Loss of antithrombin-III
1Blood viscosity
2Blood flow
Growth Disturbance
Marked stunting Loss of IGF-binding protein
2Serum IGF-I
2Serum IGF-II
2IGF-receptor mRNA
IgG ⫽ circulating immune gamma-globulin, IGF ⫽ insulin-like growth factor, mRNA ⫽ messenger RNA, rhGH ⫽ recombinant human growth hormone
or recurrent episode of nephrotic syndrome. However,
there is no justifiable reason to use anticoagulant therapy
during remission because coagulopathy is a result of
serum protein abnormalities introduced by renal protein
wasting. In those very few outpatients who have refrac-
tory nephrosis, it may be worthwhile to consider chronic,
low-dose anticoagulants. In all children experiencing an
acute nephrotic episode, platelets are hyperaggregable.
There is limited experience with dipyridamole, an agent
that interferes with platelet aggregation, in this disease.
Several factors converge to create a marked propensity
for thrombus formation: increased platelet aggregation,
increased fibrinogen concentration combined with uri-
nary loss of antithrombin-III, increased blood viscosity,
and decreased blood flow. Venous thrombosis predom-
inates and can be found in deep vessels of the extremities,
the renal vein, the pulmonary venous system, and the
cerebral cortical system. Arterial occlusion is uncommon
but has been associated with serious morbidity and even
mortality. The potential for this particular complication
should be carefully considered. Initial coagulation stud-
ies should be obtained on admission for treatment and
anticoagulants used judiciously only when appropriate,
based on the results.
The well-known hyperlipidemia associated with the
nephrotic syndrome generally is not a source of clinical
complications. Because most cases of minimal-change
nephrosis are steroid-responsive, the hyperlipidemia gen-
erally is reversed within 4 to 6 weeks. However, in more
246 Pediatrics in Review Vol.23 No.7 July 2002
Comments
Stretching of the skin contributes to breakdown of its integrity
Decreased antibody and complement activation predispose to
infection; decreased flow and sludging cause microinfarction
Depending on site, may become devastating; contributing cause
in peritonitis; can be treated with heparinization
High-dose steroids may cause growth retardation; use of rhGH
in treatment not yet proven to be of benefit
chronic situations, it may become necessary to institute
long-term dietary changes and, possibly, drug therapy.
Finally, growth often is impaired in the nephrotic
syndrome. Clinical evidence suggests that the proteinuria
may cause the marked stunting that is seen in congenital
nephrosis. There may be losses of insulin-like growth
factor (IGF)-binding protein, which could account for
the depressed serum concentrations of IGF-I and IGF-
II. Moreover, experimental evidence shows that IGF-
receptor mRNA also is depressed. Because high doses of
steroids also may impair growth, the effects of loss of
intrinsic growth factors may be compounded by treat-
ment. Finally, there is experimental evidence that admin-
istration of growth hormone to nephrotic rats worsens
the severity of glomerulosclerosis. Much more study is
required before use of recombinant human growth hor-
mone becomes accepted treatment for growth distur-
bances in the nephrotic syndrome.
Prognosis
Mortality in minimal-change nephrotic syndrome is
approximately 2%, with the majority of deaths due to
peritonitis or thrombus, which may occur even under
the best of treatment circumstances. These complica-
tions may occur in the acute phase of the disease,
despite steroid responsiveness. Thus, although those
who have congenital nephrosis are steroid- and
immunosuppressant-resistant, mortality cannot be at-
tributed to this form of the disorder alone. Nonetheless,

the rare patient who has congenital nephrotic syndrome
represents a considerable therapeutic challenge, requir-
ing constant attention to serum protein and fluid levels,
monitoring of nutrition balance, and treatment of infec-
tion.
Of the remaining 98% of children who have minimal-
change nephrosis, most are steroid-responsive and can be
expected to return eventually to a normal state. By its
nature, minimal-change nephrotic syndrome results in
relapses; about two thirds of patients experience at least a
single relapse, with another third possibly developing a
protracted series of such relapses over many years. It is
important to note that a child who is steroid-responsive
at the initial presentation may relapse more than once
before the disease ultimately disappears. Many clinical
observers have reported an inverse relationship between
the age of presentation and the length of the disease
course. In general, most patients who have minimal-
change disease do very well, ultimately become disease-
free, and have a normal life expectancy.
Most patients who have presumptive minimal-change
nephrotic syndrome and become steroid-resistant later in
the disease course have developed focal segmental glo-
merular sclerosis (FSGS) (Fig. 3), which arguably is a
later evolutionary stage of minimal-change disease to
which some patients progress. The early clinical signs of
FSGS are indistinguishable from minimal-change dis-
ease, but at least one third of patients whose disease
evolves to FSGS progress to end-stage renal failure
within 5 years. In general, those who have more severe
nephrotic syndrome, with hypertension and active urine
sediments, and those who are older than 12 years of age
at onset are the most likely to develop FSGS. However, it
is not clear whether the severity of disease is a true
prognostic marker, rather than a factor that may be more
likely to result in intrinsic renal damage.
The hypovolemia and decreased renal perfusion in-
trinsic to the nephrotic syndrome render the affected
individual susceptible to acute renal failure during an
acute episode. Acute renal failure is defined as a sudden
loss of renal function that is easily and physiologically
reversible if no significant cellular injury has occurred due
to hypoxia. In the latter event, there is a high risk of acute
tubular necrosis, which greatly increases the risk of irre-
versible damage to the kidneys. If such damage occurs,
chronic renal insufficiency supervenes and reverses the
relatively good prognosis of minimal-change nephrosis.
renal disease nephrotic syndrome
For those patients whose chronic renal insufficiency
progresses to end-stage renal disease, there is always the
promise of hemodialysis/renal transplantation. How-
ever, for patients who have FSGS, there is a 25% risk of
recurrence of FSGS in the transplanted kidney, and ne-
phrotic syndrome occasionally occurs after renal trans-
plantation independent of whether it was previously
present.
The long-term prognosis for all categories of ne-
phrotic syndrome (Table 4) in patients younger than 19
years of age is as follows: 20% will continue in remission,
50% will have one or two relapses in any 5-year follow-up
period, and the remaining 30% will develop either
frequent-relapsing nephrosis or steroid-resistant nephro-
sis. The third category of patients requires diagnostic
renal biopsy. If minimal-change disease is confirmed,
there is a 50% chance for these children to go into
remission after a course of combined cytotoxic and pred-
nisone therapy.
Recovery is deemed permanent if the child is
symptom-free and off medications for more than 2 years.
Suggested Reading
De Sain-van der Velden MG, Kaysen GA, Barrett HA, et al. In-
creased VLDL in nephrotic patients results from a decreased
catabolism while increased LDL results from increased synthe-
sis. Kidney Int. 1998;53:994 –1001
Fliser D, Zurbruggen I, Mutschler E, et al. Coadministration of
albumin and furosemide in patients with the nephrotic syn-
drome. Kidney Int. 1999;55:629 – 634
Furth SL, Neu AM, Sullivan EK, et al. Immunization practices in
children with renal disease: a report of the North American
Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol.
1997;11:443– 446
Liang K, Vaziri ND. Down-regulation of hepatic high-density
lipoprotein receptor, SR-B1, in nephrotic syndrome. Kidney
Int. 1999;56:621– 626
Licht C, Eifinger F, Gharib M, et al. A stepwise approach to the
treatment of early onset nephrotic syndrome. Pediatr Nephrol.
2000;14:1077–1082
Srivastava T, Simon SD, Alon US. High incidence of focal segmen-
tal glomerulosclerosis in nephrotic syndrome of childhood.
Pediatr Nephrol. 1999;13:13–18
Tune BM, Lieberman E, Mendoza SA. Steroid-resistant nephrotic
focal segmental glomerulosclerosis: a treatable disease. Pediatr
Nephrol. 1996;10:772–778
Yoshioka K, Ohashi Y, Sakai T, et al. A multicenter trial of mizor-
ibine compared with placebo in children with frequently relaps-
ing nephrotic syndrome. Kidney Int. 2000;58:317–324
Pediatrics in Review Vol.23 No.7 July 2002 247
renal disease nephrotic syndrome

PIR Quiz
Quiz also available online at www.pedsinreview.org.

6. A 5-year-old previously healthy boy presents with headache and swelling of the face of 1 day’s duration.
The mother has noticed that his urine is tea-colored. Physical examination reveals an oral temperature of
98°F (36.3°C), respiratory rate of 20 breaths/min, heart rate of 90 beats/min, and blood pressure of 145/
105 mm Hg. There is mild puffiness of the eyelids. Urinalysis shows dark urine that is strongly positive for
blood and has 1ⴙ protein, a specific gravity of 1.030, numerous red blood cells (RBCs), and RBC and
epithelial casts. Hemoglobin is 11 g/dL (110 g/L) with a normal peripheral smear, blood urea nitrogen is
38 mg/dL (13.6 mmol/L), serum creatinine is 1.6 mg/dL (141.4 mcmol/L), and albumin is 3.0 g/dL (30 g/L).
Which of the following is the most likely diagnosis?
A. Acute glomerulonephritis.
B. Goodpasture syndrome.
C. Hemolytic-uremic syndrome.
D. Minimal-change nephrotic syndrome.
E. Renal vein thrombosis.

7. A 3-year-old previously healthy boy presents with swelling of his face and extremities of 1 day’s duration.
Physical examination reveals an oral temperature 98°F (36.3°C), heart rate of 94 beats/min, respiratory rate
of 24 breaths/min, and blood pressure of 86/50 mm Hg. His face is markedly puffy, and 3ⴙ pitting edema
is noted on the dorsum of hands and feet. Urinalysis reveals 4ⴙ protein and a specific gravity of 1.030.
Serum albumin is 1.5 g/dL (15 g/L) and cholesterol is 340 mg/dL (8.8 mmol/L). Abnormality of which of
the following structures best explains his clinical condition?
A. Glomerulus.
B. Loop of Henle.
C. Proximal tubule.
D. Renal artery.
E. Renal vein.

8. A 5-year-old previously healthy girl presents with periumbilical abdominal pain of increasing severity over
the past 2 days. She has been receiving treatment for nephrotic syndrome with prednisone for the last
3 weeks. Physical examination reveals an oral temperature 102°F (38.5°C), heart rate of 124 beats/min,
respiratory rate of 34 breaths/min, and blood pressure of 80/50 mm Hg. Peripheral perfusion is poor. Her
face appears mildly puffy, and 3ⴙ pitting edema is noted on the dorsum of hands and feet. There is
generalized abdominal tenderness with guarding and rebound tenderness. Bilateral shifting dullness and a
fluid wave are noted on abdominal examination. Urinalysis reveals 4ⴙ protein and a specific gravity of
1.030. Abdominal ultrasonography shows considerable ascites. Which of the following is the next most
appropriate diagnostic step?
A. Abdominal paracentesis.
B. Barium enema.
C. Computed tomography of the abdomen.
D. Doppler ultrasonography of renal vessels.
E. Exploratory laparotomy.

9. Which of the following conditions constitutes the need for renal biopsy in a patient who has nephrotic
syndrome?
A. Age between 2 to 6 years at initial presentation.
B. Lack of response after 1 week of prednisone therapy.
C. Low serum complement level at initial presentation.
D. Relapse 1 year after initial diagnosis.
E. Serum albumin level less than 2 g/dL (20 g/L).

248 Pediatrics in Review Vol.23 No.7 July 2002