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A retrospective study of kidney transplant recipients from living unrelated donors

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A retrospective study of kidney transplant recipients from living unrelated donors
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  ARetrospectiveStudyofKidneyTransplantRecipientsfromLivingUnrelatedDonors RICARDOSESSO,*tMICHELLEA.JOSEPHSON, MEIDE S. AN#{231}AO,T SERGIOA.DRAIBE,*andDANIELSIGULEM *DivisionofNephrobogv,DepartmentofMedicineand HeabthInformaticsCenter,EscolaPaulistadeMedicina,UniversidadeFederaldeS {227}oaulo,S {227}oaulo,Brazil;and SectionofNephrobogy,DepartmentofMedicine,UniversityofChicago,Chicago,Illinois.Abstract. Duetotheshortageofeadavenicorgans,kidneysfromlivingunrelateddonors(LUD)areincreasinglybeing usedfortransplantation.Thelong-termoutcomeforLUDrecipientsisnotcompletelyknown.Thisstudywasundertaken toevaluatethelong-termgraftsurvivalinLUDrecipientsandcompareitwiththatofcadaverdonorallognaftrecipients.Threehundredandsixty-fourLUDand3881eadavenickidney recipientswereevaluatedusingdataobtainedthroughthe BrazilianRenalTransplantRegistry.TransplantsperformedbetweenJanuary1 , I987, andJune30,1996,wereeligiblefor analysis.Graftandpatientsurvivalwereestimatedbythe Kaplan-Meienmethod.SixtypercentoftheLUDwerefrom spouses.Themediandurationoffollow-upwas23.8mo(0to117.2mo).Patientsurvivalrateswerenotsignificantlydiffer- entforLUDandcadaveniekidneyrecipients(69%[95%con- fidenceinterval(CI),61.9to76.1%] versus 73.2%[71to75.4%]at5yr;69%[61.9to 76.l%I versus 60.6% [55.1 to 66.1 %] at9.6yr).GraftsurvivalratesforrecipientsofLUDallograftsweresimilartothoseforeadaveriekidneysat5yr (50.1%[43.2to57%] versus 50.4%[48.1to52.8%])andhigher,althoughnotsignificantly,at 9.6 yr(45.7%[37.7to53.7%] versus 32.7%[26.4to39%],respectively, P -0.14). InamultivaniateanalysisusingtheCoxproportionalhazards regressionmodel,afteradjustingforrecipientage,race,history ofprevioustransplantation,andyearoftransplantation,theriskofgraftfailurewas16%(95%CI,-3%to31%)lowerfor LUD thancadavenicrecipients.WeconcludethatLUDareanexcellentalternativetoeadaveniekidneydonors.Thelong-termpatientandgraftsurvivalratesforrecipientsofLUDallografts areatleastasgoodasthoseforrecipientsofeadaveriekidneys. (I AmSocNephrol9:684-691,1998) Transplantationistheoptimalrenalreplacementtherapytreat-mentformanypatientswithend-stagerenaldisease.However, therearenotenoughavailablecadaveniekidneydonors ( I,2).Patientsareoftenonadialysislistforyearsandmaydiewaitingforanallograft.Despiteattemptstoincreasetheavail-abilityofcadaverieorgans,thegulfbetweenpotentialnecipi-entsandthenumberofavailabledonorswidens(1-3).InBrazil,theaveragewaitforacadavenicallograftisapproxi-mately2yr.Weestimatethatin1996morethan1350patientsdiedonchronicdialysiswaitingforatransplant.InBrazil,manychronicrenalfailurepatientsdiewithoutbeingaccepted foranyformofrenalreplacementtherapy(4).However,even thosepatientsfortunateenoughtohaveawillinglivingrelated donor(LRD)maynotreceivethekidneybecauseofABO incompatibilityonapositivecrossmatch.Theuseofeadaveniedonorshasbeenincreasingoventhepastdecade.Cadaveriedonorsaccountedfor49.4%ofthe1674renaltransplantsReceivedJuly16.1997.AcceptedSeptember24,1997.Correspondence to Dr.RicardoSesso,EscolaPaulistadeMedicina,Division of Nephrology,RuaBotucatu740,S#{227}oaulo,SPBrazil04023-900andMichelleAJosephsonMD.University of Chicago.NephrologySection.5841S.Maryland Ave.MC5100.Chicago.IL60637.I()46-6673/09()4-0684$03.00/0JournaloftheAmericanSocietyofNephrologyCopyrightU1995bytheAmericanSocietyofNephrology performedin1996comparedwithonly28.5%in1988(5,6).Althoughthetotalnumberoflivingunrelateddonor(LUD) transplantsreportedtothenationalregistryalsoincreased,therelativeproportionoftransplantsperformedwithLUDde-creasedbetweentheperiodsfrom1987to1991and1992to 1996 from5.7%(165of2892)to3.5%(199of5690).InapreviousstudyofrecipientsofkidneysfromLUDinBrazil,followedforanaverageof15.8mo,wereportedthat they hadgraftsurvivalratescomparabletothoseofzero haplotype-matehedLRDandratesthattendedtobebetterthanthoseforeadaveniekidneyrecipients,althoughthesediffer-encesdidnotreachstatisticalsignificance(7).Table1sum-manizesthecurrentworld experiencewithlivingunrelateddonation.Atleast3285LUDtransplantshavebeenperformedbetween1966and1995.One-yearLUDgraftsurvivalwas reportedtobeaslowas20%beforetheintroductionofcyclosponine(10).Overallgraftsurvivalratesrangebetween83and93%for1yr.70to92%for3yr,and49to74%forfiveyr(7-12,15-20,22).Ofthesixstudiesthatreportedonboth LUD graftsurvivalsandsimultaneouslyperformedeadaveriedonortransplants,allreportedbetteroutcomesforLUDgrafts, althoughstatisticalsignificancewasrarelycalculated(7,8,12,15,16,22).OfthosethatcomparedLUDwithLRD,sevenhadcomparablegraftsurvivalrates,onehadbetterLUD thanLRDoutcome,andthreehadworseLUDthanLRDoutcome(7,8,11-13,15-19,22).  C . . Q- . . C . . C,, U   0. F- 0 C 0 .C > > > > > > > <<<< <<<< ocZ c ZZ oor-ZZr--r-- ZZZZ c c - ( - r tr r << < <<<<< 0 ZN ZZc c ZZxZZZZZ co oo I- > r 1 - . c I.. I >. ,_,_ . > N> >.> > > > > > o - c N r r’ - -. 222 4. m  C000\  ir 0 ‘fl(‘1 00 Z s Z r r-r-   Zo oco ocr- cZZZo oc >- !! - 4’,I’ Q\0\ C occ o r- o Zr-ooo’Z r a ooZZo’Z ZZZZZo o oc In 0\> - - t-. I_.,1-   C,, I_   >-.oc   oc -   > U > > > > _ 0’> > > > > > > . > > > > r > I< > > --( 1 -r - r n ,rCoc0. nCIn0. mC\InInococ Q r c c oc t- r oc in C ococ 0 o oc ,, oc   ocr- o c c - Z oc a InU oo I-  .I   oc ,   .-, .. - > > > _ 0 > > > r’- > - r r In - -   c #{231}  c c c ‘ , coc C-0. -ooIn -c\r-- o oco’o.ZZ-Z ZZZZZo’c oc 0’ >->->- - ilU >- oc . 0’   0’0’ . ococ oo 0. CN 0o. oc oc In (- “I’r Clr r -- -Int 1In 0’   - ocr- 1  -  rn  0 InS‘t In oc 0’0’0’0’0’0’0’0’0’0’000’0’ 0’O 0’ 0’ 0’0’0 0 0’0’0’0’0’ 0’ 000 oc0’ 00000000000 . 0’0’ InN In C t- r-In 0 r- 00 oc ocococococococ  ‘ oo  0 C C0 0’ 0’0’0’ I-   0’0 0’0’0’0’0’0’0’0’0’ --- 0. Z ------ - r 1  S   R z;   n == -.- r 0’0’ 0’ ! I 4 ;: II  I- z: #{149} #{176}   : #{176}‘ . : #{149} > . . Eo LL <oc >. O( - a. < n..U U . CO EE U .0 CO CO > CO 0 C z U 0 C 0 . . U > CO -u CO C) U 0 C 0  0 -u I) CO U C .; C)C 0 0. 0C) >1 C) C,, U C 0 CO C CO 0. C CO> CO F- . 0C) C 0 CO C) . 0a C 0 CO C CO 0. C CO I- C 0 C,, C) C,, C) C)C) I- 0 C)C) 0. C,, LivingUnrelatedRenalTrans’lantation685  656Journal of theAmericanSocietyofNephrology Shortfollow-uptimeandthesmallersamplesizemayhavelimitedtheabilityofour1992studytodetectsignificantdifferencesingraftsurvivalforlivingunrelatedandeadavericallognaftrecipients.Inthisreport,weextendedthemeanfol- low-upperiodforrecipientsofkidneyallograftsfromLUDto 33.3moandincreasedmorethantwofoldthenumberofpatientsevaluated.Themainobjectiveofthisstudywastoassessthelong-termgraftsurvivalinLUDrecipientsandcompareitwiththatofeadavenicdonorrecipients. MaterialsandMethods Fromatotalof8582transplantsperformedat94transplantcenters throughoutBrazilsince1987,364recipientsofkidneysfromLUD and3881recipientsofcadavericdonorswereincludedinthisstudy.ThedatawerecollectedbytheBrazilianRenalTransplantationReg- istry.avoluntaryregistryincludingalltransplantcentersinthecoun-try.Compliancewiththeregistryhasvariedduringthepast10yr.Theresponseratereachedmorethan95%in1992anddecreasedtoapproximately45%in1996.Confidentialityregardingpatientrecordsandtheresultsatindividualcentersisguaranteed. Themethodologyofdatacollectionandthelistofparticipating centerswerereportedpreviously(23).Briefly,usingstandardizedforms,weobtaineddatafromeachcenterregardingdemographiccharacteristics,clinicalfeatures,typeofdonor,graftfunction,losstofollow-up,anddeath.Alldatawerecollectedprospectivelyandwerereportedevery3motothestudycenteratEscolaPaulistadeMedicinainS#{227}oaulo.Alltransplantswith LUDorcadavericdonorsperformed betweenJanuary1,1987,andJune30,1996,wereconsideredeligibleforanalysis.Therewerenoexclusions.Thefollow-upperiodendedonSeptember30,1996.BeginninginJanuary1994,additionaldatahavebeencollectedregardingdurationofdialysis;baselinecomor-bidity;localofharvestingandcold-storagetimeforcadaverickid-neys:prophylacticuseofantilymphocyteglobulinandOKT3mono-clonalantibodies;panelreactiveantibodylevel;acutetubularnecrosis(ATN)(definedasdelayedrenalfunctionrequiringdialysiswithinthefirstweekoftransplant);HLAtyping;anddonorcharacteristics(age,sex,andrace).PanelTlymphocytereactivityandHLAtypingwereperformedinlessthan20%ofthepatients;therefore,thenumberofpatientsstudiedwiththesefactorsissmall,limitingpossibleconclu-sions.SerologicHLAtypingisusuallynotdonebeforeLUDandcadavenicdonortransplantationinBrazil.Ithasnotbeenusedasaroutinecriterionforselectionofrecipients.Themethodologyforgraftandpatientsurvivalcalculationshasbeendescribedpreviously(7).Recipientdeathswerecountedasgraftlosses.GraftandpatientsurvivalwasestimatedbytheKaplan-Meiermethod.Statisticalsignificancebetweensurvivalcurveswasassessedbythelog-ranktest.SurvivalcurvesforpatientgroupsclassifiedaccordingtothepresenceofATNordonoragehaveshorterdurationoffollow-upbecausethisinformationhasbeencollectedsince1994.Ifcentersdiscontinuedsendinginformation,thefollow-upofLUD (andcadavenic)kidneyrecipientsperformedinthesecenters was interruptedatthedateofthelastinformationsent. StatisticalAnalyses TheCoxproportionalhazardsregressionmodelwasusedtodeter- minetheindependentassociationsofseveralvariableswithgraftsurvival.Thevariablestestedincluded:typeofdonor;recipientage,gender.andrace;primarydisease;durationofdialysis;yearoftrans-plantation ; cold-ischemiatime;previoustransplantation;positivemarkersforhepatitisBonCvirus;placeofharvesting;panelofreactiveantibodieslevel;numberofHLAantigenmatches;ATN;donorage,gender,andrace;typeofcenteraccordingtothenumberof LUD transplantsdone;andcentercompliance.Toassesstheeffectofdonortypeandidentifyindependentassociations,twomultivariatemodelswereconstructed,includingdonortypeandthevariablesthatweresignificant (P < 0.10)inunivariateanalysis.Inthefirstmodel,thevariablestestedincludedthosewithavailableinformationsince thebeginningofthestudy,andinthesecondweaddedthevariables collectedafter1994.Adjustedhazardratios(riskratios[RRI)and 95% confidenceintervals(CI)forgraftfailurewerecalculated.Like-lihoodratiochi-squarestatisticswereusedtotestforthesignificanceofpredictorvariables.Theassumptionofproportionalityinthene-gressionmodelwasinvestigatedbylogminuslogsurvivalfunctionplots.Interactionsbetweentypeofdonorandtheothercovariatesofinterestwereexaminedinregressionmodelsinitiallycontainingtypeofdonor,acovariate,andtheinteractionterm.Subsequently,thisprocedurewasrepeatedinmultivaniatemodels.Interactionsbetweentimeoftransplantation( 1993. > 1993)andtheothercovaniatesweresimilarlyanalyzed.Continuouslydistributedvariableswerecomparedby t testortheMann-Whitney U testwhenappropriate.Chi-squaretestsortheFisherexacttestwereusedtocompareproportions.Allreported P valuesweretwo-tailed.StatisticalanalysiswasdoneusingBMDPStatisticalSoftware(LosAngeles,CA,1992). Results Of the 364transplantationswithkidneysfromLUD,218 (60%) werefromaspouseand146(40%)werefromsomeotherunrelateddonor.Demographicprofilesandclinicalchar- aeteristiesofrecipients,andfeaturesofthedonorsforLUDandeadavericdonorgroupsareshowninTable2.TheLUD groupwasslightlyolder,hadagreaterproportionofmen,includedmoretransplantsperformedbefore1992,andhadalowerproportionofretransplantedpatientsthantheeadaverie kidneyrecipientsgroup.RecipientsofLUDhadbeenondial-ysisfora shorterdurationoftimeandhadasignificantlylowerincidenceofATN.AssessmentofpanelTlymphocytereac-tivityandHLAtypingwasperformedinasmallpercentageof LUD andeadaverierecipients(reportedonlyafter1994).FortheHLA-Bantigen,thenumberofpatientswith0,1 , or2matcheswere,respectively,I9,7,and0forLUDrecipients (n = 26)and79,48,and13forcadaverierecipients (n = 140) (P, NS).ForHLA-DR,thecorrespondingvalueswere13,3, and0forLUDrecipients (n = 16)and45,44,and30for eadavenickidneyrecipients (n = 119) (P < 0.01).With regard todonorcharacteristics,theLUDwereolderandmorelikelyto bewomencomparedwiththeireadaveriecounterparts.Themedian(range)durationoffollow-upforpatientswithafunctioninggraftwas23.8mo(0to117.2mo)forLUDand 20.4mo(0to116.8)foreadavenierecipients.Fifty-oneLUDkidney recipients(22%ofthosewithafunctioninggraft)werefollowedformorethanSyr.Sevenhundredandsevendeathsand1524graftfailuresoccurredduringthestudyperiod.Of these,70andI31 , respectively,occurredinLUDrecipients.PatientsurvivalrateswerenotsignificantlydifferentforLUDandeadaveriekidneyrecipients(69.0%[95%CI,61.9to76.1%] versus 73.4%[71to 75.4%1 atSyrand69.0%[61.9to76.1%] versus 60.6%[55.1 to66.l%1at9.6yr.respectively; P = 0.90). GraftsurvivalratesforrecipientsofLUDwere  Medianage(yr)34240375638’>45yr.105(31)1078(29) Malesex 364 270(74)38812401(62)c Race3633839black96(27)1072(28) non-black267(73)2767(72) Primarydisease3553790glomerulonephnitis136(38)1474(39) diabetesmellitus16 (5) 160(4) hypertension60(17)640(17)otherorunknown143(40)1516(40)Comorbidconditions hypertension4534(76)775551(71) cardiacdisease459(20)761178(23) HBsAg-positive452(4)73562(8)anti-HCV-positive326 ( 19)615111(18) Median(range)durationofdialysis(mo)6018(3to84)93028(Ito198)’ Yearoftransplantation>1992 364 110(30)38811772(46)c Prior transplantation35713(4)3833 264 (7)d Cold-isehemiatime>24hNA873303(35)HarvestingNA910local509(56) othercenter401(44) Acutetubularnecrosis567(13)879499 (57)C PanelTlymphocytereactivityS165mean(SEM)3.0(3.0)9.8(1.5) >10%1(20)34(21) Mean(SEM)HLA-antigenmatches A270.33(0.12)1450.55(0.05) B260.27(0.45)1400.53(0.66) DR160.19(0.10)1190.90(0.07)c Tripleimmunosuppressiveregimen’ 341276(81 ) 36983001(81)Anti-OKT3orantilymphocyteglobulin60 904 prophylactictreatment2(3)33(4)Mediandonorage(yr)653589726C >45yr9(14)108(12) Donormalesex 218 55(25) 910623(69)e Donorrace, n (%) 69851 black14(20)182(21) non-black55(80)669(79) a HBsAg,hepatitis B surfaceantigen; HCV, hepatitisCvirus;NA,notapplicable.OtherabbreviationsasinTable1. b Numberofpatientswithavailableinformation.Valuesare n(%) unlessotherwiseindicated. C p < 0.01forthecomparisonwithLUDgroup. dp< 005 C Prednisone,azathioprine,andcyclosporine. t IntheLUDgroup,the valuesareonlyforspousaldonors. LivingUnrelatedRenalTransplantation687 Table2. CharacteristicsofkidneytransplantrecipientsaccordingtotypeofdonorC Characteristic nb LUD nb Cadavenicsimilartothoseforeadaverickidneyrecipientsat5yr(50.1% 143.2 to57%] versus 50.4%[48.1 to52.8%])andhigher,althoughnotsignificantly,at9.6yr(45.7%[37.7to53.7%] versus 32.7%[26.4to 39%], respectively; P = 0.14 forcorn-parisonoftheoverallcurves)(Figure1).Figure2showsthecomparisonsofgraftsurvivalratesaccordingtothedonor’sage.Thesurvivalratesforkidneysfromyoungerdonorswerehigherthanthoseforolderones.However,graftsurvivalratesforLUDkidneyswerenotsignificantlydifferentthanthoseforcadaveriegraftswithineachagecategory.ThesmallnumberofolderLUDandtheshorterlengthoffollow-upofrecipientsinwhomthisinformationwasavailablelimitthepowerofthese  . OLUD - OCAD 1.0 Iv >  E 0.8 U 0.6 0 0  .4 .0 IV  0.20.0 0 0CADwithoutATN t&CADwith ATN II III 1.0 IV  E 0.8 Cl)  0.6 0 0 .0 IV  0.20.0 11i11,i,IIIIIIIIIIIII 012345678910 YearsafterTransplantation 0364221 149 103755128198303 19761371 927543347 17284408 Figure1. Graftsurvivalbydonortype.Graftsurvivalforrecipientsof a kidneyfromlivingunrelateddonor(LUD)oncadavenicdonor (CAD). P = 0.14forthecomparisonbetweenthecurves.Atthebottomofthegrapharethenumbersofpatientsatriskatthebegin-flingofeachtimeinterval. I.0 (V E 0.8 U 0.6 C, 0  .4 .0 IV .0 0 0.0 0 0 380 A 499 3.0.5 130 1316 . LUD 35 yr. S CAD   35yr. . DLUD>35yr. . OCAD>35yr. L i 0 III 0.51.01.52.0 Years after Transplantation U . 37 637 1918 290207 13 115 3 63 0 28121163026094713516 Figure2. SurvivalofCADandLUDgraftsaccordingtodonor’sage. Theagedistributionofthedonorsisshowninthelegend. P = 0.02 forthecomparisonCAD 35yr versus CAD >35yr. P = 0.07forthecomparisonLUD 35yr versus LUD>35 yr. P = 0.08forthecomparisonLUDS35yr versus CAD>35 yr. P = 0.06forthe comparison LUD>35 yr versus CAD 35 yr. Atthebottomofthegrapharethenumbersofpatientsatriskatthebeginningofeachtimeinterval.analyses.TheeffectofATNduringthefirstweekoftrans-plantationongraftsurvivalinrecipientsofeadaverieallognafts comparedwithgraftsurvivalinLUDrecipientsisshowninFigure3.LUDrecipientshadsignificantlybettersurvivalratesthanthoseofeadaverierecipientswithATNandinferiorout-comescomparedwiththoseofeadavenicrecipientswithout ATN.TransplantationofLUDkidneyswasdoneat58(61.7%)ofthe94centers.Amongthese58centers,themediannumberof LUD transplantswas3(range.1to46).Nineteencenters 688JournaloftheAmericanSocietyofNephrology 00.51.01.52.0 YearsafterTransplantation 241 221189149189128 7042 189 1417949 Figure3. SurvivalofCADkidneygraftsaccordingtopresenceofacutetubularnecrosis(ATN)duringthefirstweekcomparedwiththe LUD group. P = 0.04 forthecomparisonbetweenLUDandCADwithoutATN. P 0.02forthecomparisonbetweenLUDandCADwithATN. P < 0.01forthecomparisonbetweenCADgroupswithandwithoutATN.Atthebottomofthegrapharethenumbersofpatientsatriskatthebeginningofeachtimeinterval. performedbetweenoneandfiveLUDtransplants,and19centersdidmorethanfiveLUDtransplants.Overall, 44.7%(42of94)ofthecenterswerecompliantwiththeregistry.Twenty-sevenof63(42.9%)centersaffiliatedwiththeregistry until1992and15of31(48.4%)registeredafter1992contin-uedtosendinformationuntiltheendofthestudyperiod.ThenumberofLUDtransplantsperformedincompliantcenters waslowerthanthatperformedinnoneompliantones ( I69 and 195, respectively).TheproportionoftransplantsperformedincompliantcenterswasgreaterforeadaveriethanforLUDkidneyrecipients(62.8% versus 46.4%, P < 0.001).Among LUD recipients,graftsurvivalwasnotsignificantlydifferent betweentransplantsdoneatcompliantandnoneompliantcen- tens(59.1%[50.9to67.3%] versus 58.6%[50to67.2%],at3yn). Foreadaveriekidneyrecipients,thecorrespondingvalueswere58.9%(56.7to61.1%)and54.6%(50.9to58.3%) (P> 0.20).Graftsurvivalrateswerenotsignificantlydifferentbe-tweenLUDandeadaveniekidneyrecipients,eitherincompli- ant(59.1% versus 58.9%,respectively,at3yn)oninnoncom-pliantcenters(58.6% versus 54.6%,at3yr). Inunivaniateproportionalhazardsanalysis,theriskofgraft failurewaslowerforLUDthanforeadavenierecipients(RR,0.87;95% CI,0.73 to1.05),althoughtheydidnotdiffer statistically.Fortheanalysisofvariablesassociatedwithgraftsurvival,weseparatedcadaverieandLUDrecipients.Inthe formergroup,blackrecipientracewasassociatedwitha19% increasedriskofgraftfailure.Transplantsperformedbefore 1993hada20%greaterriskoffailure.Retransplantedpatientshada47%increasedriskofgraftfailure.Delayedrenalfunc- tionduringthefirstweekoftransplantationandoldendonorageincreasedthisrisktwofold.ForLUDrecipients,donorage>45yranddonormalesexsignificantlyincreasedtheriskofgraftfailure(RR,3.20;95% CI,0.98 to10.65;andRR,1.74;
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