Crescentic IgA Nephropathy New York University：新月体IgA抗体肾病纽约大学.ppt

iganephropathywithcrescents,nephrologygrandroundsmarch16th,2010adityamattoo,outline,backgroundepidemiologyclinicalpresentationprognosispathogenesishistologytreatmentrecurrenceintransplant,background,firstdescribedbybergeretalin1968.characterizedbypredominantigadepositionintheglomerularmesangium.mostcommonformofprimaryglomerulonephritisaroundtheworld.,bergeretal.jurolnephrol,74:p694,1968.,epidemiology,demographics,clinicalonsetinsecondandthirddecadesoflife.80%ofpatientsarebetweentheagesof16-35yearsatthetimeofdiagnosis.malepredominanceof2:1injapantoashighas6:1innortherneuropeandus.asiansandcaucasiansmorepronetodevelopiganthanpeopleofafricandescent.,demographics,thereappearstobeafamilialclusteringofiganwhichshowsstrongfamilypredispositioninabout10%ofcases.intheu.s.,regionsinkentucky,alabamaandotherpartsofthesoutheastexhibitahigherincidenceofigan.inotherpartsoftheworld,familialclusteringofiganseemstobemorecommoninsouthernfranceanditaly.manygeneticstudiesareunderway,tryingtoestablishcommonsusceptibilitygenesinfamilialiga.,igannationwide,epidemiology,iganprevalenceasapercentageofprimarygn:injapan,50%ofnewcasesofgnareigan(causing40%ofallesrd).30%ofnewgncasesinwesterneuropeandaustralia.10%ingeneraluspopulation(exceptionnativeamericansfromnewmexicowithprevalenceofrateof38%)crescenticigan(cigan)isseeninapproximately7%ofpatientswithigan.however,astudyconductedbyshounoetalreportedthatbyincreasingthenumberofserialsectionsexaminedforanysinglebiopsyspecimenfromthestandard20to100sections,thefindingofasegmentalnecrotizinglesionincreasesto30%.,donadioetal.nejm,347:p738,2002.shounoetal.actapatholjpn,43:p723,1993.,clinicalpresentation,clinicalpresentation,iganishighlyvariable,bothclinicallyandpathologically.clinicalfeaturesrangefromasymptomatichematuriatorpgn.classicflareincludespainlesshematuriaconcurrentwiththeonsetofviralillness(e.g.pharyngitis,gastroenteritis,etc.),clinicalpresentation,approximately40-50%ofpatientspresentwithoneorrecurrentepisodesofgrosshematuria.another30-40%havemicroscopichematuriaandusuallymildproteinuriaincidentallydetectedonaroutineexamination.grosshematuriawilleventuallyoccurin20-25%ofthesepatients.,clinicalpresentation,ofthepatientswithgrosshematuriasecondarytoigan,upto40%willdeveloptransientrenalfailure.lessthan10%presentwitheithernephroticsyndromeorrpgn(characterizedbyedema,hypertension,andrenaldysfunction).,clinicalpresentation:crescenticvsnon-crescentic,ferarrioetal.3rdcongressofnephrology,2003.,prognosis,prognosis,between5-30%ofpatientswithmildproteinuria,hematuriaormildrenaldysfunctionundergospontaneousremissionofabnormallaboratoryfindings.achinesestudyof72consecutivepatientswithiganperformeddiagnosticbiopsiesonpatientswithhematuria,butwithnoorminimalproteinuria(definedaslessthan0.4g/day).afterasevenyearfollowupperiod,proteinexcretion1g/d,htn,andserumcr1.4mg/ddevelopedin33%,26%,and7%,respectively.,hottaetal.ajkd,39:p493,2002.szetoetal.amjmed.110:434,2001.,prognosis,approximately25-30%ofpatientswillreachesrdat10years.clinicalriskfactorsassociatedwithprogressivediseaseare:htn1g/dproteinuriamalegenderpersistentmicroscopichematuriahistologicriskfactorsincludecellularcrescentsandendocapillaryproliferation.,donadioetal.nejm,347:p738,2002.,prognosiscrescenticigan,somecorrelationbetweencrescentsandclinicalriskfactorsexists(inonecaseseriesallpatientswhohadatleast10%cellularcrescentshadhypertensionand1gproteinuria).furthermore,prospectivestudieshaveshownthat40%ofpatientswithaslittleat10%cellularcrescentswillprogresstoesrdwithin3years.,tumlinetal.seminarsinnephrol24:p256,2006.,pathogenesis,pathogenesis,igaisanantibodythatplaysacriticalroleinmucosalimmunity.igahastwosubclasses(iga1andiga2)andcanexistinadimericformcalledsecretoryiga.itexistsintwoisotypes,iga1(90%)andiga2(10%):iga1isfoundinserumandmadebybonemarrowbcells.iga2ismadebybcellslocatedinthemucosaandisthemajorimmunoglobulinfoundinmucosalsecretions.iga2providesakeyfirstlineofdefenseagainstinvasionbyinhaledandingestedpathogensatthevulnerablemucosalsurfaces.iga1providesasecondlineofdefenseintheserum,mediatingeliminationofpathogensthathavebreachedthemucosalsurface,pathogenesis,panelanormaliga1moleculepanelb-structureofcarbohydrateso-linkedtoserine(ser)orthreonine(thr)residuesoniga1.theiga1heavychaincontainsahingeregion(a19-residuesequencebetweench1andch2,whichconsistedentirelyofserine,threonineandproline).glycosylationisrestrictedtothehingeregionofiga1.n-acetylgalactosamine(galnac)iso-linkedtoserorthrresidues.galnacislinkedtogalthroughtheactionoftheenzyme1,3-galactosyltransferase.sialicacidislinkedtogalthroughan2,3linkandtogalnacthroughan2,6link.,donadioetal.nejm,347:p738,2002.,pathogenesismesangialdeposition,althoughthepathogenesisofiganisnotcompletelyclear,itiswellacceptedthataberrantglycosylationpatternofigaisinvolved.thisissupportedbythefactthatinigan,mesangialdepositsofigacontainhighconcentrationsofabnormallyunder-galactosylatediga1.furthermoreithasbeendemonstratedthatenzymaticremovalofcomplexoligosaccharidesfromthehingeregionofiga1antibodiesfromnormalindividualssignificantlyenhancedigadepositioninthemesangium.,sanoetal.ndt,17:p50,2002.,pathogenesismesangialdeposition,leukocyte1,3-galactosyltransferaseactivityisdecreasedinpatientswithiganwhichmayberesponsiblefordeficientgalactosylationofiga1.abnormallyglycosylatedigahasahighertendencytoself-aggregateandformcomplexeswithiggantibodiesdirectedatepitopesinthehingeregionofiga1.,novaketal.ki62:p465,2006.allenetal.ndt.12:p701,1997.,pathogenesisdecreasedclearance,leukocytefc-receptorforiga(cd89)isdownregulated,furthermorethereceptorbindingsiteisinthech2domainclosethehinge(possiblyaffectedbydeficientgalactosylation).alterediga1clearancefromcirculation,particularlyviathehepaticasialoglycoproteinreceptor(asgpr)whosechiefligandistheterminalgalactoseofiga1(theprinciplesiteofigacatabolism).,pathogenesis-summary,floegeetal.jasn,11:p2395,2000.,pathogenesisinflammatoryresponse,igaelicitsaphenotypictransformationinmesangialcellsinvitro,withmesangialcellproliferationandsecretionofextracellularmatrixcomponent.igaappearstostimulatetheproductionofavarietyofproinflammatoryandprofibroticmolecules,suchasinterleukin-6.increasedrenalexpressionoftgf-betawhichcorrelateswithseverityoftubulointersitialdamageinigan.,barrattetal.seminarsinnephrol24:p197,2004.taniguchietal.scandjofurolnephrol.33:p243,1999.,pathogenesisinflammatoryresponse,studieshavesuggestedthatmesangialigaprobablyactivatesc3,leadingtothegenerationofc5b-9(mac),whichthenpromotestheproductionofinflammatorymediatorsandmatrixproteinsbymesangialcells.systemically,low-gradecomplementactivationthroughthealternativepathwaycanbeseeninpatientswithiganaswell.,zwrineratal.ki,51:p1257,1997.,diagnosis,diagnosis,thesuspicionofiganisgenerallybasedupontheclinicalhistoryandlaboratorydata.thediagnosiscanbeconfirmedonlybykidneybiopsydemonstratingigadeposition.giventhegenerallybenigncourseofpatientswithiganwhohaveisolatedhematuria,biopsiesareusuallyperformedonlyiftherearesignssuggestiveofmoresevereorprogressivedisease(htn,proteinuria,elevatedcr,etc.),diagnosis,askinbiopsy,lookingforigadepositioninthedermalcapillaries,hasnotproventobesufficientlypredictiveinigan.plasmapolymericiga1levelsareelevatedin30-50%ofcases,butthissuggestivefindingisnotsufficientlyspecifictoestablishthediagnosis.circulatingiga-rheumatoidfactorsandiga-immunecomplexeshavebeentestedasdiagnosticmarkersbutarenotspecificnorcantheybereliablycorrelatedwithdiseaseactivity.,susukiataljclininvest.119:p1668,2009.,diagnosis,increasedserumlevelsofgal-deficientiga1,presentinigan,maysuggestthediagnosis.however,thisassayhasnotbeenvalidatedbytestingnon-iganpatientswithgnwhopresentsimilarlytoigan.gal-deficientiga1-specificiggmaybeprovetobeaclinicallyusefuldiagnosticmarkerasserumlevelsofiggspecificforgal-defiga1areelevatedinpatientswithigan.,susukiataljclininvest.119:p1668,2009.,diagnosis,(a)gal-deficientiga1incubatedwithiggfromhealthycontrols,non-igandiseasecontrolsandiganpatients.theriggfromaniganpatientservedasapositivecontrol.serumiggfromiganpatientsboundmoretogal-deficientiga1comparedwiththeiggfromdiseasecontrolsorhealthycontrols.(b)theintensityofsignalineachwellwasmeasuredbydensitometryascomparedtoriggserumiggfromiganpatientshassignificantlyhigherreactivitytogal-defiga1comparedwiththatfromhealthy(p40%globallyscleroticglomeruliand/or40%estimatedcorticaltubularatrophyorloss.,haasetal.ajkd,29:p829,1997.,histologyhaasclassification,haasetal.ajkd,29:p829,1997.,histologyhaasclassification,haasshowedastatisticallysignificantcorrelationbetweenhistologicsubclassandrenalsurvival,withanorderi,ii(greatestsurvival)illiv,v.,histologyhaasclassificationwithcrescents,haasalsoreportedtheprobabilityofrenalsurvivalwhencrescentswerepresentinhaassubclassiiiandiv.,treatment,treatment,patientswithisolatedhematuria,noorminimalproteinuria,andanormalgfraretypicallynottreated(andoftennotbiopsied),unlesstheyhaveevidenceofprogressivediseasesuchasincreasingproteinuria,bloodpressure,and/orserumcreatinine.,treatmentace/arb,patientswithpersistentproteinuria(500-1000mg/day),mildlyreducedgfrthatisnotdecliningrapidly,andonlymildtomoderatehistologicfindingsonrenalbiopsyaretraditionallymanagedwithace/arb.inonetrial,44patientswithproteinuria(0.5g/day,mean1.9g/day)andacr1.5mg/dlatbaselinewererandomlyassignedtoeitherenalaprilorantihypertensiveagentsotherthanaceinhibitorsorarbs.atfollow-upofaboutsixyears,renalsurvival,definedas40%crescents).aftertwomonthsoftherapy,therewassubstantialclinicalimprovementcharacterizedbyreductionsincrandproteinuria.however,repeatrenalbiopsyat2monthsshowedpersistenceofcrescentsinallpatientsand50%ofpatientshadprogressivediseaseaftertherapywasdiscontinued.,roccatelloetal.ndt,10:p2054,1995.,treatmentcigantumlinetal,amoreprolongedcourseofaggressiveimmunosuppressivetherapywasevaluatedin12patientswithciganwhohadameanserumcrof2.7mg/dlandproteinuriaof4g/dayatbaseline.thetreatmentregimenconsistedofthefollowing:pulsemethlyprednisolone(15mg/kg/dfor3days)poprednisone1mg/kg/dfor60days,thenslowtaperwithallpatientson10mg/datthetimeofrepeatbiopsymonthlyivcyclophosphamide(0.5g/m2)forsixmonths.,tumlinetal.ndt,18:p1321,2003.,treatmentcigantumlinetal,afterthesixmonthcourse,therewassignificantimprovementintheserumcrconcentration(from2.7to1.5mg/dl)andinproteinuria(from4to1.4g/day).repeatbiopsyatsixmonthsrevealedtheabsenceofcellularcrescentsandendocapillaryproliferationinallpatients.throughoutathree-yearfollow-up,allpatientscontinuedprednisone(0.15mg/kgperday),andthebloodpressurewascontrolledtoagoalof130/70mmhgwithaceinhibitorsandotheragentsasneeded.comparedwith12untreatedhistoriccontrols(matchedforage,gender,baselineserumcrandhistologicseverity),theincidenceofesrdatthreeyearswassignificantlylowerinthetreatedgroup(1of12=8%versus5of12=42%).,tumlinetal.ndt,18:p1321,2003.,iganintransplants,transplantiganrecurrence,in1975,only7yearsafterhisinitialdescriptionoftheentityofigan,bergeretalreportedthefirstcaseofrecurrentigainarenalallograft.therecurrenceofigaintransplantsamongpatientswithiganintheirnativekidneysoccurredin40-60%ofcaseswhenprotocolbiopsieswereperformed.inonestudyof240recipients,afterameanfollowupof5years,13%ofexhibitedrecurrencerelatedgraftdysfunctionwith5%losingthegraftsecondarytorecurrentigan.,wangetal.ajkd,38:p588,2001.,ciganintransplantskowalewskaetal,astudyreviewed2959renalbiopsiesoveraperiodof14yearsandfound33casesofglomerulonephritiswithcrescents(1.1%).ofthese33cases,8hadthediagnosisofigan(0.2%oftotal).6ofthe8casesweretheresultofrecurrentigan,and2caseswe