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  • * Corresponding Author; Address: Division of Nephrology, Children's Medical Center, Pediatrics Center of Excellence, No 62, Dr Gharib St, Tehran, Iran E-mail: [email protected],ChildrensMedicalCenter,TehranUniversityofMedicalSciences, Allrightsreserved.

    AnEstimationofSteroidResponsivenessofIdiopathic

    NephroticSyndromeinIranianChildren

    AbbasMadani1,2,MD;DarioushFahimi1,MD;RambodTaghaodi2,MD;FatemehMahjoob2,3,MD;NiloofarHajizadeh*1,2,MD,andBehdadNavabi1,MD

    1. DepartmentofPediatrics,TehranUniversityofMedicalSciences,Tehran,IRIran2. Children'sMedicalCenter,PediatricsCenterofExcellence,Tehran,IRIran3. DepartmentofPathology,TehranUniversityofMedicalSciences,Tehran,IRIran

    Received:Apr20,2009;FinalRevision:Sep24,2009;Accepted:Mar12,2010

    Abstract Objective: Idiopathic Nephrotic syndrome (INS) is the most common form of nephroticsyndrome(NS)inchildrenwiththepotentialofprogressiontoendstagerenaldisease(ESRD).INS is steroidresponsive inmost children, butnot all patients respond to it. The aimof thisstudywastodeterminetherateofsteroidresponsivenessinchildrenwithINSthatreferredtoChildren'sMedicalCentersince1995to2007.

    Methods:Inasacrosssectionalstudy,themedicalrecordsofallchildrenwithINSaged1to15years who were referred to our referral hospital was reviewed. All patients with onset ofdiseaselessthan1yearofage,spontaneousremission,secondaryformsofNSassociatedwithsystemicdiseases,andfollowupdurationoflessthan12monthswereexcludedfromthestudy.Patientswerecategorizedinto6groups:Group1neededbiopsypriortoanytreatment,group2nonrelapsingNS,group3infrequentlyrelapsingNS,Group4frequentlyrelapsingNS,group5steroiddependentNSandgroup6steroidresistantNS.

    Findings:Atotalof238patientswereenrolledinthestudy.Kidneybiopsywasperformedin79cases.Minimalchangelesion(MCL)wasthemostcommon(36.7%)pathologicaldiagnosis.Steroidresponsivenesswasfoundin81.5%ofallcasesincluding: 96%ofMCL(consistingofbiopsyprovencasesandpresumedones),32%offocalandsegmentalglomerulosclerosis,73%of diffuse mesangial proliferation and 58% of membranoproliferative glomerulonephritispatients.Duringminimalfollowupperiodof12months,therewere194patientsinremission,32patientswithactiveNS,and12patientsinESRD.

    Conclusion: Our study results showed that 81.5%of all patients, 96.2%ofMCL and 32%ofFSGSpatientsinitiallyrespondedtosteroidtherapy.

    IranianJournalofPediatrics,Volume20(Number2),June2010,Pages:199205

    KeyWords:IdiopathicNephroticSndrome;SteroidResponsiveness;Glomerulonephritis;FSGS

    Original Article Iran J Pediatr Jun 2010; Vol 20 (No 2), Pp:199-205

  • 200 SteroidResponsivenessofIdiopathicNephroticSyndrome;AMadani,etal

    Introduction

    Idiopathicnephroticsyndrome(INS)isthemostcommon form of NS in children with thepotential of progression to end stage renaldisease (ESRD)[1]. It is more common in boysthan in girlswith a ratio of 1.6:1 and occurs inchildren at a median age of 4 years[2]. Themortality rate of nephrotic syndrome (NS)was40%before1940,primarilyduetoinfection;butthis has been significantly reduced with theintroductionofsteroidtreatmentandantibiotics.Steroidshave longbeenusedas the first lineoftreatment in NS, however, other immunesuppressives may be indicated whenprednisolone fails to induce or sustainsremission[3].The overall incidence of childhood INS hasbeen generally stable over the past threedecades (two to seven cases per 100,000children)[3].However, thehistologicalpatternofchildhood INS is changing, and the incidence ofFSGS seems to be increasing[4,5]. Histopathological findings inNSmay reflect in patterns ofresponsiveness[1].ThemostcommonformofNSin children is minimal change lesion (MCL)[6,7].ThevastmajorityofpatientswithMCL (>90%)respond to steroid therapy. Other types of INSlike focal and segmental glomerulosclerosis(FSGS), diffuse mesangial proliferation (DMP),membranoproliferative glomerulonephritis(MPGN) and membranous glomerulonephritis(MGN)arelesssteroidresponsive.Morethan90percent of patients who respond to steroidtherapy have MCL[6]. MCL can accurately bediagnosed based on presenting clinical findingsinchildrenyoungerthan6yearsofage,absenceof hypertension, absence of hematuria, normalcomplementlevels,andnormalrenalfunction[1].Corticosteroids play a key role in thetreatmentof INS.Althoughahighproportionofpatients experience relapses, many of themcontinue their steroid responsiveness. TheInternational Study for Kidney Diseases inChildren (ISKDC) first introduced an empiricaltreatment protocol for INS which later facedsome minor changes. The ISKDC recommendsthat the initial episode be treated withprednisoloneatadailydosageof60mg/mfor4wk, followed by 40mg/m for 3 days out of a

    week(intermittenttherapy)foranother4wk[8,9].Roughly 95% of patients with MCL and 20%withFSGSachievedremissionwiththisprotocol[2,3]. Approximately 90% of patients who willrespond to steroids (urine traceornegative forproteinfor3consecutivedays)dosowithinfourweeksafterstartingsteroids[10].Majority of children with INS experiencerelapses (proteinuria >40mg/m2/hr or urineprotein test tape3+ ormore for3 consecutivedays after achieving remission)which could becategorizedas infrequent relapsingNS (IFRNS):lessthan3relapsesduring1yearafterachievingremission, Frequent Relapsing NS (FRNS): 3 ormore relapses during 1 year after achievingremission, and steroid dependentNS (SDNS): 2consecutive relapses during steroid therapy orwithin2weeksafterdiscontinuationoftherapy.On the basis of response to empiricglucocorticoidtherapy,patientswithINScanbeclassified into GlucocorticoidResponsive andGlucocorticoidResistant. Resistance to steroidtherapyrepresents10%ofINS[11].Gulatietalbyreviewing histopathology of 136 steroidresistant NS (SRNS) children found that FSGSwasthemostcommoncauseofSRNSinchildrenwithonsetofNSatallagegroups[12],alsoKariinSaudi Arabia[13] reported the same results. DelRio et al by reviewing thepreviously publisheddataonSRNS in literature showeda rise in theincidence of FSGS[4]. A literature review ofsteroidsensitive NS (SSNS) by Hodson et alindicated that the mechanism of steroidsensitivity is due to lymphocytederivedcirculating factors leading to podocyte injurywithsubsequentproteinuria[14].The current study aimed to define the truesteroid responsiveness pattern of Iranianchildren with INS, since there is not muchstatistical information regarding this issue inIranianchildren.

    SubjectsandMethods

    The study was conducted as a cross sectionalretrospective descriptive study. The medicalrecords of all children with INS aged 1 to 15

  • 201IranJPediatr;Vol20(No2);Jun2010

    years who were referred to the hospital since1995 to 2007 were reviewed. Cases wereselectedinanonrandomsimplefashion.Medicalrecords of patients with INS who fulfilled thestudycriteriawerethesourceofinformation.Exclusioncriteriawereageofonsetofdiseaselessthan1year,secondaryformsofNS,lessthan12 months followup, and initial spontaneousremission. In each patient clincopathologicalfindings, responsiveness to employed treatments, and outcome or status at the follow upperiodofatleast12monthswasdetermined.Renal biopsy was performed prior totreatmentinthosewiththeonsetofthediseaseoccurredat>7yearsofage,hypertension,renalfailure, macroscopic or high grade microscopichematuria, lowC3 level, familyhistoryofAlportsyndrome, and in steroidunresponsivepatientsatanytimeduringthecourseoftreatment.Prednisolonewasadministeredatadosageof60 mg/m2/day (maximum 80mg/day) threetimesadayfor4weeks;inthecaseofremission,it continued at the dosage of 40mg/m2/dayevery other day for another 4 weeks and thentapered 10mg/m2 each 2 weeks in all patientsexcept MPGN cases. Patients with MPGN weretreatedwithprednisoloneatthedosageof2030mg/m2/day plus dipyridamole 23 mg/kg/dayfor2years.On the basis of the steroid responsivenesspatternandthenecessityofkidneybiopsypriorto initial treatment, patients were categorizedinto 6 groups: Group 1: those needed renalbiopsy prior to initial treatment, Group 2: nonrelapsing NS patients (NRNS) (no relapse in atleast 12 months after discontinuation of initialtherapy),Group3:IFRNS(lessthantworelapseswithin6monthsorthreerelapsesduring1yearafter achieving remission), Group4: FRNS (twoor more relapses within 6 months or three ormore during 1 year after achieving remission),Group5:SDNS(twoconsecutiverelapsesduringtapering of steroid therapy or within 2 weeksafter discontinuation of therapy), and Group 6:SRNS.Data were analyzed using the StatisticalPackage of SPSS (version 17). Descriptivestatistics were used, such as meanstandarddeviation (SD) for continuous variables andpercentage (%) to describe the proportion of

    categorical variables such as sex and thefrequency of different histopathologicaldiagnosis.

    Findings

    Atotalof282patientsinitiallyenteredthestudy;44caseswereexcludedduetoinadequatefollowup (34 cases), secondary forms of NS (8 cases)and spontaneous remission (2 cases). Finally238patientsremainedinthestudy.Theagerangeofpatientswas115yearswithanaverageonsetof4.52years.Therewere152(63.8%) males and 86 (36.2%) females. Themale/female ratio was 1.76 in this study. Sexdistribution of our six study groups issummarized in Table 1. Range of follow upperiod was 12144 months with a mean of 51months.Prior to the initial treatment, kidney biopsywasperformedin35patientsonthebasisofoneor two indications (family history of Alportsyndrome in 1 case, high grade microscopichematuria in 23 cases, onset of the diseaseoccurred at >7 years of age in 22 cases,hypertension in9 cases,decreased complementlevel in7 cases, and renal failure in5 cases;17cases had more than one indication for renalbiopsy).Prednisolone was administered in theremainder 203 patients without initial renalbiopsy,butlaterinthecourseoftreatment44ofthesepatientsunderwentrenalbiopsy(Group4:13 cases, Group 5: 13 cases, and Group 6: 18cases). Renal biopsy is performed in totally 79patients.Histopathological diagnoseswereMCLin 29 patients (36.7%), FSGS in 22 patients(27.8%),DMP in 11 patients (13.9%),MPGN in12 patients (15.1%), and others (MGN:membranous glomerulonephritis, Alportsyndrome, FPGN: focal proliferative glomerulonephritis)in5patients.Histopathological diagnoses were MCL in 29patients (36.7%), FSGS in 22 patients (27.8%),DMP in 11 patients (13.9%), MPGN in 12patients (15.1%), and others membranousglomerulonephritis(MGN),Alportsyndrome,

  • 202 SteroidResponsivenessofIdiopathicNephroticSyndrome;AMadani,etal

    Table1:Characteristicsofgroupsofpatientswithnephriticsyndromeonthebasisofthesteroidresponsiveness

    Group No(%) Male Female Histopathologicaldiagnosisonrenalbiopsy

    Statusafterthefollowupperiod

    1* 35(14.7) 21 14 MCL:13;FSGS:5;DMP:5;MPGN:11;Alport:1Remission:19;activedisease:12;ESRD:4

    2(NRNS) 45(18.9) 32 13 Remission:453(IFRNS) 44(18.4) 30 14 Remission:44

    4(FRNS) 39(16.3) 25 14 MCL:7;FSGS:3;DMP:2;FPGN:1 Remission:37;Activedisease:2;ESRD:0

    5(SDNS) 47(19.7) 3116

    MCL:8;FSGS:3;DMP:1;FPGN:1Remission:44;Activedisease:3;ESRD:0

    6(SRNS) 28(11.7) 1513

    MCL:1;FSGS:11;DMP:3;FPGN:1;MGN:1;MPGN:1

    Remission:5;Activedisease:15;ESRD:8

    *Group1:allpatientsunderwentbiopsybeforetreatment;NRNS:nonrelapsingnephroticsyndrome;IFRNS:infrequentrelapsingnephroticsyndrome;FRNS:frequentrelapsingnephroticsyndrome;SDNS:steroiddependentnephroticsyndrome;SRNS:steroidresistantnephroticsyndrome;MCL:minimalchangelesion;FSGS:focalandsegmentalglomerulosclerosis;DMP:diffusemesangialproliferation;MPGN:membranoproliferativeglomerulonephritis;MGN:membranousglomerulonephritis;FPGN:focalproliferativeglomerulonephritis,ESRD:endstagerenaldisease10patientswerenotbiopsied,ofwhom3patientsexperiencedESRDandotherswereinactivedisease.

    focalproliferativeglomerulonephritis(FPGN)in5patients.Steroid responsiveness was totally found in194patients(81.5%)ofwhom175cases(73.5%ofall)were inGroups25, and19 (7.9%of all)cases inGroup1 (outof23patients inGroup1whoreceivedsteroids).Group6patients(11.7%of total)werenot responsive to steroids (Table1).Thesteroidresponsivenessofthe79patientswithhistopathological diagnosis on thebasis ofrenalbiopsyissummarizedinTable2.The most prevalent relapsing patterns ofpresumed MCL patients were 410 relapseswithameanfollowupperiodof60monthsin37(24.8%) patients, 2 relapses with mean followupperiodof51months in26(17.4%)patients,one relapse with mean follow up period of 35months in 21 (14%) patients, and 3 relapseswithmeanfollowupperiodof54months in17(11.4%)patients.

    Ifwe consider total number ofMCL cases as178 cases including biopsy proven ones (29cases) and presumed ones (149 cases) (allpatients of Group 2 and Group 3 plus nonbiopsiedcasesofGroup4andGroup5),steroidresponsivenessofMCLwas96.2% in this study(171caseswereresponsivetosteroidsandonly7casesdidnotrespond).

    Discussion

    Theaimofourstudywastoidentifythesteroidresponsivenesspattern in Iranian childrenwithINSduring12years.Ourstudyfindingsshowedthat majority of children with NS (81.5%)respond to steroid therapy. This finding issimilar to other studies in other countries in

    Table2:Steroidresponsivenesscharacteristicsofbiopsiedpatients

    Histopathologicaldiagnosis No

    Initialsteroidresponsiveness

    Statusafterthefollowupperiod

    MCL 29 22 Remission:22;activedisease:6;ESRD:1FSGS 22 7 Remission:6;activedisease:12;ESRD:4DMP 11 8 Remission:8;activedisease:1;ESRD:2MPGN 12 7 Remission:7;activedisease:4;ESRD:1Others(MGN,Alportsyndrome,FPGN) 5

    0(steroidin3patientswithFPGN) Remission:0;activedisease:4;ESRD:1

  • 203IranJPediatr;Vol20(No2);Jun2010

    Middle East and around Iran, but is less (94%)thanthatinISKDCreport[11].Table 3 shows comparison of our findingswiththose of other studies. However, there arefew studies that reported a smaller rate ofsteroidresponsivenessinINS(66%bySafaeietal[15]and22.5%byEke[16]).Jung Sue Kim et al in 2005 found that thefrequency of SRNS in children is higher thanreported earlier. During the initial steroidtherapy, 71% were steroidsensitive, 15%steroidresistant and 14% achieved partialresponse. The follow up study showed that atleast45%ofthechildrenwithnewonsetNSdidnotshowthetypicalsteroidresponsivepattern.Two factorswereassociatedwithdevelopingsteroid resistanceafter initial response: shorterinterval to the first relapse (2.2 vs 5.4months)andthefirstrelapseoccurringduringthe initialsteroidtreatment[17].InElSheikhetalstudy,94.5%ofthepatientsunderwent kidney biopsy amongst which MCLwas the commonest (28.84%) histopathologicaldiagnosis[18]. In a study on the role ofhistopathologyonsteroidresistance,Gulatietalfound that SRNS children constituted 15.1% ofthechildrenreferredtotheirinstitute[12]. Inourstudy,Kidneybiopsywasperformedin33.2%ofthe cases. MCLwas themost common (36.7%)pathologicaldiagnosis.FSGSwasfoundin27.8%,MPGN in 15.1%, DMP in 13.9%, and otherlesionsin6.3%ofthepatients.MCLwasfoundin22.2%FSGSin44.4%,MPGNin14.8%andotherpathologies in 1.5% of steroid resistant cases.By histopathological classification of renal

    biopsies in patients nonresponsive to steroidsZaki et al found MPGN in 55.5%, and FSGS in33.3% of their cases[18]. In Bircan et al study,DMPandMPGNwerefrequenthistopathologicalfindings[19] and Ahmadzadeh (another studyfromsouthernIran)reportedthatFSGSwasthemostcommon(44%)histopathologicalfindinginnonrespondingpatients[20].TherateofsteroidresponsivenessinchildrenwithMCLinourstudyisclosetoresponsivenessratereportedbySrivastava[18].InSrivastavaetalstudy, 76.5% of the cases were diagnosed asMCL,andnearlyallofthem(98%)respondedtosteroids[17].MCLwas themost common provenhistopathologicaldiagnosisofstudiesconductedbySoadElSheikh inSaudiArabia[18],DavutogluinTurkey[21], andSrivastava in India[17],but thepredominant histopathological diagnosis inAfricancountrieswasMGNduetohighhepatitisBprevalence[22].Sharples et al compared the natural historyand steroid responsiveness of NS in Asians,Europeans,andAfroCaribbeansbyconductingaretrospective study on 42 patients. Theincidence of NS was six fold higher in Asianchildren. They estimated annual incidence ofSRNS16.9per100000inAsians,2.6per100000in Europeans, and 3.4 per 100000 in AfroCaribbeans[23]. This rate in Zaki study fromKuwait has been reported 6 per 100,000childrenbelow12yearsofage[24].InBhimmaetal investigation steroid sensitiveness was62%[25].TheusuallyexpectedSSNSpatternwasuncommon in blacks, and MGN accounted for40%ofcasesofwhich86.2%wereassociated

    Table3:ComparisonofourstudywithotherstudiesinMiddleEast

    Study Country Noofpatients

    Responsetosteroidtherapy

    Infrequentrelapsers

    Frequentrelapsers

    Steroiddependents

    Zakietal[24] Kuwait 55 84 16.6 15.2Bircanetal[19] Turkey 114 86.9 21.9 16.7 21.9Davutogluetal[21] Turkey 62 79.8 57.1 22.6Ahmadzadehetal[20] Iran 231 87 26.4 34.8 Safaeietal[15] Iran 44 66 26.4 38.8 13.5Gulatietal[26] India 127 82.7 37.9 21.6 18.1

    ElSheikh[18] SaudiArabia 55 89.3 21 45

    Ourstudy Iran 238 81.5% 25.1 22.2 27

  • 204 SteroidResponsivenessofIdiopathicNephroticSyndrome;AMadani,etal

    uncommon in blacks, and MGN accounted for40% of cases of which 86.2% were associatedwithchronichepatitisBvirusantigenemia.Only14.4% of blacks had either biopsyprovensteroidsensitiveMCLorSSNS[22].TherateofresponsivenesstosteroidtherapyinourstudyismorethanAfricanstudies[22,25].There are some major differences whencomparedwithAfricancountrieswhichcouldbeexplained by NS histopathological patternvarieties. In our study 25% patients had norelapse, that was fewer than in other studiesespecially other reports from Iran. This rate inSafaei, Ahmadzadeh and El Sheikh studies was23%,37%and38.8%,respectively[15,18,20].

    Conclusion

    Our study showed that the rate ofresponsiveness to steroid therapy is 81.5%which is close to thoseof several other studies.In addition, 96.2% of MCL and 32% of FSGSpatients initially responded to steroid therapy.Therateofnonrelapsersinthisstudywas25%,this is smaller than that reported in otherinvestigationsinIran.

    Acknowledgment

    This researchwas approved by Vicechancellorfor Research of School of Medicine of TehranUniversityofMedicalSciences.

    ConflictofInterest:None

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