Sindrome nefrótico

Nephrotic Syndrome:Pathogenesis and ManagementKarl S. Roth, MD,*

Barbara H. Amaker, MD,*

James C.M. Chan, MD†

Objectives After completing this article, readers should be able to:

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.

IntroductionThe estimated annual incidence of nephrotic syndrome in healthy children is 2 to 7 newcases per 100,000 children younger than 18 years of age, making it a relatively commonmajor 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 thenephrotic syndrome is, by nature, a recurrent disorder, so each new-onset case likely willcontinue to manifest disease for some time. Nephrotic syndrome is one of the mostfrequent reasons for referral to a pediatric nephrologist for evaluation, although itsinsidious onset frequently causes delay in diagnosis.

Careful examination of the anatomy of a nephron permits characterization of theglomerular basement membrane as the barrier between the circulation and the externalenvironment. Thus, the glomerular membrane, which permits passage in an adult ofapproximately 180 L/d of fluid, is the final determinant of how much of the soluteoriginally contained in this volume enters the tubular lumen. The normal glomerularmembrane is remarkably selective for protein compared with other solutes (Table 1). Oncethis selectivity is lost, the ensuing proteinuria defines not only the diagnosis of nephroticsyndrome, but many pathophysiologic consequences as well. It is the purpose of this articleto discuss the definition, causes, pathophysiologic consequences, and management ofnephrotic syndrome. The emphasis is on the idiopathic form, which most often occurs inchildren as minimal-change nephrotic syndrome; other types of the nephrotic syndromeare mentioned briefly.

DefinitionAs anticipated from the name, the composite of clinical findings can be found either aloneor in association with a number of systemic disorders, including toxicities. The sine qua nonof the diagnosis of nephrotic syndrome is the presence of urinary protein, with the albumindisproportionately greater than the globulin, deriving from a loss of glomerular membraneselectivity. In the pediatric age group, urinary protein loss of 50 mg/kg per 24 hours orgreater is a firm diagnostic criterion. It is imperative to recognize the distinctive origin ofthe proteinuria in the glomerulus rather than the tubule; nephrotic syndrome may be seenas exclusively glomerular in origin without any associated tubular dysfunction. Addition-ally, as a syndrome, the clinical picture may be either primary or secondary, and underlyingcauses 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.

Article renal disease

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

Clinical Diagnostic CriteriaThe diagnostic criteria are: 1) generalized edema; 2) hy-poproteinemia (�2 g/dL [20 g/L]), with dispropor-tionately low albumin in relation to globulin; 3) urineprotein (mg/dL) to urine creatinine (mg/dL) ratio inexcess of 2 in a first morning void or a 24-hour urineprotein that exceeds 50 mg/kg body weight; and 4) hy-percholesterolemia (�200 mg/dL [5.17 mmol/L]).

The reduced serum albumin, which can fall to as lowas 0.5 g/dL (5 g/L), causes a marked reduction inplasma oncotic pressure. Consequently, circulatory vol-ume is lost to the interstitial spaces, resulting in general-ized edema. Often, the initial swelling is observed asfacial (especially periorbital) and pretibial edema, withprominent swelling of the scrotum or labia also seen. Anadditional consequence of the lowered oncotic pressureis reduced perfusion of the splanch-nic capillary bed, which can causeabdominal pain. Pleural effusionsmay form, and frank pulmonaryedema also may occur, with eitheror both resulting in tachypnea andchest pain.

Levels of serum cholesterol,triglyceride, and lipoprotein cho-lesterol are consistently elevated.The mechanism(s) underlyingthese changes are not understoodcompletely, in part due to the com-plexity of lipid transport and thedifficulties inherent in human clini-cal studies. Increases in very-lowdensity and low-density lipoprotein

(VLDL and LDL, respectively) cholesterol are character-istic findings. VLDL-cholesterol is increased as a conse-quence of decreased hepatic catabolism, thus increasingcirculating triglyceride and cholesterol. LDL-cholesterolis increased due to an enhanced synthetic rate. Whatremains to be elucidated is the cause for these distur-bances in hepatic lipid metabolism.

Primary nephrotic syndrome may occur at any age,from the neonate to the adult. The neonatal or congen-ital nephrotic syndrome, also called Finnish congenitalnephrosis, is clearly defined as a genetic mutation in thenephrin gene and has been mapped to chromosome19q13.1. Nephrin is a glomerular basement membraneprotein that participates in formation of anionic-richsites, causing electrochemical repulsion of plasma pro-teins. The mutation also has been reported in a Menno-nite group in Pennsylvania who have no Finnish heritageand is believed to have arisen independent of the Finnishtype. Primary childhood nephrotic syndrome rarely ap-pears before 18 months to 2 years of age and peaks inincidence at about 3 years of age.

Laboratory FindingsThe primary laboratory feature of the nephrotic syn-drome is a marked proteinuria, in excess of 50 mg/kg per24 hours (Table 2). The excreted protein is predomi-nantly albumin, although immunoglobulins (Igs) alsoare lost. In uncomplicated cases of idiopathic nephroticsyndrome, it is unusual to see gross hematuria in thepresence of proteinuria, although microscopic hematuriaoccurs in a sizeable proportion of cases. For patients whohave gross hematuria and proteinuria, IgA nephropathyalways must be a diagnostic consideration.

In the presence of clinical edema, measurement of

Table 2. Laboratory Findings in the NephroticSyndromePrimary Finding Diagnostic Concentration

Proteinuria >50 mg/kg per 24 hHypoproteinemia <2.0 g/dL (20 g/L)Cholesterolemia >200 mg/dL (5.17 mmol/L) (frequently

>500 mg/dL [12.9 mmol/L])

Secondary Finding Frequently Found Values

Hypocalcemia (ionizedfraction normal)

<9.0 mg/dL (2.25 mmol/L)

Hyperkalemia >5.0 mEq/L (5.0 mmol/L)Hyponatremia <136 mEq/L (136 mmol/L)Hypercoaguability 2partial thromboplastin time (PTT)

Table 1. Selected Materials inGlomerular Filtrate Versus Urine*

Material

24-hourGlomerularFiltrate Urine (24 hour)

Sodium 24,000 mEq 50 to 200 mEqPotassium 680 mEq 10 to 100 mEqCalcium 7 to 10,000 mg Approximately 200 mgGlucose 200 g <50 mgAmino Acids 10 g 50 to 150 mgProtein ** <150 mg/LWater 180 L 1.5 L

*Data are presented for a “standard adult male”; values for infants andchildren vary with gestational age, age in years, and stage of renaltubular development.**Data are lacking in the literature.

renal disease nephrotic syndrome

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

serum protein will yield low values; the serum albumin islikely to be 2.0 g/dL (20 g/L) or lower. Albuminconcentrations as low as 0.5 g/100 mL can be seen, andthe albumin/globulin ratio is commonly less than 1.0.Concomitantly, and directly related to the reduced se-rum protein, hypocalcemia is found frequently, as re-flected in reduced total and ionized fractions. However,hypocalcemia rarely is manifested clinically.

Of much greater significance than hypocalcemia topatients who have nephrotic syndrome is the increasedconcentrations of coagulation factors, especially those ofhigh molecular weight. Thrombin also is increased, whilefibrinolytic activity and circulating quantities of plateletadhesion inhibitors are decreased. As a consequence ofthese changes, as well as the intravascular hypovolemia,affected patients are at greatly increased risk of thrombo-sis. In addition, IgG in plasma is reduced, which incombination with large steroid doses, may predispose toinfection.

Children who become oliguric from diminished intra-vascular volume have a tendency to develop hyperkale-mia. The use of diuretics may complicate the electrolytedisturbances further, necessitating close monitoring ofserum electrolyte levels during treatment.

The Need for a Renal BiopsyIn the acute stage of childhood nephrotic syndrome,especially during the initial episode, renal biopsy usuallyis unnecessary. The key indications for biopsy in any renaldisorder are the need to make a specific diagnosis fortherapeutic reasons or to provide a prognosis. The treat-ment of initial-onset nephrotic syndrome is the same,irrespective of cause, and the need for determining aprognosis never can outweigh the risks of thrombosis,bleeding, and infection due to a biopsy in the acute stageof the disorder.

The subsequent disease course in a patient can help todetermine the timing of a renal biopsy. In an uncompli-cated case in which proteinuria clears within a few weeksin response to orally administered corticosteroids andnormal renal function, the diagnosis is presumed to beminimal-change nephrotic syndrome. If there is no sig-nificant proteinuria between relapses that continue torespond promptly to corticosteroids, this diagnosis isstrengthened. If the child is younger than 10 years of ageat the initial presentation, no renal biopsy need be con-sidered. At age 10 years or older, the increasing risk ofunderlying primary disease compels the need to obtain abiopsy for histologic diagnosis. In such cases, renal bi-opsy can be deferred until the child is stable and the

family’s anxieties over the immediate medical problemshave dissipated.

In contrast, when there is poor or no response of theinitial episode after 4 to 6 weeks of standard treatment(defined as steroid-resistance disease), biopsy should beconsidered as soon as the patient is medically stable. Insuch cases, the biopsy is essential to distinguish thenature and severity of the glomerular process, which maybe primary or secondary (Table 3). It should be clearfrom the plethora of types and causes of glomerularnephropathy that treatments and prognoses vary consid-erably, making specific diagnosis imperative. Becauseproteinuria and microscopic hematuria are injury re-sponses of the glomerulus, the need for clarificationthrough renal biopsy is plain. The underlying pathology

Table 3. Primary and SecondaryGlomerulopathiesIdiopathic Minimal-change Nephrosis

Focal Segmental Glomerulosclerosis

IdiopathicObesityUnilateral renal agenesisGlycogen storage diseasePostinfectious glomerulonephritisObstructive uropathyLupus nephropathySickle cell diseaseAlport syndrome

Membranous Glomerulonephritis

IdiopathicLupus nephropathySickle cell diseaseSarcoidosisHashimoto thyroiditisHeavy metal toxicityCaptoprilPenicillamineNonsteroidal anti-inflammatory drugsSyphilisHepatitis B and C

Membranoproliferative Glomerulonephritis

Chronic bacterial infectionChronic viral infectionLupus nephropathyRheumatoid arthritisChronic liver diseaseSickle cell diseaseRenal transplantBone marrow transplant



(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 Table5.

Beyond the issue of renal biopsy for initial diagnosis,there are circumstances in which a subsequent biopsymay be considered. Glomerular injury may evolve overtime 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 thekidney by an underlying disease such as lupus nephrop-athy. In these situations, a second renal biopsy should beconsidered for evaluation of progressive renal disease.

Technological developments in ultrasonography havereduced 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 theability of the histopathologist to interpret the specimenaccurately. Nonetheless, a renal biopsy is not always

essential to good medical care, and its use should beviewed judiciously in all patients.

TreatmentThe treatment of primary childhood nephrotic syndromeis 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 maybecome short of breath due to pulmonary edema; stillothers may become oliguric and develop a functionalazotemia. The latter is due to reduced circulating volumein the vascular space that results in temporary renalinsufficiency. Any of these presentations, alone or incombination, demands immediate attention to symp-tomatic treatment.

Treatment of Acute-onset DiseaseThe unifying factor in this disease is depleted bloodvolume as a consequence of low oncotic pressure. There-fore, treatment should be directed at returning fluid to

Figure 1. A. Light microscopic view of a normal glomerulus(Jones silver stain). B. Electron micrograph showing normalglomerulus with well-defined epithelial cell foot processes.

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 effacementis seen, and lipid droplets are present in the cytoplasm of thevisceral epithelial cell.



the vascular space and encouraging diuresis to avoidvolume overload (Table 6). The intuitive solution to thediminished oncotic pressure is to restore serum albuminconcentration 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 serumprotein. The degree of urinary loss can be illustrated bythe hepatic rate of albumin synthesis, which in adults canbe 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 onlybe a temporary remedy. Nonetheless, for a patient whohas pulmonary edema or renal shutdown, intravenousalbumin (1 g/kg of a 25% solution) can be very effectivein mobilizing fluid into the vascular space. The rate ofincrease in oncotic pressure is directly proportional to therate of expansion of intravascular volume. Thus, toorapid an infusion will place the child at risk for congestive

heart failure. Accordingly, intravenous albumin shouldbe infused continuously over 8 to 12 hours under closesupervision.

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 thisopportunity. Keeping in mind that a normal or lowserum sodium concentration is likely to represent theresult of a dilutional effect, the choice of diuretic shouldbe directed at sodium as well as at water excretion. Anideal choice is a loop diuretic such as furosemide, whichcan be administered at a dose of 1 to 2 mg/kg intrave-nously and acts within 15 minutes. Furosemide-inducedinhibition 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 albumininfusion or it all can be administered at the end of the

Figure 3. A. Segmental sclerosis of the glomerular tuft as seen with light microscopy (PAS stain). B. Immunofluorescencedemonstrates the presence of IgM in the segmentally sclerotic portion of the glomerulus. C. The visceral epithelial cell containsvacuoles, and focal foot process effacement is seen.



infusion, depending on the volume of urine output andthe degree of edema.

Debate continues over the true benefit of albumininfusion, and no resolution is in sight. Nonetheless, it isdifficult to argue against its use in the clinical settings ofpleural effusion, pulmonary edema, or impending renalshutdown due to depleted intravascular volume.

The child should be started on oral corticosteroidtherapy after a negative tuberculosis skin test result hasbeen determined. Prednisone is the usual drug of choice,and the recommended maximum daily dose is 60 mg/m2

Figure 4. A. Hypercellularity and lobulation is seen in thisglomerulus (PAS stain). B. Broad granular staining for com-plement 3 is present along glomerular capillary walls. C.Electron micrograph showing a large, discrete, electron-densesubendothelial deposit and “reduplication” of the glomerularbasement membrane.

Figure 5. A. Diffuse uniform thickening of the capillary wallsis seen (PAS stain). B. Finely granular staining with IgG is seenalong the capillary walls. C. Electron micrograph showingidiopathic 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.



or 2 mg/kg. The daily dose should be maintained for4 to 6 weeks. Opinion varies regarding this recommen-dation, ranging from daily treatment administered justlong enough to achieve remission to 6 weeks of dailytreatment. Following remission, the dose should be keptconstant while changing to an alternate-day schedule foran additional 6 weeks. A measurable decrease in urine

protein excretion should not be an-ticipated for at least 7 to 10 daysfollowing the initiation of treat-ment, so the patient’s degree ofproteinuria should not determinethe length of a hospital stay. Chil-dren who have mild-to-moderateedema, no pulmonary edema, and agood diuretic response generally re-quire a hospital stay of no morethan 2 to 3 days.

Fluid balance must be moni-tored closely in the early stages oftreatment. Optimal nutrition, in-

cluding high-quality protein in amounts required forgrowth, is essential because the demand for albuminreplacement is increased. The child should follow a “nosalt-added” diet, with maintenance sodium provided forreplacement during diuresis. Daily weights are key toassessing the therapeutic progress. Other adjunctivetreatment, such as anticoagulation therapy, should beused judiciously. If laboratory evidence is sufficient toconsider coagulopathy, heparin may be used at a dose of

Table 4. Underlying Renal Pathology in NephroticSyndrome in Childhood

1 to 12 Yearsof Age

13 to 19 Yearsof Age

Minimal-change nephrotic syndrome 76% 43%Focal segmental glomerulonephropathy (FSGS) 7%* 13%Membranoproliferative glomerulonephropathy 7% 14%Membranous nephropathy 2% 22%Others 8% 8%

*In Asian and African-American children, the risk of FSGS is 14%.

Table 5. Indications for InitialKidney Biopsies in NephroticSyndrome1. Patients who have steroid-resistant nephrotic

syndrome and continue to have proteinuria andedema despite a full course of prednisone.

2. Patients who have steroid-responsive nephroticsyndrome and have more than two relapses in a 6-month period (the so-called “frequent relapsers”)

3. Patients who have low serum complement at thetime of initial presentation of nephrotic syndromenot related to acute postinfectiousglomerulonephritis. A biopsy is indicated to rule outhypocomplementemic membranoproliferativeglomerulonephropathies.

4. Nephrotic syndrome with hypertension atpresentation. The risk of focal segmentalglomerulonephropathy (FSGS) is higher.

5. Patients younger than 1 year of age at presentation.Biopsy is indicated because of a high likelihood ofcongenital nephrotic syndrome.

6. Patients older than 10 years of age at presentation.Biopsy is indicated to rule out more serious renalpathology than minimal-change disease.

7. Systemic lupus erythematosus with proteinuria ornephrotic syndrome.

8. Evidence of chronic renal insufficiency withpersistent elevation of serum urea nitrogen andcreatinine.

Table 6. Treatment of Acute-onset Nephrotic SyndromeSteroids (a negative tuberculosis skin test result must

be determined before starting steroid medications)

Prednisone60 mg/m2 or 2 mg/kg daily for 6 weeks60 mg/m2 or 2 mg/kg every other day for 6 weeks

Diuretics

Furosemide0.5 to 2.0 mg/kg per dose intravenously

Protein Replacement*

Salt-free albumin1.0 g/kg infused intravenously over 8 to 12 hours

Additional Measures

Heparin if sufficient hypercoagulability isdemonstrated

Adequate protein in diet for endogenous synthesis ofalbumin

No salt-added diet to reduce fluid retention

*Many authorities dispute the need for or safety of this measure. Thedegree of urinary protein loss makes any long-term improvement ofserum albumin concentrations unlikely. Such a measure is indicatedonly when edema is sufficiently severe to cause potential compromise topulmonary function or integumental integrity.



50 U/kg intravenously and 100 U/kg every 4 hoursintravenously for maintenance.

Using the treatment outlined previously, 85% to 90%of children who have an initial onset of minimal-changenephrotic syndrome will achieve satisfactory therapeuticresponses. For the few who do not experience a remissionwith absence of proteinuria within the first 2 to 3 monthsafter onset, alternative therapies are available.

Chronic and Outpatient TreatmentFor most children who have minimal-change nephroticsyndrome, the proteinuria will clear by the third week oforal prednisone treatment. This is a sufficient diagnosticcriterion to confirm the diagnosis. The small percentageof children who are not completely free of proteinuria forat least 3 to 5 days or those whose proteinuria continuesbeyond 3 months are classified as frequent relapsing/steroid-dependent or steroid-resistant patients, respec-

tively. For many such patients, different steroid-basedstrategies or alternative treatments may be required(Table 7).

Long-term maintenance on daily or alternate-daylow-dose oral prednisone may be appropriate for patientswho experience frequent relapses. Many children remainin long-term remission on such a regimen with few, ifany, adverse effects. If the child can be kept in remissionwith relatively low steroid doses in the absence of adverseeffects, this approach is optimal because it is the leastharmful of the available choices. On the other hand,when high steroid doses are required for maintenance orwhen steroid-related adverse effects supervene, alterna-tive medications are required because the child clearly hasa steroid-resistant nephrotic syndrome.

Among the alternative medications are several immu-nosuppressive agents as well as an antihelminthic andcertain nonsteroidal medications (Table 7). The usual

Table 7. Steroidal and Nonsteroidal TreatmentMedication Dosage Comments

Steroidal AgentsPrednisone 2 mg/kg per day orally

(maximum, 60 mg/d)Daily for 6 wk, followed by alternate-day dosing for 6 wk.

This 12-wk regimen is more effective than an 8-wkregimen in reducing relapse. Adverse effects: growthretardation, cataracts, osteoporosis

Methylprednisolonesodium succinate

30 mg/kg per week intravenously;combined with prednisone2 mg/kg on alternate days forvariable duration according tounderlying diseases

In partial steroid-resistant cases, this relatively high-doseregimen may aid in moderating development of FSGS

Nonsteroidal AgentsCyclophosphamide 2 mg/kg per day for 8 wk;

prednisone 60 mg/m2 onalternate days

May induce steroid sensitivity in later relapses. Adverseeffects: sterility, bone marrow depression, sepsis,alopecia. To avoid hemorrhagic cystitis, administermedication early in the day and encourage oral fluidintake

Chlorambucil 0.2 mg/kg per day for 8 to 12 wk Same as for cyclophosphamide. Adverse effects as forcyclophosphamide; risk of marrow depression may behigher

Cyclosporine 5 mg/kg per day to maximum20 mg/kg per day for up to 4 y

Effectively maintains remission, but relapses occur ondiscontinuation. Adverse effect: nephrotoxicity

Levamisole 2.5 mg/kg per day duringremissions

May help to maintain remission in steroid-dependentdisease

Angiotensin-convertingEnzyme Inhibitors

5 to 10 mg/kg per day chronically Renoprotective by reducing glomerular hyperfiltration.Adverse effects: hypotension, cough

Indomethacin 50 kg/day for short term (<3mo)

Reduces glomerular hyperfiltration. Adverse effect:hepatorenal toxicity

Mizoribine 2 to 5 mg/kg per day for 24 wk Reduces relapsing nephrotic syndrome. Blocks purinebiosynthesis, inhibits mitogen-stimulated T- and B-cellproliferation. Adverse effect: hyperuricemia

Mycophenolate mofetil 25 mg/kg per day in two divideddoses for up to 1 y

Effective in conjunction with prednisone to control diffuseproliferative lupus nephropathy. Primary adverse effectsare gastrointestinal. Generally well tolerated



choices are cyclophosphamide and chlorambucil, each ofwhich can be used to achieve an initial remission or torender the steroid-resistant child relatively more steroid-responsive. The recommended dose of each is listed inTable 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 alternativemodalities. Either may be used over 2 to 3 months toinduce a complete remission, but after completion oftreatment, more than 50% of patients experience a re-lapse, usually within 2 years. Moreover, in many suchrelapses, the degree of steroid resistance is greater thanprior to the use of the immunosuppressive agent. Cyclo-sporine also has been used for induction of a remission insteroid-resistant patients. Although effective in this re-spect, relapse occurs on drug discontinuation, unlikechlorambucil and cyclophosphamide. Thus, the primaryadvantage of all three drugs in steroid-resistant nephroticsyndrome 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 inrelapsing nephrotic syndrome. The double-blind,placebo-controlled, multicenter trial examined the im-munosuppressive drug mizoribine (Table 7). The agentdecreased the relapse rate and prolonged remission inchildren 10 years of age and older, with relatively fewadverse effects. However, additional experience with thisdrug must be acquired before it can be considered forroutine use. A clinical trial of the drug mycophenolatemofetil in treatment of diffuse proliferative lupus nephri-tis documented equivalent efficacy to cyclophosphamidewith far fewer adverse effects. Its use in treatment ofidiopathic nephrotic syndrome has not yet been re-ported, nor can its safety for use in children be assumed atthis time.

Nonsteroidal agents (Table 7), such as anti-inflammatory drugs and angiotensin-converting enzymeinhibitors, may be of limited use as alternative therapeu-tic agents in those very few patients who are refractory tosteroids. A combination of captopril and indomethacinhas 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 onrenal blood flow and glomerular filtration rather than toimmunosuppression, so the decrease in proteinuriaachieved is not a result of alterations in the basic diseasemechanism. Secondary effects of altered renal perfusionmay predispose the already intravascularly depleted pa-tient to acute renal failure, requiring careful monitoringwhen using these agents.

Because minimal-change nephrosis occurs most com-monly in young children, there may be problems relatedto routine childhood immunizations. It is clear that nochild should receive immunizations during treatmentwith 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, useof live virus vaccines during remissions are viewed withdisfavor by some nephrologists. A recent study suggestedno unanimity of opinion among pediatric nephrologistswith respect to immunization practices for children whohave nephrotic syndrome. Because affected patients areprone to pneumococcal infection, the American Acad-emy of Pediatrics recommends use of the polyvalentvaccine (Pneumovax�) in children older than 2 years andprophylactic penicillin in those younger than 2 years.

ComplicationsBecause minimal-change nephrotic syndrome is a self-limited disease in the majority of affected children, a cleardistinction should be made between complications of thedisease and those that more likely are related to thetreatment. For example, a patient treated with high-doseprednisone is at greater risk for the development of manysteroid-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 thetendency to develop infections (eg, peritonitis, cellulitis,sepsis). A major source of morbidity from infection inthose who have nephrosis is peritonitis, which resultsfrom multiple abnormalities of the humoral antibodysystem. IgG antibody is lost in the urine, and comple-ment activation is impaired by concomitant loss of factorB. Other events in the bowel may contribute to thetendency. Marked intravascular depletion causes dimin-ished splanchnic blood flow and hypoxia, and a markedtendency to thrombosis may cause microinfarctions, low-ering resistance of the bowel wall to bacterial passage.The organisms causing peritonitis include Streptococcuspneumoniae and Escherichia coli. Peritonitis is a majorcontributor to the 1% to 2% mortality in nephrotic syn-drome and always should be considered in an affectedpatient who complains of abdominal pain. Abdominalparacentesis then should be performed. Bacterial inva-sion of the skin, usually by gram-positive organisms,appears as erysipelas, with sharply demarcated bordersand associated lymphangitis.

The second major contributor to both mortality andmorbidity in this disease is thromboembolism. There is areal risk of thrombosis in children experiencing an initial



or recurrent episode of nephrotic syndrome. However,there is no justifiable reason to use anticoagulant therapyduring remission because coagulopathy is a result ofserum protein abnormalities introduced by renal proteinwasting. In those very few outpatients who have refrac-tory nephrosis, it may be worthwhile to consider chronic,low-dose anticoagulants. In all children experiencing anacute nephrotic episode, platelets are hyperaggregable.There is limited experience with dipyridamole, an agentthat interferes with platelet aggregation, in this disease.Several factors converge to create a marked propensityfor 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 thecerebral cortical system. Arterial occlusion is uncommonbut has been associated with serious morbidity and evenmortality. The potential for this particular complicationshould be carefully considered. Initial coagulation stud-ies should be obtained on admission for treatment andanticoagulants used judiciously only when appropriate,based on the results.

The well-known hyperlipidemia associated with thenephrotic syndrome generally is not a source of clinicalcomplications. Because most cases of minimal-changenephrosis are steroid-responsive, the hyperlipidemia gen-erally is reversed within 4 to 6 weeks. However, in more

chronic situations, it may become necessary to institutelong-term dietary changes and, possibly, drug therapy.

Finally, growth often is impaired in the nephroticsyndrome. Clinical evidence suggests that the proteinuriamay cause the marked stunting that is seen in congenitalnephrosis. There may be losses of insulin-like growthfactor (IGF)-binding protein, which could account forthe depressed serum concentrations of IGF-I and IGF-II. Moreover, experimental evidence shows that IGF-receptor mRNA also is depressed. Because high doses ofsteroids also may impair growth, the effects of loss ofintrinsic growth factors may be compounded by treat-ment. Finally, there is experimental evidence that admin-istration of growth hormone to nephrotic rats worsensthe severity of glomerulosclerosis. Much more study isrequired before use of recombinant human growth hor-mone becomes accepted treatment for growth distur-bances in the nephrotic syndrome.

PrognosisMortality in minimal-change nephrotic syndrome isapproximately 2%, with the majority of deaths due toperitonitis or thrombus, which may occur even underthe best of treatment circumstances. These complica-tions may occur in the acute phase of the disease,despite steroid responsiveness. Thus, although thosewho have congenital nephrosis are steroid- andimmunosuppressant-resistant, mortality cannot be at-tributed to this form of the disorder alone. Nonetheless,

Table 8. Complications of Nephrotic SyndromeComplications Cause Comments

InfectionSuperficial peritonitis Edema Stretching of the skin contributes to breakdown of its integrity

2Serum IgG2Factor B2Mesenteric blood flow1Coagulability

Decreased antibody and complement activation predispose toinfection; decreased flow and sludging cause microinfarction

ThromboembolusGenerally venous 1Platelet aggregation

1[Fibrinogen]Loss of antithrombin-III1Blood viscosity2Blood flow

Depending on site, may become devastating; contributing causein peritonitis; can be treated with heparinization

Growth DisturbanceMarked stunting Loss of IGF-binding protein

2Serum IGF-I2Serum IGF-II2IGF-receptor mRNA

High-dose steroids may cause growth retardation; use of rhGHin treatment not yet proven to be of benefit

IgG � circulating immune gamma-globulin, IGF � insulin-like growth factor, mRNA � messenger RNA, rhGH � recombinant human growth hormone



the rare patient who has congenital nephrotic syndromerepresents 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 beexpected to return eventually to a normal state. By itsnature, minimal-change nephrotic syndrome results inrelapses; about two thirds of patients experience at least asingle relapse, with another third possibly developing aprotracted series of such relapses over many years. It isimportant to note that a child who is steroid-responsiveat the initial presentation may relapse more than oncebefore the disease ultimately disappears. Many clinicalobservers have reported an inverse relationship betweenthe age of presentation and the length of the diseasecourse. 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-changenephrotic syndrome and become steroid-resistant later inthe disease course have developed focal segmental glo-merular sclerosis (FSGS) (Fig. 3), which arguably is alater evolutionary stage of minimal-change disease towhich some patients progress. The early clinical signs ofFSGS are indistinguishable from minimal-change dis-ease, but at least one third of patients whose diseaseevolves to FSGS progress to end-stage renal failurewithin 5 years. In general, those who have more severenephrotic syndrome, with hypertension and active urinesediments, and those who are older than 12 years of ageat onset are the most likely to develop FSGS. However, itis not clear whether the severity of disease is a trueprognostic marker, rather than a factor that may be morelikely to result in intrinsic renal damage.

The hypovolemia and decreased renal perfusion in-trinsic to the nephrotic syndrome render the affectedindividual susceptible to acute renal failure during anacute episode. Acute renal failure is defined as a suddenloss of renal function that is easily and physiologicallyreversible if no significant cellular injury has occurred dueto hypoxia. In the latter event, there is a high risk of acutetubular necrosis, which greatly increases the risk of irre-versible damage to the kidneys. If such damage occurs,chronic renal insufficiency supervenes and reverses therelatively good prognosis of minimal-change nephrosis.

For those patients whose chronic renal insufficiencyprogresses to end-stage renal disease, there is always thepromise of hemodialysis/renal transplantation. How-ever, for patients who have FSGS, there is a 25% risk ofrecurrence of FSGS in the transplanted kidney, and ne-phrotic syndrome occasionally occurs after renal trans-plantation independent of whether it was previouslypresent.

The long-term prognosis for all categories of ne-phrotic syndrome (Table 4) in patients younger than 19years of age is as follows: 20% will continue in remission,50% will have one or two relapses in any 5-year follow-upperiod, and the remaining 30% will develop eitherfrequent-relapsing nephrosis or steroid-resistant nephro-sis. The third category of patients requires diagnosticrenal biopsy. If minimal-change disease is confirmed,there is a 50% chance for these children to go intoremission after a course of combined cytotoxic and pred-nisone therapy.

Recovery is deemed permanent if the child issymptom-free and off medications for more than 2 years.

Suggested ReadingDe Sain-van der Velden MG, Kaysen GA, Barrett HA, et al. In-

creased VLDL in nephrotic patients results from a decreasedcatabolism while increased LDL results from increased synthe-sis. Kidney Int. 1998;53:994–1001

Fliser D, Zurbruggen I, Mutschler E, et al. Coadministration ofalbumin 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 inchildren with renal disease: a report of the North AmericanPediatric Renal Transplant Cooperative Study. Pediatr Nephrol.1997;11:443–446

Liang K, Vaziri ND. Down-regulation of hepatic high-densitylipoprotein receptor, SR-B1, in nephrotic syndrome. KidneyInt. 1999;56:621–626

Licht C, Eifinger F, Gharib M, et al. A stepwise approach to thetreatment 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 nephroticfocal segmental glomerulosclerosis: a treatable disease. PediatrNephrol. 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



PIR QuizQuiz 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 of98°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 forblood and has 1� protein, a specific gravity of 1.030, numerous red blood cells (RBCs), and RBC andepithelial casts. Hemoglobin is 11 g/dL (110 g/L) with a normal peripheral smear, blood urea nitrogen is38 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 rateof 24 breaths/min, and blood pressure of 86/50 mm Hg. His face is markedly puffy, and 3� pitting edemais noted on the dorsum of hands and feet. Urinalysis reveals 4� 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 ofthe 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 overthe past 2 days. She has been receiving treatment for nephrotic syndrome with prednisone for the last3 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. Herface appears mildly puffy, and 3� pitting edema is noted on the dorsum of hands and feet. There isgeneralized abdominal tenderness with guarding and rebound tenderness. Bilateral shifting dullness and afluid wave are noted on abdominal examination. Urinalysis reveals 4� protein and a specific gravity of1.030. Abdominal ultrasonography shows considerable ascites. Which of the following is the next mostappropriate 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 nephroticsyndrome?

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).



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