The Nephrotic SyndromeRoberto Gordillo and Adrian Spitzer Pediatr. Rev. 2009;30;94-105 DOI: 10.1542/pir.30-3-94The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/30/3/94Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthlypublication, it has been published continuously since 1979. Pediatrics in Review is owned,published, and trademarked by the American Academy of Pediatrics, 141 Northwest PointBoulevard, Elk Grove Village, Illinois, 60007. Copyright 2009 by the American Academy ofPediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009ArticlenephrologyThe Nephrotic SyndromeRoberto Gordillo, MD,*Adrian Spitzer, MDObjectives1.2.3.4.5.6.7.After completing this article, readers should be able to:Author DisclosureDrs Gordillo andSpitzer have disclosedno nancialrelationships relevantto this article. Thiscommentary does notcontain a discussionof an unapproved/investigative use of acommercialproduct/device.Explain the mechanism and the consequences of proteinuria.Make a presumptive diagnosis of minimal-change nephrotic syndrome.Interpret the signs associated with steroid resistance.Ascertain the timing and the indications for a kidney biopsy.Gauge the indications for referral to a pediatric nephrologist.Determine the adequacy of the therapy.Predict the disease course.IntroductionThe word nephrosis was introduced in the medical literature at the beginning of the20th century in an attempt to distinguish diseases of the kidney characterized by exudationand proliferation from those characterized by inammation (nephritis). As it becameapparent that this is not a single disease, not even a group of related diseases, the termnephrosis was supplanted by nephrotic syndrome. The clinical features that charac-terize the nephrotic syndrome result from alterations of the glomerular capillary wall andconsist of heavy proteinuria and hypoalbuminemia, often associated with edema andgeneralized hyperlipidemia.PathophysiologyProteinuria and HypoalbuminemiaAbbreviationsACE:BSA:CNF:CNS:FSGS:HDL:Ig:IL:ISKDC:LDL:MCNS:MN:MPGN:RAA:SLE:UPr/Cr:VLDL:angiotensin-converting enzymebody surface areacongenital nephrotic syndrome of the Finnishtypecongenital nephrotic syndromefocal segmental glomerulosclerosishigh-density lipoproteinimmunoglobulininterleukinInternational Study of Kidney Disease inChildrenlow-density lipoproteinminimal-change nephrotic syndromemembranous nephropathymesangioproliferative glomerulonephritisrenin-angiotensin-aldosteronesystemic lupus erythematosusurine protein/creatinine ratiovery low-density lipoproteinProteinuria is the result of alterations in the integrity of theglomerular ltration barrier. This barrier is composed ofthree layers in series: the fenestrated endothelium, the glo-merular basement membrane, and the visceral glomerularepithelium, comprised of podocytes and their slit dia-phragms. Podocyte is the name of the epithelial cell, and footprocess is the segment of the cell that extends into theurinary space. (In the nephrotic syndrome, there is efface-ment of the foot process, but the rest of the cell usually ispreserved.) Endothelial cells have numerous openings that are 70 to100 nm in diameter, called fenestrae, which form a physicalbarrier for passage of macromolecules from plasma intothe renal tubule. Electron microscopic studies led to theidentication of negatively charged particles (heparan sulfateproteoglycans) in the glomerular basement membrane,which preclude the passage of anionic macromolecules,such as albumin. Removal of these charges in animals by insitu perfusion of heparitinase resulted in proteinuria. Until recently, the podocytes were considered to play apassive role in the process of glomerular ltration. Thisconcept changed dramatically with the discovery that muta-*Postdoctoral Fellow.Professor of Pediatrics, Albert Einstein College of Medicine/Childrens Hospital at Monteore, Division of Pediatric Nephrology,Bronx, NY.94 Pediatrics in Review Vol.30 No.3 March 2009Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndrometion of a protein located at the slit diaphragm, namednephrin, is the cause of the congenital nephrotic syn-drome of the Finnish type (CNF). (1) The slit diaphragmis a thin membrane that bridges the ltration poresbetween adjacent podocytes and is anchored to the cellcytoskeleton by adaptor proteins such as podocin andCD2AP. Podocytes have been found to affect the struc-ture and function of the glomerular basement mem-brane and to regulate the integrity and survival of glo-merular endothelial cells. A number of acquired andinherited diseases now are attributed to defects of the slitdiaphragm protein complex (Table 1).retention of sodium is postulated. Vasopressin excess alsocontributes to the retention of water.HyperlipidemiaIncreased concentrations of very low-density lipoprotein(VLDL), intermediate-density lipoprotein (IDL), andlow-density lipoprotein (LDL) result in elevated serumcholesterol and triglycerides concentrations. The high-density lipoprotein (HDL) fraction is normal. Conse-quently, the LDL/HDL cholesterol ratio is increased.Several mechanisms allegedly contribute to nephroticsyndrome dyslipidemia: overproduction due to lowplasma albumin concentration and low oncotic pressureand impaired catabolism of apolipoprotein B and VLDLchylomicrons.EdemaThe classic theory is that edema formation results from adecrease in plasma oncotic pressure due to loss of serumalbumin, causing water to extravasate into the intersti-tial space. Such movement reduces the intravascular vol-ume, leading to renal hypoperfusion and stimulation ofthe renin-angiotensin-aldosterone (RAA) system. Aldo-sterone increases reabsorption of sodium, particularly atthe level of the distal segments of the nephron. Thishypothesis, although attractive, is not supported fullyby clinical ndings. Plasma volume has been shown to bedecreased only in some children who have minimal-change nephrotic syndrome (MCNS), particularly dur-ing the initial phase of a relapse. The decrease is absentin others and almost always absent in adults who havenephrotic syndrome. In addition, studies have failed todemonstrate elevation of RAA hormones, and increasedsodium reabsorption was found to continue when albu-min was infused or angiotensin-converting enzyme(ACE) inhibitors were administered to suppress reninproduction. An intrinsic renal abnormality leading toEpidemiologyThe incidence of idiopathic nephrotic syndrome in theUnited States has been reported to be 2.7 new casesper 100,000 children per year, and the cumulative prev-alence rate is 16 per 100,000 children. The ratio ofmales to females is approximately 2:1 during childhood,but the sex difference wanes by adolescence. Thereis an increased familial incidence, particularly amongsiblings. The mean age at onset has been reported tobe 3.4 years in Asians and 4.2 years in Europeans. Com-pared with other populations, African American andHispanic children have a greater incidence of nephroticsyndrome, a more severe form of disease, and a poorerprognosis. (2)ClassicationNephrotic syndrome can be primary (idiopathic) or sec-ondary. Among children, 90% of cases are primary andthe rest are secondary (Table 2). The advent of percuta-neous renal biopsy in the 1950s and 1960s led to theidentication of three histologic types of idiopathic ne-phrotic syndrome: MCNS, focal segmental glomerulo-sclerosis (FSGS), and membranous nephropathy (MN).Whereas the incidence of nephrotic syndrome has re-mained stable for decades, the distribution of histologictypes apparently has changed due to an increase in theincidence of FSGS. MCNS is the most common form of disease in chil-dren, accounting for approximately 85% of cases. Onlight microscopy, the glomeruli appear normal; electronmicroscopy allows detection of fusion of the epithelialfoot processes, a nding common to all proteinuricstates. FSGS accounts for 10% to 15% of all cases ofnephrotic syndrome. Scar tissue develops initially in seg-ments of some glomeruli, leading eventually to global,Pediatrics in Review Vol.30 No.3 March 2009 95 Genetic Forms of NephroticSyndromeTable 1.Gene/ProteinLocationPhenotype InheritanceARARADARADNPHS/nephrin Slit diaphragm CNFNPHS2/podocin Slit diaphragm FSGSCD2AP/CD2AP Near slitFSGS diaphragmTRPC6/TRPC6PodocyteFSGSWT1PodocyteFSGSACTIN4Foot processFSGStRNALeuPodocyteFSGSCOQ2PodocyteFSGSAD autosomal dominant, AR autosomal recessive, CNFcongenital nephrotic syndrome of the Finnish type, FSGS focal seg-mental glomerulosclerosisDownloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndromeTable 2. Secondary Causes ofNephrotic SyndromeHepatitis B, CHuman immunodeciency virusMalariaToxoplasmosisSyphilisGoldNon-steroidal anti-inammatory drugsPamidronateInterferonHeroinLithiumLymphomaLeukemiaSystemic lupus erythematosusMesangioproliferative glomerulonephritisImmunoglobulin A nephropathyDiabetes mellitusInfections Other glomerulopathies that can be associated withnephrotic syndrome are mesangioproliferative glomeru-lonephritis (MPGN), lupus nephritis, and immunoglo-bulin A (IgA) nephropathy. In the rst two conditions,nephritic ndings (hematuria, hypertension, decreasedrenal function) predominate; in the third, microscopichematuria is interspersed with episodes of macroscopichematuria (Table 3). In all of these diseases, the oc-currence of nephrotic syndrome is associated with aguarded-to-poor prognosis.DrugsSteroid-sensitive Nephrotic SyndromeIn the 1970s, a series of prospective, controlled, multi-center studies performed under the aegis of the Interna-tional Study of Kidney Disease in Children (ISKDC)resulted in a better understanding of the relationshipsbetween the clinical course and histologic character-istics of various forms of nephrotic syndrome. Deni-tions of terms (Table 4), such as nephrotic level albumin-uria and hypoalbuminemia, response to therapy, andindications for renal biopsy, were established. Varioustherapeutic regimens were tested, and prevention ofrelapse became the primary goal of therapy for patientswho had MCNS. Care shifted from the hospital to thehome, with emphasis on daily monitoring of the urine todetect proteinuria and initiate prednisone therapy early.Today, hospitalization should be necessary only whenthere is incapacitating edema (which is preventable) orinfection. A major conclusion of these studies was that the bestMalignanciesMiscellaneousextensive glomerular sclerosis and tubular atrophy. MNis characterized histologically by diffuse thickening of theglomerular capillary walls and accounts for approxi-mately 4% of nephrotic syndrome cases in children.Table 3.Differential Diagnosis of Nephrotic SyndromePhysicalFindingsEdemaEdemaAnasarcaEdemaEdema?EdemaPurpuric rashArthritisButtery rashArthritisEdema?RenalFunctionNormalNormal or lowNormal or lowNormal or lowNormal or lowLowLowLowNormal or lowSerumAlbuminLowLowVery lowVery lowLowNormalNormal or lowNormal or lowNormal or lowC3ComplementNormalNormalNormalNormalLowLowNormalLowNormalUPr/Cr>3.01.0 to 3.0>3.0>3.0>3.03 days during initial treatmentInfrequent relapser: Fewer than three relapses within 6 months of the initial response or fewer than four relapses within any 12-month periodFrequent relapser: Three or more relapses within 6 months following initial response or four relapses within any 12-month periodSteroid-dependent: Recurrence of proteinuria on alternate-day steroid therapy or within 2 weeks after cessation of treatmentSteroid-resistant: Failure to respond to initial prednisone therapy or to 4 weeks of daily prednisone for relapse Indications for RenalBiopsy in Nephrotic SyndromeAt Time of Diagnosis:Two or more of the following: Age >10 years Persistent or gross hematuria Hypertension Renal insufciency Low C3 complement valuesSubsequently:Persistent proteinuria (at the end of 4 weeks ofdaily prednisone therapy)prognostic indicator in children who have nephroticsyndrome is steroid responsiveness. Ninety-ve percentof children who eventually respond to steroids do sowithin the rst 4 weeks of treatment (Fig. 1). (3) As aresult of this observation, children who fulll the clinicalcriteria of MCNS (heavy proteinuria, hypoalbuminemia,and hyperlipidemia) are started on prednisone therapywithout undergoing a renal biopsy. A renal biopsy at thetime of diagnosis is indicated for patients who havemacroscopic hematuria, severe hypertension, persistentrenal insufciency, or a low serum C3 complement value(Table 5). These signs may be indicative of MPGN,systemic lupus erythematosus (SLE), or postinfectiousglomerulonephritis. A biopsy also should be performed ifproteinuria persists at the end of 4 weeks of daily steroidtherapy, when the chance of subsequent response isapproximately 5%. It is worth noting that microscopichematuria is present during the rst few weeks of illnessin as many as one third of children who have MCNS.Persistence or recurrence of hematuria often is a sign ofimpending steroid resistance.Clinical FeaturesThe hallmark of nephrotic syndrome is heavy protein-uria, and the most common presenting sign is edema thatbecomes visible when uid retention exceeds 3% to 5%of body weight. Usually, edema appears initially in areasof low tissue resistance (ie, periorbital, scrotal, and labialregions). Ultimately, it becomes generalized and can bemassive (anasarca). Edema is characteristically depen-dent. In the morning, it is periorbital, frequently misin-terpreted as being caused by an allergy, and later in theday is localized primarily to the lower extremities. An-orexia, irritability, fatigue, abdominal discomfort, anddiarrhea are common symptoms. A respiratory tract in-fection preceding the onset of the disease by a few daysoften is reported, but its pathogenetic role is doubtful.A history of allergy is reported by as many as 50% ofchildren who have MCNS.Laboratory FindingsPlasma protein concentration is reduced markedly, dueprimarily to the loss of albumin in the urine; the serumalbumin concentration usually is below 2.5 g/dL (25 g/L). The low concentration of albumin stimulates synthe-sis of lipids by the liver, resulting in high concentrationsof cholesterol, triglycerides, and lipoproteins. Serum so-dium may be decreased, due, in part, to hyperlipidemiaand, in part, to the retention of water causedby hypovolemia and increased secretion of antidiureticPediatrics in Review Vol.30 No.3 March 2009 97Figure 1. Cumulative distribution of time to response forinitial responders. Note that approximately 95% of the chil-dren who eventually respond do so by 4 weeks of dailyprednisone therapy. Reprinted with permission from J Pediatr.1981;98:561564.Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndromehormone. The total calcium value may be low because ofhypoalbuminemia, but the ionized calcium concentra-tion is normal. The concentration of protein in the urine can beestimated by the dipstick method. The strips are impreg-nated with tetrabromophenol blue, which reacts prefer-entially to albumin. The color change allows the readerto distinguish between a protein concentration of ap-proximately 30 mg/dL (300 g/L) (1 ), 100 mg/dL(1,000 g/L) (2 ), 300 mg/dL (3,000 g/L) (3 ), and1,000 mg/dL (10,000 g/L) (4 ). False-positive resultsmay occur when the urine is alkaline (pH 7) or containsblood, pus, mucus, semen, or vaginal secretions. By thismethod, severity of proteinuria may be underestimatedwhen the urine is diluted or overestimated when theurine is concentrated. Patients who have a positive dipstick result shouldhave a quantitative measurement of urinary protein ex-cretion. Conventionally, this evaluation is performed ona 12- or 24-hour timed urine sample. An excretion ofmore than 50 mg/kg per day or 40 mg/m2 per hour isconsidered indicative of nephrotic syndrome. Accurate collections of urine are cumbersome, partic-ularly in children, which explains the wide acceptance ofthe urine protein/creatinine ratio (UPr/Cr) as a reliablesubstitute. A strong correlation has been found betweenthe UPr/Cr obtained in random specimens of urine andthe 24-hour excretion of protein, corrected for bodysurface area (BSA). For children older than 2 years of age,a UPr/Cr of less than 0.2 is consid-ered to be normal, a value of lessthan 0.5 is accepted as normal forchildren between 6 months and 2years of age, and a value of morethan 3.0 is consistent with ne-phrotic syndrome. Actual proteinexcretion (g/m2 per day) can becalculated by the formula: 0.63(UPr/Cr). Due to circadian varia-tions, the accuracy of the measure-ments can be increased by using arst-voided morning specimen.T-lymphocytes; increases in IL-8, IL-13, insulin-likegrowth factor-1, transforming growth factor-beta, andinterferon-gamma; abnormalities in nephrin expressionor distribution; and the presence of a circulating vascu-lar permeability factor. One such factor may be an activeisoform of hemopexin, a plasma protein that can increaseglomerular permeability by enhancing protease activity. Recently, a group of investigators developed a hu-manized animal model of idiopathic nephrotic syndromeby injecting CD34 stem cells or CD34 peripheralblood mononuclear cells from patients aficted withMCNS or FSGS into immunocompromised mice. (5)Only the injection of CD34 stem cells induced albu-minuria and effacement of the podocyte foot processes.This nding suggests that the cells responsible for thepathogenesis of MCNS, as well as FSGS, are likely im-mature cells undergoing differentiation into T cells.Treatment and Course of MCNSPrednisone is the drug of choice and should be started assoon as a presumptive diagnosis of primary nephroticsyndrome has been made, and infection, including tuber-culosis, has been ruled out (Fig. 2). The treatment pro-posed by the ISKDC consisted of 60 mg/m2 BSA perday, calculated on the basis of ideal weight for height(not to exceed 80 mg/day), divided in three doses. Dailyadministration was continued for 4 weeks, followed by40 mg/m2 BSA per day, given as a single dose in themorning, on alternate days, for an additional 4 weeks. OfCauseThe cause of MCNS remains un-known. A decrease in immune re-sponsiveness or disorders affectingT-lymphocyte number or functionhas been postulated. (4) Also, thereare reports of increased expressionof interleukin-2 (IL-2) receptors on98 Pediatrics in Review Vol.30 No.3 March 2009Figure 2. Treatment of minimal-change nephrotic syndrome.Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndromethe patients aficted with MCNS, about 90% respondedto steroids, and of those, about 60% relapsed. Subse-quent studies of small numbers of children have revealedthat similar rates of initial response can be achieved withtwice-daily or even once-daily administration of pred-nisone. There are exceptions to this rule, however. A mi-nority of children who fail to respond to a twice-dailyregimen respond when given the daily prednisone inthree divided doses. In a retrospective analysis of 389 children included inthe ISKDC studies who had MCNS, 80% were in remis-sion at 8 years. Seventy-ve percent of initial responderswho remained in remission during the rst 6 monthsafter initial response either continued to be in remissionor relapsed rarely. In contrast, initial relapsers, bothfrequent and infrequent, achieved a nonrelapsing courseonly after an average of 3 years. (6) Absence of hematuriaat presentation, remission within 7 to 9 days from thestart of treatment, and age older than 4 years have beenreported to be predictive of few relapses. (7) A prolonged initial treatment with prednisone(6 weeks of daily followed by 6 weeks of alternate-dayadministration) has been found to decrease the fre-quency of relapses. (8) In a Cochrane Review of thesubject, the authors concluded that the higher the re-lapse rate with 2 months of initial treatment, the greaterthe effect of subsequent prolonged administration ofprednisone. (9) Beginning with a relapse rate of 68% inchildren treated for 2 months, the relapse rate fell by anaverage of 7.5% with every 1-month increase in thelength of treatment (approximately 30% at 6 months). The treatment regimen used currently by most neph-rologists consists of 6 weeks of daily prednisone, given intwo divided doses, followed by 6 weeks of alternate-dayprednisone given as a single dose in the morning. A re-lapse is treated with prednisone, 60 mg/m2 BSA per day,given in two divided doses until the urine is protein-freefor 3 consecutive days, followed by 40 mg/m2 BSA perday, on alternate days, given as a single dose in themorning for 6 additional weeks, when the rst relapseoccurs more than 3 months after the initial response andfor 12 additional weeks when the rst relapse occurswithin 3 months after the initial response. Children who are frequent relapsers may benet froman alkylating agent, such as cyclophosphamide (2 mg/kgper day), generally given for 8 to 12 weeks (Fig. 3). (10)A meta-analysis revealed that the relative risk of relapsein children who received this treatment is reduced by60%. (11) The cumulative dose of cyclophosphamideshould not exceed 200 mg/kg because of gonadaltoxicity. Levamisole, chlorambucil, cyclosporine, andFigure 3. Actuarial remission rate after treatment with cyclo-phosphamide in steroid-dependent nephrotic syndrome. Re-printed with permission from Arch Dis Child. 1987;62:11021106.mycophenolate-mofetil also have been found to reducethe frequency of relapses. In a number of uncontrolledstudies, cyclosporine has been reported to reduce theincidence of relapses in 75% to 90% of patients who havesteroid-dependent nephrotic syndrome. The drug hasserious adverse effects (hypertension, hyperkalemia, hy-pertrichosis, gingival hyperplasia). Renal insufciency,initially transitory, can become permanent due to inter-stitial brosis. Often, proteinuria recurs when the treat-ment is discontinued. (12) Cyclosporine administrationrequires careful monitoring of serum concentrations andshould be undertaken only by experienced physicians.The frequency of relapses usually decreases with time,becoming rare at or after puberty. Nonetheless, as manyas 52% of patients have been reported to have at leastone relapse during adulthood. Pregnancy apparently is apredisposing factor. As long as the patient responds tosteroid therapy, the risk of progression toward renalinsufciency remains negligible.Steroid-resistant Nephrotic SyndromeSteroid-resistant nephrotic syndrome may occur at birthor during the rst postnatal year, but is more commonafter the age of 2 years. This group of patients representsno more than 10% of the entire population of childrenwho have nephrotic syndrome, but their prognosis usu-ally is bleak. Their renal function deteriorates, and even-tually they become candidates for dialysis or renal trans-plantation.Pediatrics in Review Vol.30 No.3 March 2009 99Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndromeCongenital Nephrotic Syndrome (CNS)The name implies the presence of proteinuria at birth,leading to clinical symptoms shortly thereafter. Yet, anarbitrary limit of 3 months after birth is being used toseparate the congenital from the infantile form of ne-phrotic syndrome. The most common type of CNS is the Finnish type.CNF is an autosomal recessive disease, its incidence inFinland being 1 per 8,200 live births. However, patientswho have CNF have been reported all over the world. Ina subgroup of Mennonites from Lancaster, Pennsylvania,the incidence is 1 in 500, almost 20 times that encoun-tered in Finland. In 1998, a gene (NPHS1) that codes fora protein (nephrin) located on podocytes was found tobe mutated in CNF. (1) Soon thereafter, it becameapparent that CNF also can be caused by mutations inNPHS2, which codes for another podocyte protein(podocin), and that mutations in NPHS1 sometimes maycause mild, rather than severe, nephrotic syndrome. The typical form of CNF is characterized by mas-sive proteinuria that starts during fetal life. Elevatedconcentrations of alpha-fetoprotein in the amniotic uidand normal fetal ultrasonographic ndings serve to makea presumptive diagnosis of CNF. A denitive diagnosisrequires genetic analysis of placental tissue or amnioticcells. Most affected children are born preterm, weighinga mean of 2,500 g. The amniotic uid often is meconiumstained, and the placenta is large. Edema and abdominaldistention become evident soon after birth. The serumalbumin concentration usually is below 1.0 g/dL (10 g/L). Albuminuria is massive and related directly to theconcentration of albumin in the blood. Many otherproteins, such as IgG, transferrin, antithrombin III,lipoprotein lipase, vitamin D-binding protein, andthyroid-binding protein, also are lost in the urine. Theselosses lead to metabolic disturbances, including lipidabnormalities that can produce atherosclerotic changesas early as the rst postnatal year. During the rst months of extrauterine life, renalpathology is limited to slight-to-moderate mesangial cellproliferation by light microscopy and effacement of footprocesses and thin glomerular basement membranes byelectron microscopy. During the ensuing months, therenal tubules become dilated, mesangial hypercellularityincreases, the Bowman capsule thickens, the interstitiumbecomes brotic, and glomeruli sclerose. Electron mi-croscopy reveals the disappearance of the slit diaphragms. Initial treatment aims to sustain a good nutritionalstate, control edema, and prevent complications such asinfections and vascular thrombosis. Unilateral or bilateralnephrectomy (followed by peritoneal dialysis) often is100 Pediatrics in Review Vol.30 No.3 March 2009required to curtail the massive loss of protein. Successfultreatment results in satisfactory growth and developmentand the chance for eventual kidney transplantation. Insome patients, the nephrotic syndrome recurs, due to thedevelopment of antinephrin antibodies against the for-eign antigens in the graft. Rare forms of CNS are thoseassociated with diffuse mesangial sclerosis, specically,the Denys-Drash, Galloway-Mowat, and Pierson syn-dromes. CNS also can be associated with infections suchas syphilis, toxoplasmosis, cytomegalovirus, congenitalrubella, and hepatitis B.Focal-Segmental Glomerular SclerosisFSGS was identied half a century ago as a postmortemnding in 20 children who had nephrotic syndrome. Thesignicance of this observation became apparent yearslater when the advent of renal biopsy allowed investiga-tors to associate FSGS with steroid resistance. Initially,the disease consists of hyalinization or sclerosis of someglomeruli (focal) that involves only part of the glomeru-lar tuft (segmental). The lesion appears in the juxtamed-ullary nephrons and extends to the cortex, resulting inprogressive loss of renal function. The location of thelesion within the glomerulus may have prognostic sig-nicance. Peripheral lesions opposite the origin of theproximal tubule (tip lesions) appear to have a betterprognosis than do hilar lesions, particularly those charac-terized by capillary collapse (collapsing glomerulopathy)that occur in immunocompromised patients. FSGS isfourfold more common and more aggressive in AfricanAmericans than in Caucasians or Asians. (2) As in MCNS, the major signs of disease are edema andalbuminuria. Hematuria is more frequent in FSGS thanin MCNS, but the overlap diminishes its value as anelement of diagnosis. Results of blood chemistries areindistinguishable from those in MCNS. The age at onsetalso is similar in the two conditions. Because of thesesimilarities, FSGS cannot be diagnosed at presentation,and children commonly are started on standard pred-nisone therapy. Lack of response at 4 weeks prompts arenal biopsy, which often reveals the specic histologiclesion of FSGS. The lesion may be missed, however, if thetissue sample contains a small number of glomeruli ordoes not include juxtamedullary glomeruli, which areaffected rst. In addition, about 20% of children whohave FSGS respond to steroid therapy and do not un-dergo a renal biopsy. The relationship between MCNS and FSGS remainscontroversial. Some believe that these are two distinctentities; others believe that FSGS is a severe form ofMCNS. The latter opinion is supported by the observa-Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndrometion that some children who initially respond to steroidsbecome steroid-resistant, with a renal biopsy revealingfocal-segmental lesions. FSGS is a heterogeneous condition, the histologicexpression of a variety of diseases, including heroin-associated nephropathy, acquired immunodeciencysyndrome, multiple myeloma, Alport syndrome, reuxnephropathy, diabetic nephropathy, and obesity. Heter-ogeneity also applies to idiopathic FSGS. Some pa-tients respond to steroid therapy; most do not. In somepatients, disease progression is slow, reaching end stagein about 10 years; in others, it reaches that point in about2 years. Moreover, in this latter group, the disease has ahigh likelihood of recurring in the transplanted kidney,probably due to the presence of a blood-circulatingfactor. Despite sustained efforts, no factor has been iso-lated. The heterogeneity of FSGS has been amplied bythe recognition that some cases of FSGS are due togenetic abnormalities. GENETIC FORMS OF FSGS. Inrecent years, impressive progresshas been made in describing themolecular structure of the podo-cytes and the slit diaphragms thatlink them. Specically, a numberof proteins have been identiedthat work in concert to controlthe permeability of the glomerularmembrane. Mutations in thegenes that encode these proteins are associated withnephrotic syndrome and focal-segmental glomerular le-sions. The impetus for this exploding eld of research hasbeen the discovery that lack of nephrin, a protein locatedat the slit-diaphragm, accounts for CNF. Table 1 sum-marizes the current state of knowledge. Genetic formsaccount for only a small percentage of FSGS. Geneticdiagnosis, although commercially available, is expensive,is performed in only a few laboratories, and is justiedonly in isolated circumstances. Despite the impressive progress made in identifyinggenetic types of FSGS, the cause of the disease still hasnot been identied in most patients. It has been pro-posed that genetic variants in two or more podocytegenes that alone do not produce disease may interact tocause FSGS. This concept, although enticing, is yet to beproved. TREATMENT. The therapy for FSGS, regardless of va-riety, has been and continues to be a frustrating en-deavor. It is reasonable to assert that no agent that couldconceivably be of benet to these patients has escapedclinical experimentation. Alas, no denitive evidence hasemerged that any of these drugs is effective, although afew facts have been learned from these trials. Pulse meth-ylprednisolone, hailed as being salutary for most childrenwho have steroid-resistant nephrotic syndrome, hasproven to be of minimal benet. Alkylating agents suchas cyclophosphamide also have been shown to have littletherapeutic effect, but they continue to be used. Inuncontrolled trials, cyclosporine has been reported toinduce remission in 25% to 50% of patients who havesteroid-resistant FSGS, but patients relapse promptlywhen the drug is discontinued and develop serious ad-verse effects if the treatment is sustained for long periods.A multicenter, prospective, controlled, randomized trial,sponsored by the National Institutes of Health, is inprogress. Patients younger than 40 years of age who havebiopsy-proven FSGS are assigned to treatment with ei-ther pulse steroids plus mycophenolate-mofetil or toInfections are frequent and seriouscomplications of nephrotic syndrome . . . Themost common infection is peritonitis. . . .cyclosporine. The results of this therapeutic trial will notbe known for several years. Recurrence of disease in transplanted kidneys is amajor problem; it has been reported to occur in as manyas 50% of children who have FSGS. Being older than 6years of age at onset and progression to end-stage renaldisease in fewer than 3 years are considered risk factors.For most affected children, proteinuria develops withinhours after transplantation, although it may start as lateas 3 months later. High-dose cyclosporine, plasmaphere-sis, or a combination of both is associated with partial ortotal remission in a minority of cases. The outcome of thetreatment is unpredictable.Membranous NephropathyMN was identied initially postmortem as a diffuse,irregular thickening of the glomerular basement mem-branes in the absence of any inammatory changes. Withthe introduction of acid-silver-methenamine stain andelectron microscopy, it became evident that the distor-Pediatrics in Review Vol.30 No.3 March 2009 101Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndrometion of the basement membranes is due to the presence ofblobs of silver-negative, electron-dense deposits. Thedeposits are located exclusively in the subepithelial areaand are anked by silver-positive tissue, giving the ap-pearance of spikes. MN is very rare in children and canmanifest at any age. It presents as either asymptomaticproteinuria or nephrotic syndrome. Microscopic hema-turia and hypertension are rare. No clinical or laboratoryndings allow a positive identication; the diagnosis restsultimately on the specic histologic ndings. The disease can be either primary or due to a variety ofconditions, including infections (hepatitis B, malaria,syphilis), autoimmune diseases (SLE, Crohn disease),drugs (penicillamine), tumors (Wilms, neuroblastoma),and other disorders. The pathogenesis of MN has notbeen determined precisely, although evidence points to-ward binding of an antibody to an in situ glomerularbasement membrane antigen. In several cases of neonatalMN, a podocyte antigen, neutral-endopeptidase, (13)served as the pathogen. Antibodies to this protein origi-nated in pregnant women who lacked the neutral endo-peptidase epitop due to a mutational deletion. No similarndings have been reported in older patients. The course of the disease is variable. Spontaneousremissions occur in 25% to 50% of children, whereas 25%to 30% develop renal insufciency. Treatment with ste-roids and immunosuppressive drugs is common, al-though the results have been discouraging.Complications of Nephrotic SyndromeSome patients exhibit signs of acute renal failure (ie,reduction in glomerular ltration rate and oliguria).These signs usually are reversed when the intravascularvolume is expanded by infusion of salt-poor humanalbumin and diuresis is induced by furosemide or otherdiuretic drugs. Rarely, acute renal failure can be causedby bilateral renal vein thrombosis. The diagnosis is madeby ultrasonography. Thromboembolic complications alsocan affect the lungs, the brain, and the peripheral vessels.The overall incidence of thromboembolic events is about3%. Such events are caused by loss of antithrombin IIIand protein S in the urine as well as an increase inbrinogen concentration, leading to a hypercoagulablestate. The antiphospholipid syndrome also has been incrim-inated as a cause of thromboembolic complications insome patients who have nephrotic syndrome. This disor-der is characterized by persistently elevated concentra-tions of antibodies directed against membrane anionicphospholipids (eg, anticardiolipin antibody, antiphos-phatidylserine) or their associated plasma proteins, pre-102 Pediatrics in Review Vol.30 No.3 March 2009dominantly beta-2 glycoprotein I (apolipoprotein H).A circulating anticoagulant also may be present. Themechanism of thrombosis in this syndrome has not yetbeen dened. Emerging evidence from murine modelssuggests that antiphospholipid-mediated complementactivation may be the primary event. Irrespective of causeor pathogenesis, the rst line of treatment is low-molecular weight heparin. If the thrombosis extends,thrombolytic drugs, such as tissue plasminogen activator,followed by warfarin should be considered. Warfarinshould be discontinued as soon as the nephrotic syn-drome resolves. Infections are frequent and serious complications ofnephrotic syndrome. Urine loss of factor B (which con-tributes to opsonization of bacteria), a decrease in IgGsynthesis, and impaired T-cell function contribute to thesusceptibility to infection. The most common infection isperitonitis, which used to be due primarily to Streptococ-cus pneumoniae. Vaccination has reduced infections withS pneumoniae substantially and increased the relativefrequency of gram-negative organisms. There also hasbeen an increase in penicillin-resistant S pneumoniae. A high degree of suspicion must be maintained whencaring for patients who have ascites. Fever and chillsoccur in as many as 80% of patients who have peritonitis.Abdominal pain or discomfort is found in as many as 70%of patients and often is accompanied by ileus or diarrhea.Peritoneal uid must be analyzed for any patient inwhom peritonitis is considered. An ascitic uid neutro-phil count of more than 500 cells/mcL is the single bestpredictor of infection, with a sensitivity of 86% andspecicity of 98%. Lowering the ascitic uid neutrophilcount to more than 250 cells/mcL results in an increasedsensitivity (93%) but a lower specicity (94%). Notably,steroids do not mask the signs and symptoms of perito-nitis. (14) A combination of an aminoglycoside and ampicillinprovides empiric coverage of more than 90% of cases ofperitonitis caused by gram-negative aerobes or gram-positive cocci. The third-generation cephalosporin cefo-taxime is as efcacious and is not nephrotoxic but doesnot treat enterococci. Subsequently, antibiotic therapyshould be guided by the results of ascitic uid culturesand sensitivities. Cellulitis, meningitis, and pneumonitis also may oc-cur in patients who have nephrotic syndrome. Anasarcaand pulmonary edema are preventable complications ofnephrotic syndrome and reect massive retention of so-dium and water, consequent to the loss of albumin in theurine and its leakage into the extravascular compartment.Diuretic drugs and salt-poor albumin infusions are onlyDownloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndromepartially effective. The primary goal of therapy should bediminution of protein loss. Stunting of growth, a com-plication of prolonged steroid administration, is wellrecognized. Thirty-four patients who had a frequentlyrelapsing course and a mean age of 8.0 years at onsetwere found to have a mean height 2.5 cm below thetarget height, when evaluated 13 years later. (15)Growth rate should be monitored closely in frequentrelapsers or steroid-dependent children, and an alterna-tive therapy (cyclophosphamide, mycophenolate-mofetil,cyclosporine) should be considered as soon as the growthcurve plateaus. Reduced mineral bone density, a recently recognizedcomplication of MCNS, is due to the prolonged admin-istration of steroids and, possibly, to vitamin D de-ciency. In a randomized, controlled study of 40 childrenwho had MCNS, daily administration of 400 IU ofvitamin D and 1 g of calcium diminished, but did notend, the decrease in bone mineral density.Ancillary Therapy of Nephrotic SyndromeEdema in nephrotic syndrome requires treatment onlywhen it is associated with severe ascites, peritonitis, re-spiratory distress, or heart failure. The rst line of therapyis diuretic drugs. Commonly used are loop diuretics(furosemide, ethacrynic acid), which block reabsorptionof sodium in the loop of Henle, and thiazide diuretics(hydrochlorothiazide), which block reabsorption of so-dium in the distal tubule. For patients who fail to respondto diuretics, concomitant administration of salt-poor al-bumin (0.5 to 1 g/kg body weight up to 25 g, in a 25%solution administered intravenously over 30 to 60 min-utes) may induce diuresis. This treatment appears to beparticularly effective in children who have very low serumalbumin concentrations ( 1.5 g/dL [15 g/L]) and inthose who have clinical signs of intravascular volumecontraction. Aggressive administration of diuretic drugsmay induce hypovolemia and secondary renal failure,thromboembolism, or electrolyte disturbances. Hypovo-lemia can be prevented or treated by administration ofsalt-poor albumin. Approximately 20 years ago, it was noticed that an-giotensin II inhibitors diminished proteinuria, indepen-dently of their effect on blood pressure and glomerularltration rate. As a result, ACE inhibitors and angioten-sin receptor blockers, given alone or in combination,have become important components of the antiprotein-uric therapy. Twelve weeks of treatment were reported toreduce proteinuria by about 1 g/24 hours. Recently, ithas been found that ACE inhibitors prevent loss ofpodocytes and preserve nephrin expression; they alsomay slow progression of renal disease. A protective effecton renal function also was seen with angiotensin receptorblockers. Hyperlipidemia is one of the primary features of thenephrotic syndrome that may persist well beyond remis-sion. Several studies have revealed premature coronaryatherosclerosis and increased incidence of myocardialinfarction in patients who have nephrotic syndrome.Hyperlipidemia also may contribute to progression ofrenal disease. These observations have prompted manyphysicians to use statins in patients who have had per-sistent hyperlipidemia. Statins also have been found toslow the progression of chronic renal disease, albeit to atrivial extent. These effects may be due to improvementof endothelial function, systemic or intrarenal anti-inammatory actions, amelioration of oxidative stress,and inhibition of macrophage recruitment and function. Vaccination of children who have nephrotic syn-drome has been found to be generally effective. Antibodyresponses to pneumococcal, inuenza, varicella, and hep-atitis vaccines have been adequate, and the adverse effectshave not been found to be different from those reportedin the general population. However, pneumococcal andhepatitis antibody concentrations were reported to de-cline faster in children who had nephrotic syndrome thanin the general population. The Committee on InfectiousDiseases of the American Academy of Pediatrics recom-mends vaccination with the conjugated pneumococcalvaccine. The state of immunity to varicella should beassessed for patients who have not been vaccinated, andtreatment with acyclovir should be started as soon as anat-risk patient is exposed to the virus. Retention of sodium is paramount to water retentionand the development of edema. Thus, a low-sodium dietis warranted, although uid intake does not need to berestricted as long as sodium intake is limited. Prolongedloss of proteins in the urine may compromise the nutri-tional status of the children and must be prevented by anadequate diet and, when necessary, the addition of high-protein products. Vitamin D and calcium supplementa-tion also are advisable.Summary and ConclusionsNephrotic syndrome encompasses a diverse group ofconditions that share the common denominator of mas-sive loss of protein in the urine. Progress in identifyingthe cause and pathogenesis of each of these conditionshas been slow. The current identication of variousforms of nephrotic syndrome is based primarily on histo-logic ndings, which are not always pathognomonic.Pediatrics in Review Vol.30 No.3 March 2009 103Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndromeTreatment has and still depends on drugs that lack spec-icity and have numerous, often serious, adverse effects. The following conclusions are worth remembering:2. Ingulli E, Tejani A. Racial differences in the incidence and renaloutcome of idiopathic focal segmental glomerulosclerosis in chil-dren. Pediatr Nephrol. 1991;5:3933973. The primary nephrotic syndrome in children: identication ofpatients with minimal change nephrotic syndrome from initialresponse to prednisone. A Report of the International Study ofKidney Disease in Children. J Pediatr. 1981;98:5615644. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of Tcell function. Lancet. 1974;2:556 5595. Sellier-Leclerc AL, Duval A, Riveron S, et al. A humanizedmouse model of idiopathic nephrotic syndrome suggests a patho-genic role for immature cells. J Am Soc Nephrol. 2007;18:273227396. Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr. Prognosticsignicance of the early course of minimal change nephrotic syn-drome: report of the International Study of Kidney Disease inChildren. J Am Soc Nephrol. 1997;8:769 7767. Constantinescu AR, Shah HB, Foote EF, Weiss LS. Predictingrst-year relapses in children with nephrotic syndrome. Pediatrics.2000;105:492 4958. Brodehl J. The treatment of minimal change nephrotic syn-drome: lessons learned from multicentre cooperative studies. EurJ Pediatr. 1991;150:380 3879. Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroidtherapy in nephrotic syndrome: a meta-analysis of randomizedcontrolled trials. Arch Dis Child. 2000;83:455110. Cyclophosphamide treatment of steroid dependent nephroticsyndrome: comparison of 8-week with 12-week course: report ofthe Arbeitsgemeinschaft fur Pediatrische Nephrologie. Arch DisChild. 1987;62:1102110611. Durkan AM, Hodson EM, Willis NS, Craig JC. Immunosup-pressive agents in childhood nephrotic syndrome: a meta-analysis ofrandomized controlled trials. Kidney Int. 2001;59:1919 192712. Niaudet P, Habib R. Cyclosporine in the treatment of idio-pathic nephrosis. J Am Soc Nephrol. 1994;5:1049 105613. Dubiec H, Guigonis V, Mougenot B, et al. Antenatal mem-branous glomerulonephritis due to anti-neutral endopeptidase an-tibodies. N Engl J Med. 2002;346:2053206014. Krensky AM, Ingelnger JR, Grupe W. Peritonitis in child-hood nephrotic syndrome: 1970 1980. Am J Dis Child. 1982;136:73273615. Motoyama O, Iitaka K. Final height in children with steroidsensitive nephrotic syndrome. Pediatr Int. 2007;49:623 625Most children who have nephrotic syndrome haveMCNS, which is responsive to prednisone therapy.Response to steroid therapy is the best prognosticindicator.Most ( 60%) of children who have MCNS relapse,some of them frequently. Cyclophosphamide and cy-closporine decrease the incidence of relapses.Compelling evidence suggests that renal biopsy shouldbe performed at onset only in children who, in additionto proteinuria, have macroscopic hematuria, hyperten-sion, persistent renal insufciency, or low C3 comple-ment values. Another indication is failure to respond tosteroid therapy (proteinuria still present at the end of4 weeks of daily prednisone therapy).Most children who have nephrotic syndrome and failto respond to steroids have FSGS. Most alkylatingagents are ineffective. Cyclosporine has been reported,in uncontrolled studies, to induce remission in 20% to50% of patients who failed to respond to steroids. Thedrug requires monitoring of serum values and hasserious adverse effects. Proteinuria recurs in most pa-tients as soon as the treatment is discontinued.Several genetic forms of FSGS, due to mutations thatencode proteins at the level of the podocytes, havebeen identied. They account for a small minority ofpatients who have nephrotic syndrome, and none re-sponds to treatment.Dialysis and transplantation have improved the long-term prognosis of patients who reach end-stage renaldisease, even infants who have CNS.Some glomerulopathies, such as FSGS, MPGN, andpossibly CNS, may recur in renal transplants. Treat-ment with immunosuppressive agents and plasma-pheresis is effective in about 30% of such patients.Suggested ReadingReferences1. Trygvason K, Patrakka J, Wartiorova J. Hereditary proteinuriasyndromes and mechanisms of proteinuria. N Engl J Med. 2006;354:13871401Eddy AA, Symons JM. The nephrotic syndrome. Lancet. 2003;362: 629 639Shankland SJ. The podocytes response to injury: role of proteinuria in glomerulosclerosis. Kidney Int. 2006;69:21312147104 Pediatrics in Review Vol.30 No.3 March 2009Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009nephrologythe nephrotic syndromePIR QuizQuiz also available online at www.pedsinreview.aappublications.org.6. A 4-year-old boy presents with swelling of the face and extremities of 2 days duration. Physical examination reveals an otherwise happy child who has swelling of the face and pitting edema of all extremities. Vital signs and the rest of the physical examination ndings are normal. Urinalysis shows 4 proteinuria and 5 red blood cells per high-power eld. Of the following, the most likely abnormality on histologic examination of this boys kidney is:A.B.C.D.E.Deposition of immunoglobulin A in mesangium.Diffuse thickening of glomerular capillary walls.Fusion of epithelial foot processes only.Mesangial cell proliferation and thickening of Bowman capsule.Scar tissue in segments of some glomeruli.7. A 4-year-old boy presents with swelling of the face and extremities of 2 days duration. Physical examination reveals an otherwise happy child who has swelling of the face and pitting edema of all extremities. Vital signs and the rest of the physical examination ndings are normal. Urinalysis shows 4 proteinuria and 5 red blood cells per high-power eld. Of the following, the best indicator of good outcome for this child is:A.B.C.D.E.Normal C3 complement value.Normal serum creatinine concentration.Resolution of symptoms with prednisone treatment.Serum cholesterol less than 500 mg/dL (13.0 mmol/L).Urine protein:creatinine ratio less than 5.8. You are treating a 9-year-old girl who has nephrotic syndrome with prednisone. Which of the following is the strongest indication for performing renal biopsy?A.B.C.D.E.Lack of response to therapy after 1 week.Microscopic hematuria showing more than 5 red blood cells per high-power eld in urine.Reduced serum concentration of C3 complement.Serum albumin less than 1.5 g/dL (15 g/L).Urine protein:creatinine ratio of 1 at presentation.9. A 6-year-old girl is admitted for swelling of her face and extremities. Findings on her physical examination and vital signs are normal except for generalized anasarca. Urinalysis shows 4 protein with no casts or red blood cells. Serum albumin is 1.3 g/dL (13 g/L), cholesterol is 550 mg/dL (14.2 mmol/L), and creatinine is 0.4 mg/dL (35.4 mcmol/L). This patient is at greatest risk for:A.B.C.D.E.Centrilobular hepatic necrosis.Cerebral edema.Congestive heart failure.Myoglobinuric renal failure.Peritonitis.Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009Pediatrics in Review Vol.30 No.3 March 2009 105 The Nephrotic SyndromeRoberto Gordillo and Adrian Spitzer Pediatr. Rev. 2009;30;94-105 DOI: 10.1542/pir.30-3-94Updated Information& ServicesSubspecialty Collectionsincluding high-resolution figures, can be found at:http://pedsinreview.aappublications.org/cgi/content/full/30/3/94This article, along with others on similar topics, appears in thefollowing collection(s):Renal Disordershttp://pedsinreview.aappublications.org/cgi/collection/renal_disordersInformation about reproducing this article in parts (figures,tables) or in its entirety can be found online at:http://pedsinreview.aappublications.org/misc/Permissions.shtmlInformation about ordering reprints can be found online:http://pedsinreview.aappublications.org/misc/reprints.shtmlPermissions & LicensingReprintsDownloaded from http://pedsinreview.aappublications.org at Health Internetwork on March 20, 2009