GlomerularDiseasesClassificationofGlomerularDiseaseBasedonetiologyPrimary(idiopathic)versussecondary(infection,diabetes,lupus,vasculitis,etc)BasedonnephroticversusnephriticsyndromesMostglomerulardiseaseshavebothBasedonhistologyMostglomerulardiseaseisdefinedbasedonhistologicalchangesandimmunecomplexdepositionasreflectedbytheirnamesNephriticsyndromeNephroticsyndromePrimaryglomerulardiseaseIgAnephropathyFocalsegmentalglomerulosclerosisPost-streptococcalGNMembranousnephropathyMembranoproliferativeGNIdiopathicnecrotizingGNMinimalchangediseaseAnti-GBMdisease(Systemicdisease)SecondaryglomerulardiseaseLupusnephritisDiabetesmellitusVasculitis(ANCA-GN):-Wegenergranulomatosis-MicroscopicpolyarteritisAmyloidosisHenoch-SchonleinpurpuraGoodpasturesyndromeCryoglobulinemia(HCV)DiseaseNephroticfeaturesNephriticfeaturesMinimalchangedisease++++-Membranousglomerulopathy+++++Diabeticglomerulosclerosis+++++Amyloidosis+++++FSGS+++++Fibrillaryglomerulonephritis+++++Mesangioproliferativeglomerulopathy++++Membranoproliferativeglomerulonephritis+++++Proliferativeglomerulonephritis+++++Acutepostinfectious

glomerulonephritis+++++Crescenticglomerulonephritis+++++TendenciesofGlomerularDiseasestoManifestNephroticversusNephriticSyndromePrimaryGlomerularDiseaseswithNephroticsyndromeMinimalchangedisease(Nildisease)Focalsegmentalglomerulosclerosis(FSGS)Membranousnephropathy(MN)EPIDEMIOLOGYMinimalchangedisease,alsocallednil(Nothing-In-Lightmicroscopy)disease,isamajorcauseofnephroticsyndromeinbothchildrenandadults.Minimalchangediseaseaccountsfor10%to20%ofallcasesofprimarynephroticsyndromeinadultsand50-90%inChildrenbasedontheage.MinimalChangeDisease(MCD)PATHOLOGYTheglomeruliappearnormalonlightmicroscopyinpatientswithMCDandtherearenocomplementorimmunoglobulindepositsonimmunofluorescencemicroscopy.Glomerularsizeisusuallynormal.ThecharacteristichistologiclesioninMCDisdiffuseeffacementoftheepithelialfootprocessesonelectronmicroscopy.Morespecifically,thereisretraction,widening,andshorteningofthefootprocesses.Footprocessesregainanormalappearancewithremissionofproteinuria(Reversibleeffacement).MinimalChangesDiseasePATHOGENESIS

TheunderlyingmechanismofMCDisunclear.SystemicTcelldysfunctionGlomerularpermeabilityfactor(angiopoietinlike4),whichdirectlyaffectstheglomerularcapillarywall,resultinginmarkedproteinuria.ETIOLOGYMostcasesofMCDareidiopathic(orprimary).However,MCDcanbeassociatedwiththefollowing:Drugs(NSAIDsorlithium),Neoplasms(Hodgkinlymphomaandotherless-commonlymphomasorleukemias),Infections,Allergy,andOtherglomerulardiseasesCLINICALMANIFESTATIONSSuddenonsetproteinuriathatmaybesignificant(urineprotein-creatinineratiomayexceed9mg/mg).Microscopichematuriaandhyperlipidemiaalsomaybepresent.Occasionally,acutekidneyinjurydevelopsinadultpatientswithminimalchangediseasewhohaveatherosclerosisandarapidonsetofsevereproteinuriaoredema.Hypertensionandprogressiontoend-stagekidneydisease(ESKD)arerareinminimalchangedisease.MinimalChangeDiseaseDIAGNOSIS:Basedonkidneybiopsy:effacementofthepodocytefootprocessesseenonelectronmicroscopyandnormalfindingsonlightandimmunofluorescencemicroscopy.THERAPY:Dailyoralternate-daytherapywithprednisone.Patientswhoseurineprotein-creatinineratiodecreasesbelow0.3mg/mgareconsideredtohaveafullresponsetotreatmentandshouldexperienceresolutionofminimalchangedisease.10%ofpatientswithminimalchangediseasebecomecorticosteroid-dependentoraretreatmentresistant.Corticosteroid-dependentmeansthatproteinuriaincreaseswhensteroiddosereduces.Resistanceisdefinedasalackoffullresponsetothistreatmentdespite8weeksoftherapy.Approximatelyonethirdofpatientswithminimalchangediseasehaveonlyoneepisodefollowedbyalong-termremission.However,mostpatientshavearelapsingdiseasecourse,andtheinitialrelapseusuallyoccurswithinthefirst6months.Relapsemeansthatproteinuriareoccursafterremission.Immunosuppressiveagentssuchascyclophosphamide,cyclosporine,tacrolimus,andmycophenolatemofetilhavebeenusedincorticosteroid-dependentor-resistantpatientsandinthosewhohavefrequentrelapses.MinimalChangeDiseaseSummaryonMinimalchangediseaseMCDoccursmoreinChildrenbutalsoadultandpresentsusuallyasnephroticsyndrome.MCDhasnormallightmicroscopicfindingbuthasdiffusefootprocesseffacementonEM.Diseaseislikelycausedbyimmunologicaldisorder(Tcells)andacirculatingfactor.MCDcouldbe2ndtodrugortumors.MCDrespondquitewelltosteroidwithreversiblefootprocesseffacement,butpatientscoulddevelopsteroid-dependentorresistanceandhaverelapse.FocalSegmentalGlomerulosclerosisDEFINITION:

FSGSisdefinedasaclinicopathologicsyndromemanifestingwithproteinuria,usuallyofnephroticrange,associatedwithlesionsoffocal(asubsetofglomeruli)andsegmentalglomerulosclerosis(portionoftheglomerulartuft)andfoot-processeffacement.Epidemiology:FSGSisthemostcommoncauseofidiopathicnephroticsyndromeinadults(35%)andthemostcommoncauseofthenephroticsyndromeinblackadults(50%)inUSA.FSGSaccountsfor10-15%ESRDpatientsinChina.EtiologicClassificationofFSGS:Primary(idiopathic)SecondaryFSGSVirus-associated.A:HIV-1(HIV-associatednephropathy);B.ParvovirusB19.Drug-induced:A.Heroin(heroinnephropathy);B.Interferon-:C.Lithium;Mediatedbyadaptivestructural-functionalresponsesA.ReducedrenalmassB.ReducedperfusionsuchasSicklecellanemiaortypeIDm;Resultfromrenalscarringduetopreviousinjury.(focalproliferativeglomerulonephritis,vasculitis,andlupusnephritis)PathogenesisofFSGS

PrimaryFSGS:anidiopathicdiseasethat,inmanycases,isthoughttobeetiologicallyrelatedtobutmoreseverethanminimalchangedisease.PodocyteinjuryappearstobetheprimaryprobleminmostformsofFSGS.GeneticmutationofpodocyteproteinsPodocytelossfromapoptosisanddetachmentCirculatingpermeabilityfactor-uPAR.PodocytecomponentHumandiseaseNephrinCongenitalnephropathyoftheFinnishtypePodocinsteroidresistantnephroticsyndrome(autosomalrecessiveformofFSGS)TRPC6hereditaryFSGS(autosomaldominant)α-actinin4hereditaryFSGS(autosomaldominant)INF2AutosomaldominantFSGSFAMILIALORGENETICFORMSOFFSGSPathologyFSGSCLINICALMANIFESTATIONS:FSGSisamoreindolentformofthenephroticsyndromethanminimalchangedisease.PatientswithprimaryFSGSusuallyalsopresentwithmicroscopichematuria,hypertension,andkidneyinsufficiency.PatientswithsecondaryFSGShaveminimaledemaandrarelyhavethefullspectrumofthenephroticsyndrome,suchasnephrotic-rangeproteinuria.FSGSInnon-nephroticpatients,angiotensin-convertingenzyme(ACE)inhibitorsorangiotensinreceptorblockers(ARBs)areindicated.PatientswithFSGSandpersistentnephroticsyndromerequiresteroidinadditiontoACEinhibitor/ARB.Corticosteroidtherapyaloneisassociatedwithcompleteremissionin30%to60%ofpatientswithFSGS,noresponsein40%to50%,andpartialremissioninothers.FSGSpatientswithmutationofpodocyteproteinsareresistanttosteroidtherapy.Cyclosporinewasusefulinachievingremissioninupto70%ofcorticosteroid-resistantpatientswithFSGS.However,relapseoccurredin40%ofthesepatientswhencyclosporinetherapywasdiscontinued.Patientswithsteroid-dependentdiseasecanbetreatedwitheithercyclosporineorcyclophosphamide.TREATMENTUpto50%ofpatientswithFSGSandpersistentnephrotic-rangeproteinuriadevelopESRDwithin5years.Thepresenceofmassiveproteinuria(urineprotein-creatinineratioabove10mg/mg)inparticularisassociatedwithapoorprognosis.Remissionofproteinuriaisasignificantpredictorofkidneysurvival,andevenpartialremissionisassociatedwithaslowerrateofkidneyfunctiondeclineandareducedriskofkidneyfailure.PatientswithserumCr>2mg/dlhavepoorprognosis.PrognosisofFSGSSummaryonFSGSFSGSisacommoncauseofidiopathicnephroticsyndromeinadult.FSGSiscausedbypodocyteinjury:apoptosis,detachment,mutationofstructuralproteins(genetic)FSGScouldbesecondarytopreviousinjury,hypertrophicresponse,orviralinfection.FSGSusuallypresentsasindolentnephroticsyndrome.PrimaryFSGSresponseslesswelltosteroid(50%)thanminimalchangediseaseandoftenneedsotherimmunosuppressivemedicationssuchascyclosporine.SecondaryFSGSorfamiliarFSGSareusuallyresistanttosteroidtherapy.PRIMARYFSGSVersusMCD

MCDFSGSMoreinChildrenMoreinAdultNormallightmicroscopicfindingFocalandsegmentalsclerosisNotubularinjuryFocaltubulointerstitialinjury/fibrosisEM:diffusefootprocesseffacementDiffuseorfocalfootprocesseffacementNephroticrangeproteinuriaBothnon-nephroticornephroticrangeCouldpresentasAcutekidneyfailureindolentFootprocesseffacementreversibleFootprocesseffacement:irreversibleTcells,Angiopoietinlike4Podocytelossandmutation,SolubleuPAR,MostcompleteremissionMostpartialremissionMoststeroidsensitiveMoresteroidresistantBetterprognosisWorseprognosisDEFINITION:ThetermMNreflectstheprimaryhistologicalchangenotedonlightmicroscopy:glomerularbasementmembranethickeningbecauseoftheelectron-denseimmunecomplexdepositswithinGBM,withlittleornocellularproliferationorinfiltrationEPIDEMIOLOGY:Approximately15%to33%ofadultswithproteinuriaandthenephroticsyndromehavemembranousnephropathy.Thisconditionhasa2:1malepredominanceandtypicallydevelopsinpatientsbetween30and50yearsofage.MembranousNephropathy(MN)DIAGNOSIS:ThediagnosisofMNcanonlybemadebykidneybiopsyMembranousnephropathyisusuallyidiopathic.ButmayoccursecondarytoconditionssuchashepatitisBorCvirusinfectionandsystemiclupuserythematosus;useofdrugssuchasNSAIDsandpenicillamine;andmalignanciesofthebreast,colon,stomach,kidney,andlung.MembranousNephropathy(MN)PATHOLOGY

Onlightmicroscopy:-Diffusethickeningoftheglomerularbasementmembrane(GBM)throughoutallglomeruliwithnohypercellularity.OnEM:-SubepithelialelectrondensedepositsontheouteraspectoftheGBM,andexpansionoftheGBMbydepositionofnewextracellularmatrixbetweenthedeposits(whicharethe"spikes"seenwithspecialstains).-Effacementofthefootprocessesoftheoverlyingpodocyte,MembranousNephropathyMembranousNephropathyPATHOGENESIS:PhospholipaseA2receptor

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TheM-typephospholipaseA2receptor(PLA2R),atransmembranereceptorthatishighlyexpressedinglomerularpodocytes,hasbeenidentifiedasamajorantigeninhumanidiopathicMN.Thecirculatinganti-PLA2RantibodieswerepredominantlyIgG4,theIgGsubclassthatismostabundantintheglomerularimmunedepositsinidiopathic(butnotsecondary)MN.Anti-PLA2Rstronglycorrelatedwithclinicalstatus

andadeclineinanti-PLA2Rpredictedtheclinicalresponsetoimmunosuppressivetherapy.Geneticassociations

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Agenome-wideassociationstudythatincluded75French,146Dutchand335Britishindividualsidentifiedsingle-nucleotidepolymorphisms(SNPs)attwolocithatarehighlyassociatedwithidiopathicmembranousnephropathy.ThetwolociarewithinthegenesforthephospholipaseA2receptor(PLA2R)onchromosome2q24,andtheHLAcomplexclassIIalphachain1A(HLA-DQA1)onchromosome6p21.MembranousNephropathyCLINICALMANIFESTATIONS:Membranousnephropathyusuallymanifestsasthenephroticsyndrome(80%),butsomepatientsmayhaveasymptomaticproteinuria.Hypoalbuminemiaandseverehyperlipidemiaarealmostalwayspresentatdiagnosisinpatientswiththenephroticsyndrome.Microscopichematuriaandanabsenceoferythrocytecastsalsoarecommon(50%).Approximately70percentofpatientshavenormalbloodpressureandglomerularfiltrationrate(GFR)atpresentation.Acuterenalfailure(ARF)isuncommon.MembranousNephropathyNATURALHISTORY

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InviewofthepotentialtoxicityofthedrugsusedtotreatidiopathicMN,thedecisiontoinitiatetherapyisbased,inpart,uponanunderstandingofthenaturalhistoryofuntreatedpatients,withandwithoutfeaturesofthenephroticsyndromeatpresentation:Spontaneouscompleteremissionofproteinuriaoccursin5to30percentatfiveyears.Spontaneouspartialremission(≤2gofproteinuriaperday)occursin25to40percentatfiveyears.Theoccurrenceofend-stagerenaldiseaseinuntreatedpatientsisapproximately14percentatfiveyears,35percentat10years,and41percentat15years.NatureHistoryofMembranousNephropathyBasedonthis,wedefinelow,moderate,andhighriskpatientsubsetswithvaryingdegreesofriskforprogressiontoCKD(definedasacreatinineclearance≤60mL/minper1.73m2)overfiveyears:Lowrisk—Proteinuriaremainslessthan4g/dayandcreatinineclearanceremainsnormalforasix-monthfollow-upperiod.Suchpatientshavealessthan8%riskofdevelopingchronicrenalinsufficiencyoverfiveyears.Moderaterisk—Proteinuriaisbetween4and8g/dayandpersistsformorethansixmonths.Creatinineclearanceisnormalornearnormalandremainsstableoversixmonthsofobservation.Chronicrenalinsufficiencydevelopsoverfiveyearsinapproximately50%ofthesepatients.Highrisk—Proteinuriaisgreaterthan8g/dayandpersistsforthreemonthsand/orrenalfunctionthatiseitherbelownormal(andconsideredduetoMN)ordecreasesduringtheobservationperiod.Approximately75%ofsuchpatientsareatriskofprogressiontochronicrenalinsufficiencyover5years.MembranousNephropathyLowrisk-observationForpatientswhoremainatlowriskofprogressionoverasix-monthperiod,werecommendcontinuedobservation.Suchpatientsshouldbeperiodicallymonitoredtoassessfordiseaseprogressionthatmightwarranttherapy.MembranousNephropathyModerateriskFormoderateriskpatientswithoutimprovementorwithaproteinexcretionthatremainsabove4g/dayafter6months’observation,wesuggestimmunosuppressivetherapyratherthancontinuedobservation.Werecommendeithercyclophosphamide-steroidorcalcineurininhibitor-steroidregimenwitheithercyclosporine

ortacrolimus.HighriskForpatientswhoremainathighriskofprogressionoverathree-monthobservationperiodandhavenormalornearnormalrenalfunction(definedasacreatinineclearanceabove80mL/min),werecommendtheinitiationofimmunosuppressivetherapyratherthancontinuedobservation.Amongpatientsconsideredtobeathighriskbecauseofreducedrenalfunction,werecommendtheinitiationofimmunosuppressivetherapywithoutdelay.Werecommendeitheracytotoxic-basedorcalcineurininhibitor-basedregimen.Non-immunosuppressivetherapyForpatientswithpersistentproteinuria,werecommendanACEinhibitororanARB.Theproteinuriagoalislessthan1000mg/day.Forthosewhocannotattainthisgoal,wesuggestagoalofatleastpartialremission,whichhasbeendefinedasproteinexcretionbelow3.5g/dayplusa>50%reductioninproteinexcretionfromthepeak.Thegoalbloodpressureislessthan130/80mmHg.Themanagementofdyslipidemiainthesepatientswithstatin.Patientswithmembranousnephropathyrepresentthehighestriskgroupforthromboembolism,andtheriskincreasesprogressivelywithserumalbuminlevelsbelow2.8g/dL.MembranousNephropathyRelapsingpatients

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Relapseofproteinuriaoccursin25to30percentofpatientstreatedwithcyclophosphamide

andahigherpercentageofthosetreatedwithacalcineurininhibitor.Thechoiceoftherapyvarieswiththeinitialregimenthatwasusedandwithconcernsabouttoxicity.Resistantpatients

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Resistantpatientsaredefinedasthosewithmoderateorhighriskdiseasewhofailanadequatetrialoftreatmentwithbothcyclophosphamide-basedandcalcineurininhibitor-basedregimens.Otherregimeswillbetried.NewTherapy:RitaximabandACTHRituximabisachimericmonoclonalantibodyagainsttheproteinCD20,whichisprimarilyfoundonthesurfaceofimmunesystemBcells.RituximabkillsBcells.MembranousNephropathySummaryonMNOneofthemostcommoncauseofidiopathicnephroticsyndrome.DiagnosedbyrenalbiopsyshowingthickeningofGBM2ndtoimmunecomplexdepositswithinGBMIdiopathicMNiscausedbyantibodyagainstphospholipaseA2Receptor.MNcouldbe2ndtomedication,tumor,andHBVinfectionTherapyisbasedontheriskofprogressionusingACEIandsteroid/immunosuppressivemedicationsAbout1/3MNhasspontaneousremission,1/3haspartialremission,and1/3developtoESRDover10yearswithouttreatment.ComparisonbetweenMCD,FSGSandIMNAge:MCDinyoung,IMNinold,FSGSinallageNephroticsyndrome:occursmoreofteninMCDandIMNthanFSGS.Renalfailure:moreinFSGS,thenIMN,andthenMCDMechanism:Podocyte-specificantigen/antibody-mediatedimmunecomplexdepositforIMN;mutationofpodocyteproteinsorpodocytelossforFSGS;Tcell-mediated,reversiblefootprocesseffacementforMCD,CirculatingfactorsexistforFSGSandMCDPrognosis:WorseinFSGS,thenIMN,andthenMCDTreatment:Steroidandimmunosuppressivemedications,betterresponseinMCD.SecondaryGlomerularDiseasewithNephroticSyndromeDiabeticnephropathyOverallIncidenceandPrevalenceofDiabeticKidneyDisease(DKD)inUSAUSRDSdata2013DiabeticpatientsincreasesdramaticallyinChina(90millions)andtheincidenceofdiabeticnephropathyhasbeenalsoincreasedsignificantlyinChinafrom5%to15-25%oftotalESRDpatientpopulationoverlastdecade.Type1DiabeteswithnormoalbuminuriaMicroalbuminuriaMacroalbuminuriaESRDSurvival1/3(15-20y)1/3(10y)1/31/3(10y)1/3(5y)EpidemiologydataofDKDInChina,thereis90Mdiabeticpatientsandabout15-45%ofDMpatientsdevelopkidneydiseaseand1/3patientswithdiabeticnephropathydevelopESRD90Mx1/3x1/3x1/3x100,000RMPPathologyofdiabeticNephropathyClassicfindings(accumulationofECMisthecentralpathology):Earlystage:ThickeningofGBM,theearlieststructuralfinding(1.5-2.5yearsaftertheonsetoftype1DM).Mesangialexpansionwithmatrixdeposition(5-7yearsaftertheonsetoftype1DM).laterstage:Afferentandefferentarteriolarhyalinosis(aquitespecificfindingforDN)Kimmelstiel-Wilsonnodules(aspecificfindingforDN)Tubularbasementthickening(paralleltoGBMthickening).DiagnosisTypeIDM:basedonclinicalevidence(94%):HistoryofDMmorethan10years.Microalbuminuriaorproteinuria.Slowprogression.Presenceofdiabeticretinopathy(KleinetalDiabetes2005).Lessclearintype2Dm:Duration?Incidenceofnon-diabeticnephropathy:25-50%,especiallyinpatientswithoutretinopathy.AtypicalPresentation:needkidneybiopsy.Rapidprogressiverenalfailure.Activeurinesediments:HematuriawithRBCcastsanddysmorphicRBC.HistoryofDMisshortintype1.AbsenceofdiabeticretinopathySuddenonsetofnephroticsyndromewithnormalrenalfunctionSignsorsymptomsofsystemicdiseasePathogenesisMetabolicfactors(Hyperglycemia)Environmentalfactors(Diet)GeneticriskfactorsAGEPolyolpathwayPKCDiabeticNephropathyROSGrowthfactorsTGF-bVEGFIGF-1Podocyte:apoptosisMesangialcell:hypertrophyECMsynthesisIntraglomerularHyerfiltration-HypertensionEndothelialcell:fenestrationCTGFHemodynamicfactorsAgIICellularchangesScreeningScreeningformicroalbuminuriaisstronglyrecommendedforallpatientswithdiabetes.Annualmeasurementoftheurinealbuminexcretionforpatientswhohavehadtype1diabetesfor5yearsormoreandforallpatientswithtype2diabetesbeginningatthetimeofdiagnosis.Screeningformicroalbuminuriausuallyinvolvesobtaininganalbumin-creatinineratioonafirstmorningvoidurinesample.Microalbuminuriaisconfirmedwhentwoofthreesamplesobtainedwithina6-monthperiodrevealaurinealbumin-creatinineratiobetween30and300mg/g.DiabeticNephropathyClinicalPresentationStageI:

GlomerularhyperfiltrationandhypertensionwithincreasedGFR,withnomicroalbuminuria,normalBP.Normalstructure.StageII:

MildincreasedGFRwithnormalorintermittentmicroalbuminuria,normalBP.IncreasingGBMthicknessandmesangialarea.StageIII:

Persistentmicroalbuminuria,GFRstartstodeclinetowardthelatestage,elevatedBP,moreGBMthickeningandmesangialexpansionwithsomeglomerularclosure.StageIV:

Overtproteinuria,markedHTN,decreasedGFR,moreglomerularclosure.StageV:

ESRD,uremia,GFR0-10ml/min.Generalizedglomerularclosure.ProgressionofDKDinType1DMManagementHemoglobinA1c

levels<7%:glycemiccontrolinpatientswithdiabetesdelaysorpreventstheprogressionofdiabeticnephropathy.ACEinhibitorsorARBsshouldbeusedtoreduceproteinuria,eveninthepatientwithouthypertension.ACEinhibitorsandARBsarealsorecommendedfordiabeticpatientswithhypertensionregardlessoftheirlevelofurinealbumin.ACEinhibitorsandARBshaveanequivalentrenoprotectiveeffectandthecombinationtherapyisnotrecommendedbasedonthecurrentclinicaltrials.BPcontrolwithtargetof<130/80.LipidcontrolandstopsmokingKidneytransplantationisthepreferredkidneyreplacementtherapyforpatientswithESRDsecondarytodiabetes.DiabeticNephropathySummaryonDiabeticNephropathyDiabeticnephropathyisthemostcommoncauseofESRDintheworldandtheincidencehasbeenincreasingdramaticallyinChina.Diabeticnephropathyisacomplexdiseasecausedbymultiplefactorsincludinggenetic,metabolic,andhemodynamicfactors.PathologyischaracterizedbyGBMthickening,mesangialexpansionandpodocyteloss.Clinically,patientspresentswithhyperfiltration,thenmicroalbuminuria,andthenovertproteinuriaassociatedwithHTN,andfinallyprogresstoESRD.ACEI/ARBs,tightglycemicandBPcontrolremainthecurrentgoldstandardoftreatment.Earlyscreeningofdiabeticpatientsfornephropathyiscriticaltodiseasepreventionandtherapy.PrimaryGlomerularDiseasewithNephriticSyndromeIgAnephropathyMPGNPost-infectiousGNIgAnephropathyisthemostcommonprimaryglomerulonephritis(GN)throughouttheworld.IgAnephropathyoccurswithgreatestfrequencyinAsiansandCaucasians,andisrelativelyrareinblacks.InaChinesestudyof13,519renalbiopsies,IgAnephropathyconstituted45percentofallcasesofprimaryglomerulonephritis.IgANephropathyEpidemiologyLightmicrographofamesangialglomerulonephritisshowingsegmentalareasofincreasedmesangialmatrixandcellularity(arrows).Thisfindingalonecanbeseeninmanydiseases,includingIgAnephropathyandlupusnephritis.Immunofluorescencemicroscopydemonstratinglarge,globularmesangialIgAdepositsthatarediagnosticofIgAnephropathy.LowpowerelectronmicrographinIgAnephropathy.Theprimaryfindingiselectrondensedepositsthatarelimitedtothemesangialregions(D).PathologyofIgANephropathyIgAdepositsmayalsobeseenonkidneybiopsyinindividualswithnoevidenceofrenaldisease.ThereportedincidenceofmesangialIgAdepositioninhealthyindividualsrangesfrom3to16%AnincreasedplasmaIgAlevelaloneisnotsufficienttoproducemesangialIgAdeposits.PatientswithIgAnephropathymustproduceaspecialpoolofcirculatingIgAmoleculeswiththefollowingcharacteristics:TheserumIgAisanionicandlambdalightchainsareover-represented.ThereisanincreasedamountofpolymericIgA1intheserum.ThereisahighproportionofpoorlyO-galactosylatedIgA1.TherearealterationsinIgA1sialylation.MechanismofIgAabnormalityThereisalsoageneticfactorforIgANephropathy.CLINICALFEATURESPatientswithIgAnephropathytypicallypresentinoneofthreeways:Approximately40to50percentpresentwithoneorrecurrentepisodesofgrosshematuria,usually2-3daysfollowinganupperrespiratoryinfection.Another30to40percenthavemicroscopichematuriaandusuallymildproteinuria,andareincidentallydetectedonaroutineexamination.Inthesepatients,thediseaseisofuncertainduration.Grosshematuriawilleventuallyoccurin20to25percentofthesepatientsLessthan10percentpresentwitheithernephroticsyndromeoracuterapidlyprogressiveglomerulonephritispicturecharacterizedbyedema,hypertension,andrenalinsufficiencyaswellashematuria.IgANephropathyDIAGNOSIS

DiagnosisofIgAnephropathyisgenerallybasedupontheclinicalhistoryandurinaryanalysis.Thediagnosiscanbeconfirmedonly

bykidneybiopsywithimmunofluorescencestudiesforIgAdeposits.Indicationsforrenalbiopsy

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GiventhegenerallybenigncourseofpatientswithIgAnephropathywhohaveisolatedhematuria,arenalbiopsyisusuallyperformedonlyiftherearesignssuggestiveofmoresevereorprogressivediseasesuchaspersistentproteinexcretionabove1000mg/day(whichmayincreaseovertime)oranelevatedserumcreatinineconcentration.IgANephropathyPROGNOSISPatientswithIgAnephropathywhohavelittleornoproteinuria(lessthan500to1000mg/day)havealowriskofprogression.Amongpatientswhodevelopovertproteinuriaand/oranelevatedserumcreatinineconcentration,progressiontoend-stagerenaldiseaseisapproximately15to25percentat10yearsand20to30percentat20years.Clinicalpredictorsofprogression

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ElevatedserumcreatinineconcentrationHypertension(>140/90mmHg)Persistentproteinexcretionabove1000mg/dayOxfordclassificationofIgAnephropathy

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AconsensusonthepathologicclassificationofIgAnephropathyIgANephropathyRenalsurvivalinIgAnephropathyCut-off:1gm/dayManagementIPatientswithisolatedhematuria,minimalproteinuria(lessthan1g/day),andanormalglomerularfiltrationrate(GFR)aretypicallynottreatedandoftennotbiopsied.However,thesepatientsshouldbemonitoredevery6to12months.Patientswithpersistentprote