REVIEW Open Access Renal involvement in autoimmune con - PDF document

REVIEWOpenAccess Renalinvolvementinautoimmuneconnective tissuediseases AndreasKronbichlerandGertMayer * Abstract Connectivetissuediseases(CTDs)areaheterogeneousgroupofdisordersthatsharecertainclinicalpresentations andadisturbedimmunoregulation,leadingtoautoantibodyproduction.Subclinicalorovertrenalmanifestations arefrequentlyobservedandcomplicatetheclinicalcourseofCTDs.AlterationsofkidneyfunctioninSjögren syndrome,systemicscleroderma(SSc),auto-immunemyopathies(dermatomyositisandpolymyositis),systemic lupuserythematosus(SLE),antiphospholipidsyndromenephropathy(APSN)aswellasrheumatoidarthritis(RA)are frequentlypresentandphysiciansshouldbeawareofthat. InSLE,renalprognosissignificantlyimprovedbasedonspecificclassificationandtreatmentstrategiesadjustedto kidneybiopsyfindings.Patientswithsclerodermarenalcrisis(SRC),whichisusuallycharacterizedbysevere hypertension,progressivedeclineofrenalfunctionandthromboticmicroangiopathy,showasignificantbenefitof earlyangiotensin-converting-enzyme(ACE)inhibitoruseinparticularandstrictbloodpressurecontrolingeneral. Treatmentoftheunderlyingautoimmunedisorderordiscontinuationofspecifictherapeuticagentsimproves kidneyfunctioninmostpatientswithSjögrensyndrome,auto-immunemyopathies,APSNandRA. Inthisreviewwefocusonimpairmentofrenalfunctioninrelationtounderlyingdiseaseoradversedrugeffects andimplicationsontreatmentdecisions. Keywords: Renalinvolvement,Connectivetissuediseases,Sjögrensyndrome,Sclerodermarenalcrisis, Dermatomyositis/polymyositis,Systemiclupuserythematosus,Antiphospholipidsyndrome,Rheumatoidarthritis Background Impairmentofrenalfunctionispresenttosomeextent inmanyconnectivetissuediseases(CTDs)withvariable occurrenceinSjögrensyndrome[1,2],roughly5%in systemicscleroderma(SSc)[3],rarelyininflammatory auto-immunemyopathies,aprevalenceofapproximately 50%insystemiclupuserythematosus(SLE)[4],andrare occurrenceinantiph ospholipidsyndrome[5]andrheuma- toidarthritis(RA).Apartfromthat,kidneyinvolvement canbeofsignificantprognosticvalueandoftenentails specifictherapeuticimplications. Lymphocyticinfiltration,leadingtoacuteorchronic tubulointerstitialnephritis,isthepredominantrenal pathologyinSjögrensyndrome[2,6,7].Scleroderma renalcrisis(SRC)isasevere,potentiallylife-threatening complicationinsclerodermaandis,inmostcases, accompaniedbymalignanthypertension,overexpression ofpro-inflammatorycytokinesandrapiddeclineofrenal function[8-10].Inrarecasespatientspresentwith normotensiveSRC,whichisassociatedwithapoorer prognosisandaprompterneedfordialysis[11-13]. Earlycommencementofangiotensin-converting-enzyme (ACE)-inhibitorsandother antihypertensivedrugsis mandatoryinthemanagementofSRC.Rhabdomyolysis withacutetubularnecrosisorg lomerulardisorders,includ- ingminimalchangedisease,membranousnephropathy, IgAnephropathyordiffuseproliferativeglomeruloneph- ritis,hasbeenreportedinpatientswithauto-immune myopathies[14,15]. Lupusnephritisisoneofthemostsevereorgan manifestationsofthediseaseand,dependingonbiopsy findings,needsaggressiveimmunosuppressivetherapy. Thehistopathologicclassificationoflupusnephritis guidestherapeuticinterventionswiththeaimtoreduce proteinuriaandpreservekidneyfunction.Renalmanifest- ationinprimaryandsecondary antiphospholipidsyndrome (APS)isawell-describedcomplication,frequentlyleading *Correspondence: gert.mayer@i-med.ac.at DepartmentofInternalMedicineIV,NephrologyandHypertension,Medical UniversityInnsbruck,Anichstraße35,Innsbruck6020,Austria ©2013KronbichlerandMayer;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsofthe CreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse, distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. KronbichlerandMayer BMCMedicine 2013, 11 :95 http://www.biomedcentral.com/1741-7015/11/95 toarterialhypertensionandoccasionallyimpairmentofrenalfunction[5,16].PatientswithRAareatanincreasedriskofdevelopingsecondaryamyloidosisduetolong-lastingchronicinflammationaswellasmesangialglomerulonephritisandmembranousnephropathyrelatedtospecificdrugs[17].Table1summarizesspecifickidneybiopsyfindingsinthecontextofCTDs.SjögrensyndromeIntroductionPrimarySjögrensyndrome(PSS)isanautoimmunedisorderofhithertounknownoriginwhichischaracterizedbypolyclonalB-cellactivationaswellaslymphocyticinfiltrationoftheexocrineglands,resultinginkerato-conjunctivitissicca(dryeyesdisease)and/orxerostomia(drymouthdisease)[18].Inaddition,extraglandularmanifestationsofPSScanaffectorgansystems,suchasthelungs,bloodvessels,skin,thegastrointestinaltract,centralandperipheralnervoussystem,muscularskeletalapparatusandthekidney[19,20].Affectedpatientsareatincreasedriskofdevelopingnon-Hodgkinslymphoma,inparticularlymphomasofB-cellorigin[21].SecondarySjögrensyndromeisassociatedwithotherrheumaticdisorders,suchasRA,SLE,SScandothers.RenaldiseasewithPSSisreportedtooccurin4.2%[1]to67%[2]ofpatients.Thevariationisconsideredtobeassociatedwiththedifferentdiagnosticcriteriaused,differentstudydesignsandsmallcohortsexaminedaswellasselectionbias.Histopathology/kidneyinvolvementAcuteorchronictubulointerstitialnephritis(TIN)withdefectsintubularfunctionisthepredominantlesioninbiopsy-provenrenalinvolvement[2,6].Distal(typeI)renaltubularacidosis(RTA)isthemostcommonclinicalfinding,leadingtomildsymptomsbutalsotopotentiallylife-threateningcomplications,suchashypokalemicparalysis[22].Albeitconsideredtoberare,proximal(typeII)RTAhasbeenreportedinsomecases[6,23].Moreover,glomerulardisease,suchascryoglobulinemicmembrano-proliferativeglomerulonephritis,focalseg-mentalglomerulosclerosis(FSGS),mesangialproliferativeglomerulonephritis,membranousnephropathyandmin-imalchangediseasehavebeenreported[2,6,7,24].Asinglecaseoflong-lastingTINinapatientwithPSSledtoasecondary(AA)amyloidosiswith,consequently,renalfailureandnephroticsyndrome[18].Interestingly,inonestudySSA/Ro,SSB/Laandrheumatoidfactor,aswellashypergammaglobulinemia,weredetectedinallsubjectswithbiopsy-provenrenalinvolvement[6].Inanothercohort,allpatientswithdistalRTAhadpositiveanti-nuclearantibodiesandeitherSSAorSSBantibodiesweredetectedin85.7%ofthem[25]. Table1OverviewofkidneybiopsyfindingsinpatientswithconnectivetissuediseasesRenalbiopsyfindingsConnectivetissuediseaseTubulointerstitialnephritis(TIN)Sjögrensyndrome[],Rheumatoidarthritis[Mesangialproliferativeglomerulonephritis/IgAnephropathySjögrensyndrome[],Polymyositis[],Dermatomyositis[Systemiclupuserythematosus[],Rheumatoidarthritis[Focalsegmentalglomerulosclerosis(FSGS)Sjögrensyndrome[],Systemiclupuserythematosus[Antiphospholipidsyndrome[],Rheumatoidarthritis[Cryoglobulinemicmembrano-proliferativeglomerulonephritisSjögrensyndrome[MinimalchangediseaseSjögrensyndrome[],Polymyositis[],Systemiclupuserythematosussus82,83],Antiphospholipidsyndrome[],Rheumatoidarthritis[MembranousnephropathySjögrensyndrome[],Polymyositis[],Dermatomyositis[],ClassVlupusnephritis[],Antiphospholipidsyndrome[124],Rheumatoidarthritis[SecondaryrenalamyloidosisSjögrensyndrome[],Rheumatoidarthritis[ThromboticmicroangiopathyAntiphospholipidsyndrome[],Sclerodermarenalcrisis[DiffuseproliferativeglomerulonephritisDermatomyositis[IgMnephropathySystemiclupuserythematosus[CollapsingglomerulopathySystemiclupuserythematosus[LupusnephritisClassItoVIlupusnephritis[],drug-inducedproliferativelupusnephritis[142FibrillaryglomerulonephritisAntiphospholipidsyndrome[],Rheumatoidarthritis[Necrotizingcrescenticglomerulonephritis(includingdrug-inducedforms)Scleroderma[],Rheumatoidarthritis[FocalproliferativeglomerulonephritisRheumatoidarthritis[CrescenticGNwithFSGSPolymyositis[C3nephropathyAntiphospholipidsyndrome[KronbichlerandMayerBMCMedicinePage2of14http://www.biomedcentral.com/1741-7015/11/95 TreatmentwithglucocorticoidsshouldbeinitiatedasfirstlinetherapyinpatientswithPSSandrenalinvolvementsinceagoodresponsetoearlytreatmenthasbeenreported[6,26].Inaddition,long-termbicarbonateand/orelectrolytesupplementationshouldbecommencedinamajorityofpatientstopreventlife-threateningcomplications[26].Besidescorticosteroids,alternativeimmunosuppressivetherapies(hydroxychloroquine,rituximab,cyclophos-phamide)shouldbeprescribedbasedonkidneybiopsyfindingsaswellascomorbidities.Itwasshownthatrenalfunctionmaintainedorimprovedduringamedianfollow-upperiodof38monthsaftertreatmentwithimmunosuppressivedrugs[6].CorticosteroidsareamainstayinthetreatmentofTIN.Furtherhistologicfindingsrequirespecifically-tailoredimmunosuppressionandmostimportantly,supplementa-tionofbicarbonateand/orelectrolytes,whenindicated,shouldbecommenced.SclerodermarenalcrisisIntroductionSScisaCTDcharacterizedbydepositionandoverpro-ductionofextracellularmatrixproteinsandcollagen,resultingintissuefibrosisand,subsequently,tissuedysfunction.Affectedorgansandtissuesincludetheskin,gastrointestinaltract,heart,lungsandkidneys.InvolvementofthevascularsystemgenerallyresultsinthedevelopmentofRaynaudsphenomenonearlyinthediseasecourse.Consecutively,severeclinicalmanifesta-tionsofvasculardysfunctioncanbeobservedinsomepatientsleadingtopulmonaryfibrosisandpulmonaryarteryhypertension,esophagealmotilitydysfunction,watermelonstomach,cardiacinvolvement,aswellassclerodermarenalcrisis(SRC)[27-29].Epithelialtomesenchymaltransition(EMT),aconditionthatconveysaphenotypicconversionfromdifferentiatedepithelialcellstomatrix-producingfibroblastsandmyofibroblasts,isrecognizedasacrucialpartofthedevelopmentoftissuefibrogenesis[30,31].Severalgrowthfactors,suchastransforminggrowthfactorß(TGFß)[8],connectivetissuegrowthfactor(CTGF)[9],aswellasothermediators,suchasendothelin-1[10],areinvolvedintissueremodelling.SRCoccursinroughly5%ofpatientswithSSc[3].Severalriskfactorswithapredictivevaluewereestablished:durationofSSconsetoflessthanfouryears,higherincidenceofprogressiveskinthickeningpriortorenalinvolvement,newdevelopmentofanemiaandcardiacinvolvement(pericardialeffusionorcongestiveheartfailure)[32].Detectionofanti-RNApolymeraseIIIantibodiesdisplaysastrongriskmarkerforthepresenceofSRC,whereasthepresenceofanti-topoisomeraseandanti-centromereantibodiesinsclerodermaindicatesafavorablediseasecourse[33].Inaddition,acasecontrolstudyrevealedasignificantpositiveassociationbetweenlong-lastinghigh-dosecorticosteroidtreatment(15g/d)andtheonsetofSRC[34].Onaverage,in10%ofpatients,SRCoccursintheabsenceofhypertension.Normotensiverenalcrisiswasmorefrequentlypresentinpatientstreatedwithhighdosesofcorticosteroidsandinpatientswithredundantmicroangiopathichemolyticanemiaandthrombocytopeniainconsequencetotheunderlyingdisease[11].Inaddition,normotensiverenalfailureinSScwasassociatedwithahighermortalityrateandanearlierneedfordialysistreatment[11-13].Bloodpressurelevelsgreaterthan150/90mmHgwereobservedinalmost90%ofpatientsexperiencingSRC.HypertensiveSRCisaccompaniedbyclinicalsignsofmalignanthypertensionwithleftventricularfailure,hypertensiveencephalopathyandarrhythmia[12].Histopathology/kidneyinvolvementDiagnosisofSRCisconfirmedbyrenalbiopsy,whichshowsathromboticmicroangiopathicprocess,particularlyaffectingsmallvessels.Vascularchangesareaccompaniedbythrombosis,accumulationofmyxoidmaterialandlaterinthediseasecourse,developmentofonion-skinlesionsand/orfibrointimalsclerosis[13].Furthermore,onehastokeepinmindthatANCA-associatedvasculitisisararecomplicationofSScandingeneralpresentswithantibodiesdirectedagainstmyeloperoxidaseandp-ANCA[35].EarlyuseofACEinhibitors,onthebasisofmostexperienceinparticularcaptopril,isundoubtedlyacornerstoneinthemanagementofhypertensiveSRC.ImmediateusewithaprogressiveincreaseofACEinhibitordosage,eveninthepresenceofdeterioratingkidneyfunction,isconsideredtopreventorevenreverserenalfailure[36,37].Additionalantihypertensivetherapy(calciumchannelblockers,alpha/beta-adrenoreceptorantagonistsand/orminoxidil)ismandatorywhenbloodpressureisinsufficientlycontrolled[28,36].Recentfindingssuggestthatdialysiswasrequiredinmorethan50%ofpatientseitherincaseofvolumeoverloadtogetherwithrenaldeteriorationortocontrolbloodpressureduetotherapy-resistanthypertension[3,12].Discontinuationofdialysistreatmentcouldbeaccomplishedin16to55%patientswithSRC[3,37].Afterastablediseasecoursewithcontinuousdialysis,renaltransplantationshouldbeconsideredwhencontraindi-cationsareruledout.Inacohortof260patientswithSScwhounderwentkidneytransplantation,theoverallfive-yeargraftsurvivalratewas56.7%.Amongthose,therecurrenceofdiseaseaftertransplantationwas6.7%inareportoftheUnitedNetworkofOrganSharing(UNOS)[38].BasedonthefindingthatcyclosporineAKronbichlerandMayerBMCMedicinePage3of14http://www.biomedcentral.com/1741-7015/11/95 (CSA)mayberesponsibleforacuterenalfailureinpatientswithSSc[39],calcineurininhibitorsarenotgenerallyrecommendedasimmunosuppressantsafterkidneytransplantation.RenalinvolvementinSScisoftenaccompaniedbyprogressiverenalfailureandrapidinitiationoftherapeuticinterventionsismandatory.Bloodpressurecontrol,inparticularwithACE-inhibitorsandadditionalantihy-pertensivemedication,isessential.Ifbloodpressureisnotadjustableorthepatientshowssignsoffluidoverload,dialysisshouldbeconsideredearlyinthediseasecourse.Discontinuationofdialysiswasreportedinsomepatients.Inpatientswithchronichemodialysisandrenaltrans-plantation,acalcineurin-inhibitorfreeimmunosuppressiveregimenmightbechosen.DermatomyositisandpolymyositisIntroductionAuto-immunemyopathies,namelydermatomyositis(DM)andpolymyositis(PM),sharecommonclinicalfeatures,suchasproximalmuscleweakness,muscleinflammation,presenceofautoantibodies,elevatedmuscleenzymes,electromyographicalterationsandextramuscularmanifestations.Despiteclinicalsimilar-ities,bothdifferregardingmusclebiopsyfindingsandDMisassociatedwithcutaneousinvolvement.Thepresenceofaheliotroperash,whichischaracterizedbyaviolaceousskindiscolorationaroundtheeyes,andssign(erythematouspapuleswithinvolvementofjoints)arepathognomonicforDM[40,41].Bothentitiesareassociatedwithconcurrentincidenceofneoplasms.Inlargecohorts,malignanciesweredetectedin9.4to32%ofpatientsinDMandin4.4to17%inPMpatients[42-45]withapredominanceofadenocarcinomas[45].Histopathology/kidneyinvolvementTwotypesofrenalinvolvementhavebeendescribedinpatientswithPM/DM.First,rhabdomyolysiswithreleaseofmyoglobincanleadtoacutetubularnecrosiswithdeteriorationofrenalfunction[14,15].Second,severalreportsrevealedtheoccurrenceofchronicglomerulo-nephritisinpatientswithPM/DM[14,46-49].InPM,mesangialproliferativeglomerulonephritisrepresentstheleadingglomerularlesion[46,50,51].Moreover,otherbiopsyspecimensshowedlipoidnephrosiswithFSGS[52],membranousnephropathy[53]andcres-centicglomerulonephritiswithFSGS[54].Incontrast,thepredominantfindinginDMwithrenalinvolvementismembranousnephropathy[55-57].Nevertheless,bothmesangialproliferativeglomerulonephritis[58]anddiffuseproliferativeglomerulonephritis[49]havebeenreportedinsinglecasereports.High-doseoralcorticosteroidsarethecornerstoneofDM/PMtherapy.Moreover,theadditionofimmunosup-pressivedrugs,suchasazathioprine(AZA)orcyclo-phosphamide(CYC),aswellasanti-malariamedicationinDMandmethotrexate,CYC,intravenousimmuno-globulinsandCSAinPMhasbeenreportedtoimprovetherenaloutcomeinDM/PM[14,49,55-58].Incontrasttothesereports,onepatientprogressedtoend-stagerenaldiseasedespiteimmunosuppressivetreatment[59].Follow-upofthepatientswithDMrevealedahighmortalityrateduetocancerormulti-organfailure,whilemortalityinPMwashighduetoacuterhabdomyolysisfollowedbyseverehyperkalemiaandmetabolicacidosisinacasereport[14].Managementofpatientswithauto-immunemyopathiesandrenalinvolvementrequirespecialcaution,becausedisease-relatedmortalityduetorhabdomyolysisandhyperkalemiaisgreatlyfeared.Specialtherapeuticinter-ventionwithimmunosuppressionshouldbetailoredtotheunderlyinghistology.Inmostcases,corticosteroidsmightbeeffectiveasonetherapeuticcomponent.SystemiclupuserythematosusIntroductionSLEdepictsaremarkablecomplexautoimmunediseasewithconsiderableheterogeneityinclinicalmanifesta-tionsanddiseasecourse.ClassificationofSLEwaslasteditedbytheAmericanCollegeofRheumatology(ACR)in1997[60](Table2).Earlierdiagnosis,moreintensivetreatmentregimensanddiversealternativestrategiesandpossibilitiestotreatco-morbiditieshavecontributedtoimprovementofprognosis[61].Negativepredictivefactorswithrespecttosurvivalincludemalegender,positivelupusanticoagulant,glomerulonephritisandsevereonsetofSLE[62].Theincidenceismuchhigherinyoungwomanandtheprevalenceistwo-tofour-foldgreaterinnon-Caucasianpopulations[63].Genetic,environmentalandhormonalfactorshavebeenidentifiedaspossibleriskfactorsfordevelopingSLE[64,65].Autoantibodiesaredirectedagainstvariousnuclearantigens,inparticularagainstchromatincomponents,suchasnucleosomes,histones,anti-nuclearantibodies(ANA),double-strandedDNAantibodies(dsDNA)andribonucleoproteins.Recently,itwassuggestedthatthenucleosomemightbethedrivingautoantigeninSLE.Thishypothesisissupportedbythefindingthatglomerulardepositionofanti-dsDNAantibodiesinlupusnephritisismediatedbynucleosomes[66,67].Thekidneysareamajorsourceofautoantibody-producingplasmacellsinlupusnephritisandthesedifferentiatedplasmacellsarefrequentlyobservedinpatientswithKronbichlerandMayerBMCMedicinePage4of14http://www.biomedcentral.com/1741-7015/11/95 severerenalinvolvement(mainlyclassesIIIthroughV),potentiallyactinginamplifyingtherenaldiseasecourse[68].Additionalautoantibodiesincludeanti-Smith(Sm)antibodieswithahighspecificityforSLE,whileSSAandSSBarepresentinotherCTDsaswell[69].Complementlevelsarefrequentlyreducedinpatientswithactivedisease.GeneticcompletecomplementdeficienciescanresembleaSLE-likedisease[70].LevelsofcomplementC3andC4correlatewiththeoveralldiseaseactivity.PatientswithactivelupusnephritishadsignificantlylowerlevelsofC3andC4comparedtopatientswithinactivelupusnephritis[71].SerumC3hasgenerallyhighersensi-tivitythanserumC4,butbothtestshaveonlymodestspecificityforactivelupusnephritis[72].AssessmentoftherelationshipbetweenserumlevelsofC3orC4andrenalflaresrevealedthatC4iscriticalforinitiatingarenalflare,whileC3activationisinvolvedintheactualtissuedamage[73].AntibodiesdirectedagainstC1qweredetectedinallpatientswithactivenephritisinalargecohort[74].Moreover,anti-C1qantibodiesshowedthestrongestassociationwithproteinuriaamongpotentialbiomarkersandweresignificantlycorrelatedwithRenalActivityScore[75].However,contradictorytothesereports,inacohortof126patients,anti-C1qantibodieswerenotsignificantlyassociatedwithactivelupusnephritis[76].Histopathology/kidneyinvolvementInvolvementofthekidneyinthenaturalhistoryofdiseaseispresentinamajorityofpatientsandissupposedtoappearinalmost50%inthefirstyearofdiagnosis[4].Recentfindingsevensuggestahigherincidence,sinceaconsiderableproportionofpatientswithSLEhavesilentlupusnephritis.Diagnosisinthelattergroupwassignifi-cantlyearliercomparedtotheovertlupusnephritisgroupandurinarysedimentaswellasrenalfunctiontestswerenormal[77].Renalbiopsyfindingsarecategorizedaccordingtothecurrentclassificationoflupusnephritis,whichwaspublishedonbehalfoftheInternationalSocietyofNephrology(ISN)/RenalPathologySociety(RPS)[78](Table3).However,oneshouldbeawarethatotherglomerularchanges,suchascollapsingglomerulopathy[79],IgAnephropathy[80],FSGS,IgMnephropathy[81],minimalchangedisease[82]/glomerularpodocytopathy[83]canoccuraswellandalterationsinkidneyfunction Table2RevisedcriteriaoftheAmericanCollegeofRheumatology1.MalarrashFixederythema,flatorraised,overthemalareminences,tendingtosparethenasolabialfolds2.DiscoidrashErythematousraisedpatcheswithadherentkeratoticscalingandfollicularplugging;atrophicscarringmayoccurinolderlesions3.PhotosensitivitySkinrashasaresultofunusualreactiontosunlight,bypatienthistoryorphysicianobservation4.OralulcersOralornasopharyngealulceration,usuallypainless,observedbyphysician5.Non-erosivearthritisInvolvingtwoormoreperipheraljoints,characterizedbytenderness,swellingoreffusion6.Pleuritis/Pericarditis1.Pleuritis,convincinghistoryofpleuriticpainorrubbingheardbyaphysicianorevidenceofpleuraleffusion,or2.Pericarditis,documentedbyelectrocardiogramorruborevidenceofpericardialeffusion7.Renaldisorder1.Persistentproteinuria�0.5gramsperdayormorethan3+onurinedipsticktesting,or2.Cellularcasts(mayberedcell,hemoglobin,granular,tubular,ormixed)8.Neurologicdisorder1.Seizures,intheabsenceofoffendingdrugsorknownmetabolicderangements;forexample,uremia,ketoacidosis,orelectrolyeimbalance,or2.Psychosis,intheabsenceofoffendingdrugsorknownmetabolicderangements;forexample,uremia,ketoacidosis,orelectrolyteimbalance9.Hematologicdisorder1.Hemolyticanemiawithreticulocytosis,or2.Leukopenia2occasions,or3.Lymphopenia2occasions,or4.Thrombocytopeniamintheabsenceofoffendingdrugs10.Immunologicdisorder1.Anti-DNA:antibodytonativeDNAinabnormaltiter,or2.Anti-Sm:presencetoantibodyofSMnuclearantigen,or3.Positivefindingofantiphospholipidantibodieson:AnabnormalserumlevelofIgGorIgManticardiolipinantibodiesApositivetestresultforlupusanticoagulantusingastandardmethod,orAfalse-positivetestresultforatleastsixmonthsconfirmedbyTreponemapallidumimmobilizationorfluorescenttreponemalantibodyabsorptiontest11.Positiveanti-nuclearantibodyAnabnormaltiterofanti-nuclearantibodybyimmunofluorescenceoranequivalentassayatanypointintimeandintheabsenceofdrugsDiagnosisofsystemiclupuserythematosusrequiresatleast4outof11criteria[].ReprintpermissionwasobtainedfromJohnWileyandSons,Inc.KronbichlerandMayerBMCMedicinePage5of14http://www.biomedcentral.com/1741-7015/11/95 duetorhabdomyolysiswithacutekidneyfailure[84],aswellastypeIandIVRTA[85],havealsobeenreported.Ingeneral,useofACEinhibitorssignificantlyreducedthedevelopmentofproteinuriaand/orbiopsy-provenlupusnephritisandwasassociatedwithadecreasedriskofdiseaseactivity[86].Concomitantuseofantimalarialdrugs(chloroquineandhydroxychloroquine)atdiagnosisoflupusnephritisreducedtheriskofprogressiontoend-stagerenalfailureandfrequencyofhypertension[87].Specifictreatmentfollowstheclassoflupusnephritis,whichisdefinedbytherevisedISNcriteria.ClassIandclassIIrequirenotherapydirectedatthekidneyinconse-quenceofgoodlong-termrenaloutcome[88].Incontrast,high-dosesteroidtherapyrapidlyresolvednephroticsyndromeinamajorityofSLEpatientswithminimalchangediseaseeitherintheabsenceorwithunderlyingclassIIlupusnephritisbasedonrenalbiopsyfindings[82,83].ImmunosuppressivetreatmentisrequiredinthemanagementofclassIII(focal),classIV(diffuse)andclassV(membranousnephropathy)lupusnephritisandusuallyconsistsofhighdoseglucocorticoidtherapyalongwithintravenousCYCormycophenolatemofetil(MMF)asinductiontherapy.TheEuroLupusNephritisTrialcomparedlowdoseCYC(fortnightly,atafixeddoseof500mg,withacumulativedoseof3g)withthepreviouslyestablishedhighdoseCYC(NIH)regimen(meancumulativedose8.5g).BothstratawerefollowedbyAZAasremission-maintainingtreatment.Renaloutcome Table3RevisedclassificationlupusnephritisaccordingtotheInternationalSocietyofNephrology/RenalPathologySociety(ISN/RPS)2003[78]ClassIMinimalmesangiallupusnephritisNormalglomerulibylightmicroscopy,butmesangialimmunedepositsbyimmunofluorescenceClassIIMesangialproliferativelupusnephritisPurelymesangialhypercellularityofanydegreeormesangialmatrixexpansionbylightmicroscopy,withmesangialimmunedepositsMaybeafewisolatedsubepithelialdepositsvisiblebyimmunofluorescenceorelectronmicroscopy,butnotbylightmicroscopyClassIIIFocallupusnephritisActiveorinactivefocal,segmentalorglobalendo-orextracapillaryglomerulonephritisinvolvingofallglomeruli,typicallywithfocalsubendothelialimmunedeposits,withorwithoutmesangialalterationsClassIII(A)Activelesions:focalproliferativelupusnephritisClassIII(A/C)Activeandchroniclesions:focalproliferativeandsclerosinglupusnephritisClassIII(C)Chronicinactivelesionswithglomerularscars:focalsclerosinglupusnephritisClassIVDiffuselupusnephritisActiveorinactivediffuse,segmentalorglobalendo-orextracapillaryglomerulonephritisinvolvingofallglomeruli,typicallywithdiffusesubendothelialimmunedeposits,withorwithoutmesangialalterations.Thisclassisdividedintodiffusesegmental(IV-S)lupusnephritiswhen50%oftheinvolvedglomerulihavesegmentallesions,anddiffuseglobal(IV-G)lupusnephritiswhen50%oftheinvolvedglomerulihavegloballesions.Segmentalisdefinedasaglomerularlesionthatinvolveslessthanhalfoftheglomerulartuft.ThisclassincludescaseswithdiffusewireloopdepositsbutwithlittleornoglomerularproliferationClassIV-S(A)Activelesions:diffusesegmentalproliferativelupusnephritisClassIV-G(A)Activelesions:diffuseglobalproliferativelupusnephritisClassIV-S(A/C)Activeandchroniclesions:diffusesegmentalproliferativeandsclerosinglupusnephritisActiveandchroniclesions:diffuseglobalproliferativeandsclerosinglupusnephritisClassIV-S(C)Chronicactivelesionswithscars:diffusesegmentalsclerosinglupusnephritisClassIV-G(C)Chronicinactivelesionswithscars:diffuseglobalsclerosinglupusnephritisClassVMembranouslupusnephritisGlobalorsegmentalsubepithelialimmunedepositsortheirmorphologicsequelaebylightmicroscopyandbyimmunofluorescenceorelectronmicroscopy,withourwithoutmesangialalterationsClassVlupusnephritismayoccurincombinationwithclassIIIorIVinwhichcasebothwillbediagnosedClassVlupusnephritisshowadvancedsclerosisClassVIAdvancedsclerosislupusnephritis90%ofglomeruligloballysclerosedwithoutresidualactivityReprintpermissionwasobtainedfromtheJournaloftheAmericanSocietyofNephrology.KronbichlerandMayerBMCMedicinePage6of14http://www.biomedcentral.com/1741-7015/11/95 wassimilarinbothtreatmentarms,butthelowdoseCYCgrouphadfewersevereinfections,eventhoughthediffer-encewasnotstatisticallysignificant[89].Reportsfromthistrialwitha10-yeardurationoffollow-upconfirmedtheefficacyoftheEuroLupusregimen[90].Sinceamajorityofthesubjectswerewhiteinthistrial,theseresultsmightbelessapplicabletootherethnicities.Inamorediversifiedcohort�(50%blacks)MMF(meandailydosage2.68g)hasbeenreportedtobesuperiorasinductiontherapywhencomparedtomonthlyCYC(0.5gto1g/m)inpatientswithclassIIIthroughVlupusnephritis[91].Afurtherlarge,multi-centertrialinabalancedcohortwithrespecttoethnicitiesdesignedtoshowsuperiorityofMMF(meandailydosage2.47g)toCYCfailedtomeettheprimaryendpoint.Bothtreatmentarmsachievedvirtuallyidenticalratesofcompleteandpartialremission.Furthermore,nosignificantdifferencewithregardtosevereadverseeventsorinfectionswasreported[92].ResponsetoMMFasinductiontreatmentinpureclassV(membranousnephropathy)lupusnephritisinpatientswithdiverseracialbackgroundappearedtoshownodiffer-enceincomparisontoCYC[93].Patients(�60%black)withclassVlupusnephritisshowedabetterresponseregardinginductionofremissionafterCSAwhencomparedtoCYC,whereasrelapseofnephroticsyndromeoccurredmorefrequentlyinpatientswithpriorCSAtherapy[94].Inasmallcohort,multi-targettherapy(MMFandtacrolimus)inpatientswithclassIVandclassVlupusnephritisrevealedahigherrateofcompleteremissionwithagoodtolerabilitywhencomparedtointravenousCYC[95].Followinginductiontherapy,long-termimmunosuppres-sionismandatorytoavoidsevereflaresandtomaintainstabilizationofdiseaseactivity.Thus,immunosuppressantswithafavorablesafetyprofileandgoodefficacyaremandatory.MMFandAZAaredeemedsuitableandhaveshownefficacyinmaintainingremissionoflupusnephritis[96].EquivalenceofMMFandAZAwasreportedintheMAINTAINNephritisTrial,eventhoughatrendtowardsfewerrenalflaresintheMMFgroup(19%vs.25%intheAZAgroup)wasreported[97].Morerecently,inalargertrial,MMFwassuperiortoAZAwithrespecttomaintainingarenalresponseandpreventingrelapseinpatientswithlupusnephritis[98].B-celldepletingtherapywithanti-CD20antibodyrituximab(RTX)provedefficientinpatientswithactiveSLEincludingpatientswithlupusnephritis,whowerenonresponsivetostandardimmunosuppressivetherapy[99].InproofoftheefficacyofRTXtreatmentinmoder-atelytoseverelyactiveSLEandlupusnephritis,twolargemulti-centertrialswereconducted.TheEXPLORERtrial(moderatetosevereactiveSLE)demonstratednodifferenceinprimary/secondaryendpointsbetweenRTXandplacebo.InasubgroupanalysisabeneficialeffectofRTXwasobservedintheAfrican-American/Hispanicsubgroup[100].Inpatientswithproliferativelupusnephritisandbackgroundimmunosuppression(MMF)nodifferencewasnotedwhenRTXwasaddedwithregardtosafetyandefficacy(LUNARtrial)[101]eventhoughopportunisticinfectionsarereportedtoberathercommoninSLEpa-tientsrelatedtoRTXtreatment[102].EnthusiasmwasalsodampenedbyreportsonthedevelopmentofprogressivemultifocalleukoencephalopathyinSLEpatientsfollowingtreatmentwithRTX[103].Novelapproacheswithfocusontargetedtherapyhavebeendevelopedandarecurrentlybeingevaluatedinclinicaltrials.CirculatingB-lymphocytestimulator(BLyS)iselevatedinSLE,andtiterscorrelatewithincreaseddis-easeactivityandelevateddsDNAantibodyconcentrations[104].PatientswithserologicallyactiveSLErespondedsignificantlybettertobelimumab,anantibodythatbindstoBLySandinhibitsitsbiologicalactivity,plusstandardofcare(SOC)thantoSOCalone[105].TheefficacyofbelimumabwasfurthercorroboratedintwolargephaseIIItrials,BLISS52[106]andBLISS76[107].Inbothtrials,belimumabmetitsprimaryefficacyendpointandwasconsequentlyapprovedbytheFDAinthetreatmentofSLEwiththeexceptionofsevereactivelupusnephritisorcen-tralnervoussystemlupus.Furtherinvestigationsaddressedtoevaluatetheroleinactivelupusnephritisarenecessary.PromisingresultshavebeenobtainedinaphaseIItrialforepratuzumab,ahumanizedanti-CD22antibody[108,109].Atacicept,asolublereceptorfusionprotein,neutralizestheactivityofBLySandaproliferation-inducingligand(APRIL)andtheirheterotrimers[110].InaphaseItrial,ataciceptwaswelltoleratedanddemonstratedadose-dependentreductionofimmunoglobulinlevelsandmature/totalBcellnumbers[111].However,inpatientswithactivelupusnephritis,aphaseIItrialwasterminatedduetoanincreasednumberofinfections[109].Furthertri-alsassessingtheefficacyandsafetyarecurrentlyongoing.Inpatientswithhighlyactivelupusnephritiswithfailureofconventionaltherapy,short-termaswellasprolongedimmuno-adsorptionledtoasignificantreductioninpro-teinuriaandtosustainedremissionrates[112].Autologousstemcelltransplantationachievedsustainedclinicalremis-sionsinpatientsrefractorytoconventionalimmunosup-pressivetreatment,eventhoughthisclinicalbenefitwasassociatedwithincreasedmortalityratesinmoststudiesconductedsofar[113].Intravenousimmunoglobulinshaveshownbenefitsinpatientsnonresponsivetoothertherapiesandasasteroid-sparingagent[114].Thehistopathologicclassificationoflupusnephritisstillguidesthetherapy.Inproliferativelupusnephritis(IIIandIV),CYCandMMFhaveshownalmostidenticaltherapeuticresponsesasinductiontherapyinlargetrials.CSAmightbeanalternativetotheseimmunosuppressiveKronbichlerandMayerBMCMedicinePage7of14http://www.biomedcentral.com/1741-7015/11/95 agentsinpureclassVlupusnephritis.Inpatientsnotrespondingtoinitialtreatment,multi-targettherapymightbeaneffectivealternative.MMFseemstobesuperiortoAZAinmaintainingremission.TheroleofRTXinthetreatmentoflupusnephritishastobefurtherelucidated,aswellasthesignificanceofnoveltherapeuticapproachesinthetherapyoflupusnephritis.KidneydiseaseinantiphospholipidsyndromeIntroductionAntiphospholipidsyndrome(APS)isdefinedbytheassociationofvascularthrombosispotentiallyaffectingallsegmentsofthevascularbed,complicationsduringpregnancy(includingunexplainedconsecutivespontaneousabortions,prematurebirthsbecauseofseverepreeclampsia,eclampsiaorplacentalinsufficiencyorunexplaineddeathbeforethe10weekofgestation),andthepresenceofantiphospholipidantibodies(aPL),namelyanticardiolipinantibodies(aCL)andlupusanticoagulant(LAC)[115].TheAPSisclassifiedasprimaryAPSintheabsenceofassoci-atedautoimmunedisease,whereassecondaryAPSisfoundalongsideotherautoimmunedisorders[116].Histopathology/kidneyinvolvementRenalmanifestationsinthecontextofAPSmayresultfromthrombosisoccurringatanylocationintherenalvasculature.Renalarterystenosis(RAS)isacommoncomplicationofAPS,leadingtorenovascularhypertension[117].Inaretrospectivestudy,patientswithAPS,RASandhypertensionreceivingoralanticoagulationwithatargettroughInternationalNormalizedRatio(INR)�3.0hadbetterbloodpressurecontrolandrenalfunctionremainedstableorimproved,whileinpatientswithanINR3.0renalfunctionsignificantlydeterioratedandbloodpressurewaspoorlycontrolled[118].Arterialhypertensionisawell-documentedcomplicationofAPS.InaseriesofpatientswithprimaryAPS,alargeproportionofpatientspresentedwithhypertension,whichwasattributedtobiopsy-provenvascularnephropathy[119].Kleinknechtetal.reportedthatallpatientshadseverehypertensionandrenalinsufficiencyinasmallcohortofpatientswithsecondaryAPSduetoSLE[120].Thrombosisoftherenalveinandinferiorvenacavausuallypresentswithnephrotic-rangeproteinuriainprimaryandsecondaryAPS[121],especiallyinthosewithcirculatingLAC[122].APSNreferstokidneydamagecausedbyintrarenalvasculardamageandmaybeacute,incaseofthepresenceofthromboticmicroangiopathy,and/orchronic,inthecaseofarteriosclerosis,fibrousintimalhyperplasiaandfocalcorticalatrophy[119,123].Throm-boticmicroangiopathyischaracterizedbydistinctivemicro-scopicandultrastructuralchangesandclinicalpresentationcommonlyincludeshypertension,mildtonephrotic-rangeproteinuriaandrenalimpairment[119,123].Tektonidouetal.examinedkidneybiopsiesobtainedfrompatientswithSLEwithorwithoutpresenceofaPL.APSNwasdetectedinalmost40%withaPL,comparedwithonly4.3%ofpatientswithoutaPL[16].Fakhourietal.examined29kidneybiopsiesofpatientswithAPS[124].InnineofthesebiopsiespredominantpathologicalfeaturesdistinctfromASPNwerenoted:membranousnephropathy(threecases),minimal-changedisease/focalsegmentalglomerulosclerosis(threecases),mesangialc3nephropathy(twocases),andpauci-immunecrescenticglomerulonephritis(onecase).Furthermore,acaseoffibrillaryglomerulonephritisinapatientwithAPSwaspublishedrecently[125].Inter-estingly,thepresenceofaPLinpatientsundergoingrenaltransplantationsignificantlyincreasestheriskofrenalvascularthrombosisandgraftfailure[126,127].BloodpressurecontrolisthekeyinterventioninthetreatmentofAPS-relatedrenalinvolvement.Adequateanticoagulation(ifevidenceofmicrothrombiispresent)hasshownencouragingresultsinsmallcohortsandmaypreventprogressiontoend-stagerenaldisease[128].Evidencesupportingimmunosuppressivetherapyinthesepatientsislimitedtocaseseries[125,129]andisnotroutinelyrecommendedinAPS-relatedrenalmanifes-tations.Contrasting,patientswithcatastrophicAPS,whichischaracterizedbyseveremultipleorgandysfunctioninconsequenceofdiffusesmallvesselischemiaandthrombosespredominantlyaffectingtheparenchymalorgans,usuallyreceiveacombinationtherapy,includinganticoagulation,steroids,intravenousimmunoglobulinsandplasmapheresis,butdespitethisaggressiveapproachmortalityisstillhigh[130].BloodpressurecontrolismandatoryinpatientswithAPSN.TheroleofanticoagulationwithatargetthroughINRabove3.0inpatientswithAPSNandmicrothrombitopreventkidneyfunctiondeteriorationhastobeelucidatedinfurther,largerstudies.RheumatoidarthritisIntroductionRAischaracterizedbypersistentsynovial,systemicinflam-mationandautoantibodies(particularlytorheumatoidfactorandcitrullinatedpeptides).GeneticaswellasenvironmentalfactorscontributetotheriskofdevelopingRA[131].RenalinvolvementisrelativelycommoninpatientswithRA.Histopathology/kidneyinvolvementAstudyofrenalbiopsyspecimensindicatedthatmesangialglomerulonephritisisthepredominanthistopathologicfindinginRA,followedbyamyloidosis,membranousKronbichlerandMayerBMCMedicinePage8of14http://www.biomedcentral.com/1741-7015/11/95 nephropathy,focalproliferativeglomerulonephritis,minimal-changenephropathyandacuteinterstitialnephritis[17].Developmentofmembranousnephropathyisrelatedeithertotherapywithdiseasemodifyinganti-rheumaticdrugs(DMARDs),inparticulargoldthiomalate,D-penicillamineandbucillamine[132],andanti-TNFalphatherapy,suchasetanerceptandadalimumab[133,134],orrarelyoccursconcomitantwithRA[135].SecondaryAAamyloidosiswasprevalentin5.8%ofpatientswithRAandwasaccompaniedbyashortenedlifeexpectancy[136].Depositionofamyloidinrenaltissuecorrelatedsignifi-cantlywithparametersofrenalfunction[132],whilealackofamyloiddepositionintheglomerulusmaycharacterizesubjectswithstablerenalfunction[137].MesangialglomerulonephritisisprobablyrelatedtoRAitself,sinceitsoccurrencewasassociatedwithhighertitersofrheuma-toidfactor(RF)whencomparedwithRApatientswithoutnephropathy.DepositionofmesangialIgAcorrelatedwiththedurationofRAandelevatedserumIgAlevels,whereasmesangialIgMdepositionwascorrelatedwithserumlevelsofIgMclassRF[138].Inaddition,singlereportsrevealthepresenceofFSGS[139]andfibrillaryglomerulonephritis[140]inRApatients.Anti-TNFalphatherapycanbecausa-tiveforthedevelopmentofnecrotizingcrescenticglomer-ulonephritisandproliferativelupusnephritis[141,142].Besidestherenalsideeffectsofgoldsalts,D-penicillamineandbucillamine,CSAasanotherDMARDhasaseriouspotentialforrenaltoxicity,whichismanifestedprimarilyinadeclineincreatinineclearance[143].Improvementofclinicalandlaboratoryparameterswasachievedinmostcasesafterdrugwithdrawalandincaseofnecessaryinitiationofimmunosuppression[133,134,142,143].Inpatientswithamyloiddeposition,etanercepttreatmentreducedproteinuriaaswellasserumamyloidA.Furthermore,itentailedadecreaseinserumcreatinineinpatientswithcreatininevaluesmg/dlattheonsetofamyloidosis[144].TherapyrelateddeteriorationofkidneyfunctionhastobeexcludedinpatientswithRA.Inaddition,thepersistinginflammationcanleadtodepositionofamyloid.Thus,adequatetherapytoreducediseaseactivitymaybeeffectiveinpreventingthislate-onsetcomplication.Specificthera-peuticinterventionsshouldbetailoredtotheunderlyinghistologickidneyinvolvement.ConclusionandfuturedirectionsRenalinvolvementisfrequentlypresentinCTDsandhasvariablephenotypes.Sincethereisasteadyincreaseofknowledgeregardingthepathophysiologybehindauto-immunedisorders,morespecifictherapeuticapproacheshavebeendevelopedandarecurrentlyinclinicaltrials.AcuteorchronicTINisthepredominantkidneybiopsyfindinginSjögrensyndrome.Kidneyfunctionnormalizesinmostcasesaftercorticosteroidsareinitiated[2,6].Inaddition,severalglomerularlesionpatternshavebeendescribedinSjögrensyndrome.Resultsfromhematopoieticstemcelltransplantation(HSCT)inSScarepromising.Currentstudies,namelytheSCOTandASTIStrials,havecompletedpatientrecruitmentandthefirstresultsareexpectedsoon[145].TheASSISTtrialclearlydepictedtheefficacyofHSCTinpatientswithscleroderma,sinceall10patientsintheHSCT-groupimprovedwhencomparedtononeintheCYCtreatedcohort[146].Inaddition,endothelinreceptorantagonistsincombinationwithdualblockadeoftherenin-angiotensin-aldosteronesystem(RAAS)sig-nificantlyreducedproteinuriaandstabilizedtheserumcreatininelevelafteraninitialincreaseinapatientwithSRC[147].DespiteefficacyinpatientswithpulmonaryarterialhypertensioninSSc[148],trialswiththeaimtoshowbenefitsofendothelinreceptorantagonistsinSRChaveyettobeconducted.Diverseglomerularalterationsandrhabdomyolysishavebeenreportedinpatientswithauto-immunemyopathies.Guidedtherapywiththeaimtotreattheunderlyingdiseaseimproveskidneyfunctioninmostcases.InSLE,newtherapeuticapproacheshavegainedatten-tion.Oneofthesenovelagentsisbelimumab,aninhibitorofserumBLyS,whichwasrecentlyapprovedbytheFDAfortreatmentofSLEwiththeexceptionofactivelupusnephritisandcentralnervoussysteminvolvement.Arandomized,controlledtrialwithinclusionofactivelupusnephritisiscurrentlybeingdesigned.Furthermore,BLySinhibitionmayalsobeeffectiveinthetreatmentofPSS,sincepatientswithSjögrensyndromeexhibitincreasedBLySlevels[149].InpatientswithSLE,B-celldepletingtherapywithRTXwaseffectiveinalargercohortincludingpatientswithlupusnephritis[99],andefficacywasfurther-moreconfirmedinarecentmeta-analysisevaluatingpatientswithrefractorylupusnephritis[150].However,RTXfailedtoshowsuperiorityintwolargephaseIIItrialswithpatientseitherpresentingwithoutrenalinvolvement(EXPLORER)orwithrenalinvolvement(LUNAR)[100,101]eventhoughaposthocanalysisoftheEXPLORERtrialindicatedthatRTX-treatedpatientsachievedlowerdiseaseactivitywithoutasubsequentseverediseaseflarewhencomparedtothosetreatedwithplacebo[151].PersistentB-cellpresencewasassociatedwithnoclinicalresponsefollowingRTXtreatment[152].Inaddition,physiciansshouldbeawareofsevereinfectiouscomplicationsfollowingRTXtreatmentinSLEpatients[102,103].Despiteotherstrategies,suchasimmunoglobulinadministration,immuno-adsorptionandKronbichlerandMayerBMCMedicinePage9of14http://www.biomedcentral.com/1741-7015/11/95 stemcelltransplantation[112-114],RTXisneverthelessonealternativeinrefractorySLE[99].APS-relatedrenalmanifestationpotentiallyaffectsanysegmentofthevascularbedandiscommonlyaccom-paniedbyarterialhypertension.Bloodpressurecontroliscrucial,whereastheroleandthetargetleveloforalanticoagulationneedstobefurtherelucidated.Chronicinflammation,aswellasdrugrelatedadverseeffects,iscausativeofkidneyinvolvementinRA.EtanercepthasshownencouragingresultsinreductionofserumamyloidAinamyloidosisandpatientswithabaselineserumcreatininebelow2mg/dltendedtoshowabenefitfollowingTNF-alphainhibition[144].Basedonstudiesinnon-diabeticnephropathy,patientswithrenalinvolvementinCTDsshouldreceiveRAASblockingagentsonceproteinuriais�1g/day[149,150].Renalfunctionneedstobemonitoredaswellasserumpotassiumlevelsandbloodpressure.Inchronickid-neydiseaseinthepre-dialysisstatetheloweringofLDL-cholesterolsafelyreducedtheriskofmajoratheroscleroticevents[153].AcceleratedatherosclerosisisacommonfindinginpatientswithchronicinflammationandinCTDsinparticular[154].Thus,modificationoftheriskfactorscontributingtotheevolutionofcardiovasculardiseaseiscrucialinthesepatients.Moreover,adher-encetotherapeuticadvicemaybeanunderestimatedproblem,sincearecentstudyindicatedthatonlyone-quarterofpatientswithSLEhadanadherence80%[155].Inaddition,counsellingagainstsmokingshouldbemandatoryinpatientswithSLEandRA[156].Insummary,renalmanifestationsofCTDsarefrequent.Renalbiopsytoensurediagnosisisnecessaryinmostpatientspresentingwithdeteriorationofrenalfunction,increaseofproteinuriaorsignsofnephriticsyndrome(summarizedinTable4).AninterdisciplinaryapproachtooptimizetreatmentistheaimforpatientswithCTDs.AA:AmyloidA;ACE:Angiotensin-converting-enzyme;aCL:Anticardiolipinantibodies;ACR:Americancollegeofrheumatology;ANA:Anti-nuclearantibodies;aPL:Antiphospholipidantibodies;APRIL:Aproliferation-inducingligand;APS:Antiphospholipidsyndrome;APSN:Antiphospholipidsyndromenephropathy;AZA:Azathioprine;BLyS:B-lymphocytestimulator;CSA:CyclosporineA;CTD:Connectivetissuedisease;CTGF:Connectivetissuegrowthfactor;CYC:Cyclophosphamide;DM:Dermatomyositis;DMARD:Diseasemodifyingantirheumaticdrug;dsDNA:Double-strandedDNAantibodies;EMT:Epithelialtomesenchymaltransition;FDA:Foodanddrugadministration;FSGS:Focalsegmentalglomerulosclerosis;HSCT:Hematopoieticstemcelltransplantation;INR:Internationalnormalizedratio;ISN:Internationalsocietyofnephrology;LAC:Lupusanticoagulant;LDL:Low-densitylipoprotein;MMF:Mycophenolatemofetil;PM:Polymyositis;PSS:Primarysjögrensyndrome;RA:Rheumatoidarthritis;RAAS:Renin-angiotensin-aldosteronesystem;RAS:Renalarterystenosis;RF:Rheumatoidfactor;RPS:Renalpathologysociety;RTA:Renaltubularacidosis;RTX:Rituximab;SLE:Systemiclupuserythematosus;Sm:Smith;SRC:Sclerodermarenalcrisis;SOC:Standardofcare;SSc:Systemicscleroderma;TGFß:Transforminggrowthfactorß;TIN:Tubulointerstitialnephritis;TNF:Tumor-necrosisfactor;UNOS:UnitednetworkoforganCompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.AKperformedtheliteraturesearchandwrotethemanuscript.GMcriticallyreviewedthemanuscript.BothauthorsapprovedthefinalversionoftheReceived:15November2012Accepted:11February2013Published:4April20131.GoulesA,MasouridiS,TzioufasAG,IoannidisJP,SkopouliFN,MoutsopoulosClinicallysignificantandbiopsy-documentedrenalinvolvementinprimarySjogrensyndrome.Medicine(Baltimore)2.BossiniN,SavoldiS,FranceschiniF,MombelloniS,BaronioM,CavazzanaI,ViolaBF,ValzorioB,MazzucchelliC,CattaneoR,ScolariF,MaiorcaR:andmorphologicalfeaturesofkidneyinvolvementinprimarySjogren'sNephrolDialTransplant Table4SuggestedkidneybiopsyindicationsinconnectivetissuediseasesBiopsyindicationrapiddeteriorationofrenalfunction(excludepostrenalandprerenaldisordersfirst)Biopsyindicationproteinuria�1g/d(measuredbycollectingurine;collectionoverthecourseofa24-hourperiod;tobeginurinecollection,thepatientvoidsanddiscardstheurinealreadyinthebladder,afterwardsurineforthenext24hourshastobecollectedtoensureaccurateresults),ifothercausesofproteinuriaareruledouttheEULAR/ERA-EDTArecommendationsforthemanagementoflupusnephritissuggestperformingarenalbiopsyifreproducibleproteinuria�0.5g/dispresent(especiallywithglomerularhematuriaand/orcellularcases)[Biopsyindicationnephriticurinesediment(redbloodcellcasts)withdeteriorationofkidneyfunction(estimatedGFRml/min)ifpre-existingimpairedrenalfunctionisruledoutConsiderre-biopsyincreaseinproteinuria/serumcreatininedespiteongoingimmunosuppressivetherapy(excludepost-renalandpre-renaldisordersfirst);considerarepeatkidneybiopsyduetopotentialphenotypechange(forexample,lupusnephritis)Biopsyindicationsuspectedinterstitialnephritis,findingsofwhitebloodcellcasts;leukocyturia(duetoprotonpumpinhibitors,non-steroidalanti-rheumaticdrugs,Sjögrensyndrome,rheumatoidarthritis,andsoon)Biopsyindicationdiagnosticapproachincaseofuncertainties,whenkidneyinvolvementissuspected,butabsoluteindicationsarenotmetRenalbiopsysuggestionsdifferbetweencentersduetolocalpreferences.Generalrecommendationsaredifficulttodefineandwewouldconsiderhigherlevelsofproteinuria`-2;˜.6;�愀(1g/d)comparedtotheEULAR/ERA-EDTArecommendationsasbiopsyindicationforpatientswithlupusnephritisinourcenter.KronbichlerandMayerBMCMedicinePage10of14http://www.biomedcentral.com/1741-7015/11/95 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