Preemptive kidney transplantation in elderly recipients with kidneys discarded of very old donors: A good alternative

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RevistadelaSociedadEspañoladeNefrología

www . r e v i s t a n e f r o l o g i a . c o m

Original

article

Preemptive

kidney

transplantation

in

elderly

recipients

with

kidneys

discarded

of

very

old

donors:

A

good

alternative

Enrique

Morales

,

Eduardo

Gutiérrez,

Ana

Hernández,

Jorge

Rojas-Rivera,

Esther

Gonzalez,

Eduardo

Hernández,

Natalia

Polanco,

Manuel

Praga,

Amado

Andrés

ServiciodeNefrología,Hospital12deOctubre,Madrid,Spain

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received22August2014 Accepted18February2015 Availableonline18June2015

Keywords:

Pre-emptivekidneytransplantation Elderlyrecipient Elderlydonor Discardedorgans Graftsurvival Patientsurvival

a

b

s

t

r

a

c

t

Background:Theshortageoforgansisamajorhurdleinkidneytransplantation,andone solutiontotheproblemistoextendtheageofthedonor.However,organsfromolderdonors areoftendiscardedduetothemacroscopicappearanceoftheparenchymaormajorvessels. Ontheotherhand,alargenumberofelderlypatientsarepotentialcandidatesforkidney transplantation,whilemanykidneysfromelderlydeceaseddonorsarediscardedduetoa lackofage-matchedrecipients.Inaddition,alargenumberareoftendiscardedduetothe lackofcompatiblerecipientsamongelderlypatientsundergoingchronicdialysis.Apossible solutiontoavoidthiswastageofkidneyspotentiallysuitablefortransplantationcouldbe theperformanceofpreemptivekidneytransplantation(PKT)incarefullyselectedelderly patients.PKTimprovesgraftandpatientsurvivalcomparedtoother renalreplacement therapyoptions.ThereisnoinformationaboutPKTinelderlypatientsreceivingkidneys fromelderlydeceaseddonors.

Methods:From2007to2012,weperformedaprospectiveobservationalstudycomparing26 elderlypatientsreceivingPKTwithacontrolgroupof26elderlypatientsreceivingafirst transplantafterpriordialysis.

Results:Meanageofrecipients was74.3±2.9yearsandmeanageofdonorswas73.8± 4.1years.Inductionimmunosuppressionwassimilarinbothgroups.Death-censoredgraft survivalwas96%inthePKTgroupand68%inthecontrolgroup(p=0.02),at5yearsafter transplantation.Immediateanddelayedgraftfunctionoccurredin92%and3.8%, respec-tively,ofpatientsinthePKTgroupand53%and34.6%ofpatientsinthecontrolgroup (p=0.005).AcuterejectionwassignificantlymorefrequentinPKTpatients(23.1%vs3.8%,

p=0.043).Attheendoffollow-uptime35.5±20.1months,theglomerularfiltrationratewas similarinboth groups (42.2±11.7vs 41.7±11.2ml/min,p-value=0.72). Patientsurvival wassimilarinthetwogroups.

Correspondingauthor.

E-mailaddress:emoralesr@senefro.org(E.Morales).

http://dx.doi.org/10.1016/j.nefro.2015.05.010

0211-6995/©2015TheAuthors.PublishedbyElsevierEspaña,S.L.U.onbehalfofSociedadEspañoladeNefrología.Thisisanopenaccess articleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Conclusions:Elderlypatientswithendstageofrenaldiseasenon-dialysismaybenefitfrom PKTelderlydeceaseddonorswhosekidneysweretobediscardedfortherearenotpatients inthewaitinglist.

©2015TheAuthors.PublishedbyElsevierEspaña,S.L.U.onbehalfofSociedadEspañolade Nefrología.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Trasplante

renal

prediálisis

en

pacientes

ancianos

con

ri ˜nones

descartados

de

donantes

de

edad

muy

avanzada:

una

buena

alternativa

Palabrasclave:

Trasplanterenalprediálisis Receptoranciano

Donanteanciano Órganosdesechados Supervivenciadelinjerto Supervivenciadelpaciente

r

e

s

u

m

e

n

Antecedentes:Laescasezdeórganosconstituyeunaimportantedificultadparalostrasplantes renales,yunaposiblesolucióndelproblemaestáenampliarelmargendeedadaceptado paralosdonantes.Sinembargo,losórganosdedonantesdeedadavanzadasedesechan confrecuenciadebidoalaspectomacroscópicodelparénquimaodelosvasossanguíneos principales.Porotrolado,hayungrannúmerodepacientesancianosquesonposibles candidatosauntrasplanterenal,mientrasquemuchosri ˜nonesdedonantesancianos fa-llecidossedesechanporquenohayreceptoresdeunaedadsimilar.Además,amenudose desechaungrannúmerodeórganosacausadelafaltadereceptorescompatiblesentrelos pacientesancianosendiálisiscrónica.Unaposiblesoluciónparaevitarquesedesperdicien estosri ˜nonesquepuedenserapropiadosparauntrasplanteseríallevaracabountrasplante renalprediálisis(TRP)enpacientesancianoscuidadosamenteseleccionados.ElTRPmejora lasupervivenciadelórganotrasplantadoydelpaciente,encomparaciónconotrasopciones deterapiasustitutivarenal.NodisponemosdeinformaciónacercadelTRPenpacientes ancianosalosquesetrasplantanri ˜nonesdedonantesancianosfallecidos.

Métodos:De2007a2012llevamosacabounestudioprospectivoobservacionalenelquese compararon26pacientesancianosquerecibieronunTRPconungrupodecontrolformado por26pacientesancianosalosquesepracticóunprimertrasplantedespuésdeunadiálisis previa.

Resultados:Lamediadeedaddelosreceptoresfuede74,3±2,9a ˜nosyladelosdonantes de 73,8±4,1a ˜nos. Lainmunosupresiónde inducciónfuesimilarenlosdos gruposde tratamiento.Lasupervivenciadelórgano,concensuraparaelanálisisestadísticoalamuerte delpaciente,fuedel96%enelgrupodeTRPydel68%enelgrupodecontrol(p=0,02), 5a ˜nosdespuésdeltrasplante.Hubounafuncióninmediataytardíadelri ˜nóntrasplantado enel92%y3,8%delospacientes,respectivamente,enelgrupodeTRP,yenel53%y34,6% delospacientesenelgrupodecontrol(p=0,005).Elrechazoagudofuesignificativamente másfrecuenteenlospacientesalosquesepracticóunTRP(23,1%frentea3,8%,p=0,043). Alfinaldelperiododeseguimientode35,5±20,1meses,lafiltraciónglomerularfuesimilar enambosgrupos(42,2±11,7frentea41,7±11,2ml/min,valordep=0,72).Lasupervivencia delospacientesfuetambiénsimilarenlosdosgrupos.

Conclusiones:Enlospacientesancianos conuna enfermedadrenal terminalno dializa-dos,puederesultarbeneficiosounTRPdedonantesancianosfallecidoscuyosri ˜nonesse desecharíansinohubierapacientesenlistadeespera.

©2015TheAuthors.PublicadoporElsevierEspaña,S.L.U.ennombredeSociedadEspañola deNefrología.EsteesunartículoOpenAccessbajolalicenciaCCBY-NC-ND

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Inrecentyears,thenumberofpatientsolderthan65years withendstagerenaldisease(ESRD)hasincreased1andisnow thefastestgrowingpatientpopulationrequiringrenal replace-menttherapyinbothEuropeandtheUnitedStates.Kidney transplantationimproveslifeexpectancyandqualityoflifein patientsofallageswithESRD2,3andisanattractiveoptionfor elderlypatients,inwhomitconferslowermortalityratesand

improvedqualityoflifecomparedtodialysis.4,5 However,a vastmajorityofkidneytransplantsinelderlypatientsare per-formedafteraperiodofchronicdialysis,andinthoseelderly patientsinwhomapreemptivekidneytransplant(PKT)is per-formedtheorgancomesfromalivingdonor.Noexperience about PKTusingkidneys fromelderlydeceaseddonorshas so farbeen reported.Thislackofinformationisimportant becausePKTistheidealtreatmentforpatientswithadvanced chronickidneydisease(CKD).NotonlydoesPKTobviatethe

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need forvascular access or the placement of aperitoneal catheter, thus reducing the cost of dialysis and improving the qualityoflifeof thepatient,6 but moreimportantly, it alsoextendsthesurvivalofpatientscomparedtoother ther-apeutic optionsand attainssuperior outcomes interms of bothgraftandpatientsurvivalthantransplantationafterprior dialysis.7,8 Infact,timespentondialysispriorto transplan-tation has been shown to be one of the most significant factorsaffectingthe outcome ofkidneytransplantation.9,10 Ontheotherhand,theonsetofchronicdialysis(buildingof asuccessfulvascularaccessforhemodialysis,orperitoneal catheterplacement)ismorechallenginginelderlypatients, thusreinforcing thetheoreticaladvantagesofPKT inthese patients.

Theshortageoforgansisalimitingfactorforkidney trans-plantationinallagerangesandhasledtotheuseofexpanded criteria donors, including those aged over 60 years.4,11 In Spain,50% ofdonorsare older than 60and up to25% are olderthan70.Kidneytransplantationwithexpandedcriteria donororganshasbeenassociatedwithlongersurvivalthan dialysis,3 butdataarelimitedonelderlypatients.Although graftsurvivalisgenerallypoorerwitholderthanwithyounger donors,whenkidneysareselectedbasedonrenalfunction, macroscopicexaminationandhistologicalinformation, excel-lentresultscanstillbeattained.12Inspiteoftheshortageof organs,asignificantnumberofkidneysfromolderdeceased donors are not used because of donor hypertension, dia-betesorrenalfailure,macroscopicormicroscopicalterations inthe kidney,or importantly, the lackofa suitable recipi-ent.In a previous study,we foundthat more than 50% of kidneys from older donors were discardedmainly because therewasnopotentiallycompatiblerecipientonthewaiting list.13

Inorder toavoidthe wasting ofkidneysfrom deceased elderlydonorsduetothelackofcompatiblerecipientsamong elderly patientsundergoing chronic dialysis,we created in January2007awaitinglistofpredialysiselderlypatientsto receive thesekidneys. Herewe reportour experience with this cohort of elderly patients receiving PKTs from elderly deceaseddonorsandcompareitwiththatofacohortofelderly patientswhoreceivedakidneytransplantaftertheonsetof chronicdialysis.

Patients

and

methods

Patientsandstudydesign

This is a longitudinal, prospective, observational study of patients undergoing PKT at a single center. From January 2007toDecember2012,weconsecutivelyenrolled26patients undergoingPKTattheDepartmentofNephrologyand Trans-plantation in the Hospital 12 de Octubre, Madrid, Spain. Inclusion criteria were age >65 years, advanced CKD, GFR accordingtothefour-variableMDRD<15ml/min,progression ofrenalfailure(25%decreaseinGFRoverthepast12months), nopriorkidneytransplant,andnon-hyperimmunizedstatus. Exclusioncriteriawerestablerenalfunction(<25%decrease inGFR),activetumor,multiple=“multiple”aortoiliac calcifi-cations,andmedicaland/orsurgicalcontraindications.The

studywasapprovedbytheInstitutionalReviewBoardofthe Hospital 12 de Octubre, and all patients gavetheir signed informedconsent.

Thecontrolgroupcomprisedanadditional26patientsaged >65yearswhoreceivedafirstkidneytransplantaftertheonset of chronicdialysis. Thirteen(50%) ofthe controlsreceived pairedkidneysfromthesamedonorsasthePKTpatients;the remainingrecipientswereselectedascontrolsbecausetheir transplantswereperformedimmediatelybeforeorafterthe PKTpatients.

Thefollowingdonorvariableswererecorded:age,gender, ABO blood group, BMI,history ofhypertension or diabetes mellitus,cytomegalovirus(CMV)immunization,viralhepatic infections,sepsis,causeofdeath,serumcreatinine(Scr)levels atprocurement,estimatedGFRaccordingtothefour-variable MDRD, cold ischemia time, warm ischemia time, kidney anatomy, and perfusion solution. The following recipient characteristicswererecorded:age,underlyingrenaldisease, timeondialysis,serology,immunologicaldata,BMI,arterial hypertension, hyperlipidemia, diabetes, pre-transplant car-diovasculardisease,waitingtimeforkidneytransplant,type ofdialysis(hemodialysisorperitonealdialysis),panel-reactive antibodies, HLA-A, HLA-B, and HLA-DR mismatches, and baseline immunosuppression. Post-surgical complications, infections,tumors,modificationofimmunosuppression,and length of hospital stay were also recorded. Renal func-tion and proteinuria were recorded weekly duringthe first month,everythreemonthsduringthefirstyear,andannually thereafter.

Mainoutcomes were graftsurvivaland patientsurvival. Secondaryoutcomeswereimmediategraftfunction,delayed graftfunction(definedastheneedforatleastone hemodial-ysissessionduringthefirstweekpost-transplantation),and biopsy-provenacuterejection(BPAR).Causesofgraftlossand causesofdeathwerealsorecorded.Graftsurvivalwas calcu-latedfromthedateoftransplantationuntildeath,returnto dialysis,ortheendofthestudyperiod.Death-censoredgraft survivalwascalculatedwhendeathoccurredwithfunctioning graft.

Statistics

Continuousvariableswereexpressedasmeanandstandard deviationorasmedianandrange,asappropriate. Categori-calvariables wereexpressedasfrequenciesorpercentages. Student’sttestortheMann–WhitneyUtestwasusedto com-parecontinuousvariables.Qualitativevariableswereanalyzed with thechi-squaredtest withYates’correctionor Fisher’s exact test.Graft andpatientsurvivalwere calculatedusing the Kaplan–Meiermethodandcomparedwiththe log-rank test.Univariateandmultivariateregressionanalyses(witha backwardstepwiseprocedure)wereperformedwiththeCox proportionalhazardsmodeltoobtainhazardratios(HRs)with their95%confidenceintervals(CIs).Allfactorswithp<0.05 inthe univariateanalysisand all clinicallyrelevantfactors withp<0.2inthe univariateanalysiswere included inthe multivariatemodel. Significancewasset atp<0.05.All sta-tisticalanalyseswereperformedwithIBMSPSSStatisticsfor Windowsversion15.0.

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Results

Donorandrecipientcharacteristics

Fifty-twopatientswereenrolledinthestudy:26(11women,15 men)PKTsand26(13women,13men)controls.Table1shows thebaselinecharacteristicsofthetransplantrecipients.Mean agewas74.3±2.9years(range68–81years)inthePKTgroup and73.4±4.1years(range65–79years)inthecontrolgroup. All26patientsinthePKTgrouphadhypertension,compared toonly18(69.2%)inthecontrolgroup(p=0.02).Therewere no other significant differences in baseline characteristics between the two groups (Table 1). In the control group, the interval between onset ofchronic dialysis and kidney transplantationwas15±14months(range3–62).Twenty-five

recipients(96.2%)ineachgroupreceivedquadruple immuno-suppressivetherapywithinterleukin-2receptorantagonists, lowdosesofcalcineurininhibitors,mycophenolatemofetil, andcorticosteroids.Inductiontreatmentconsistedof basilix-imab,ananti-intcrleukin-2receptormonoclonalantibody,in 50patients(96%)andoftimoglobulinintwo(4%).

Table 1 displays the baseline characteristics of the

donors. Mediandonor age was 73.8±4.1 years (range, 65– 80 years) in the PKT group and 74.4±5.1 years (range 65–84years)inthecontrolgroup.Therewerenosignificant differences in baseline characteristics between the two groups.ThemedianScrlevelatthetimeofprocurementwas 0.7mg/dl (range0.5–1.1mg/dl) inbothgroups. Median esti-matedGFRwas90.4±19.6ml/min/1.73m2inthePKTgroup

and 94.2±24.3ml/min/1.73m2 inthecontrol group.Kidney

biopsywasperformedin16donorsinthePKTgroupandin20

Table1–Baselinerecipientanddonorcharacteristics.

Recipientcharacteristics PKTgroup

(N=26) N(%) Controlgroup (N=26) N(%) p-Value Age,yrs Mean(SD) 74.3(2.9) 73.4(4.1) 0.34 Gender Male 15(57.7) 13(50) 0.56 Female 11(42.3) 13(50) CauseofESRD Hypertensivenephropathy 10(38.5) 6(23.1) 0.23 Diabetes 4(15.4) 6(23.1) 0.48 Chronicglomerulonephritis 3(11.5) 5(19.2) 0.44 Hypertension 26(100) 18(69.2) 0.02 Diabetes 9(34.6) 10(38.5) 0.77 Dyslipemia 8(30.8) 8(30.8) 1.0

Ischemicheartdisease 5(19.2) 3(11.5) 0.44

Peripheralarterialdiseases 5(19.2) 1(3.8) 0.08

Cerebrovascularaccident 1(3.8) 1(3.8) 1.0

Neoplasia 1(3.8) 4(15.4) 0.16

HepatitisCvirusinfection 2(7.7) 2(7.7) 1.0

Donorcharacteristics PKTgroup

(N=26) N(%) Controlgroup (N=26) N(%) p-Value Age,yrs Mean(SD) 73.8(4.1) 74.4(5.1) 0.63 Gender Male 14(53.8) 17(65.4) 0.39 Female 12(46.2) 9(34.6) Causeofdeath

Acutecerebrovascularaccident 20(76.9) 21(80.8) 0.73

Cranioencephalictrauma 4(15.4) 3(11.5) 0.68

Serumcreatinine(mg/dl)a 0.7(0.1) 0.7(0.1) 0.98

GFR(MDRD)(ml/min/1.73m2)a 90.4(19.6) 94.2(24.3) 0.54

Donorrenalbiopsy 16(61.5) 20(76.9) 0.23

Glomerulosclerosissamedonor(N=10)a 6.9(3.7) 9.6(5.2) 0.20 Glomerulosclerosisdifferentdonor(N=6y10)a 7.4(7.6) 5.9(7.9) 0.71

HLAmismatches≥3 5(19.2) 4(15.4) 0.71

Coldischemiatime(hours)a 21.4(5.3) 21.6(4) 0.88 Baselineimmunosuppressionwithbasiliximab+tacrolimus+mycophenolatemofetil+steroids 25(96.2) 25(96.2) 1.0 a NumbersreflectmeanandSD.

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Initial cohort of study (n=52)

Control group (n=26) Preemptive transplant group

(n=26)

Patients alive with preserved renal

function (n=24)

Patients without preserved renal function (n=7)

Month 0:

- Thrombosis (n=1) - Ischemia-reperfusion (n=1) - Death by ischemic cardiopathy with non-functioning graft (n=1) Month 2:

- Death by sepsis with functioning graft (n=2) - Death by ischemic cardiopathy with functioning graft (n=1) - Urinary fistula (n=1)

Patients alive with preserved renal

function (n=19)

Patients without preserved renal function (n=2)

Month 0:

- Death by sepsis with functioning graft (n=1) Month 1:

- Death by liver failure with functioning graft (n=1) End of follow-up (n=22) End of follow-up (n=18) Month 24: -Return to dialysis Month 24:- Death by sepsis with

functioning graft Month 43:- Death by ischemic cardiopathy with functioning graft

Fig.1–Flowchartshowingdispositionofpatientsinthestudy.

inthecontrolgroup,andthepercentageofscleroticglomeruli was6.3%(range4.2–10%)and5.8%(4–15%),respectively.

Mediancoldischemiatimewas21.4±5.3h(range7–33.3) inthePKTgroupand21.6±4h(range8.2–26.3)inthecontrol group(Fig.1).

Mainoutcomes

Theactuarial1-, 3-,and 5-yeargraft survival rates (death-censored)were96%,96%and96%inthePKTgroupand76%, 68%and 68%inthecontrolgroup(p=0.02)(Fig.2).Primary non-functionwas observedin one patient (arterial throm-bosis)in the PKT group and inthree in the controlgroup (twocasesofarterialthrombosisandoneofvenous throm-bosis) (Table 2). Early graft loss (less than three months) occurredinonepatient inthe PKTgroup(death from liver failure with functioning graft) and in four patients in the controlgroup (one deathwithgraft thrombosis, onedeath from sepsis,onedeath from heartattack, and oneurinary fistula).

Theactuarial1-,3-,and5-yearpatientsurvivalrateswere 92%,78%and78%inthePKTgroupand83%,83%and83%in thecontrolgroup(Fig.3).Onepatientineachgroupdiedwith afunctioninggraft.Fourpatientsdiedineachgroup.Causes ofdeathinthePKTgroupweresepsis/multi-organfailure(2), acuteliverfailure(1)andunclear(1).Causesofdeathinthe controlgroupweresepsis/multi-organfailure(2)andcardiac failure(2)(Table2).

Secondaryoutcomes

Delayed graft function was observed in one patient (3.8%) in the PKT groupand in nine (34.6%)in the controlgroup (p=0.005).Sixpatients(23.1%)inthePKTgroupexperienced BPAR: fourwithacutecellularrejectionand twowithacute humoral rejection. One patient (3.8%) inthe control group experiencedacutecellularrejection(p=0.043)(Table3).After amedianfollow-upof34months,24patientsinthePKTgroup and19inthecontrolgrouphadpreservedrenalfunction with-outtheneedfordialysis(Fig.1).Attheendofthestudy,renal

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Table2–Causesofgraftloss. Cause PKTgroup (N=26) N(%) Controlgroup (N=26) N(%) p-Value Primarynon-function 1(3.8)a 3(11.5)b 0.29

Delayedgraftfunction 1(3.8) 9(34.6) 0.005

Earlygraftloss(≤3months) 1(3.8)c 4(15.4)d 0.15

Acuterejection 6(23.1) 1(3.8) 0.043

Cellular 4(66.7) 1(100)

Humoral 2(33.3) 0(0)

Exituswithafunctioninggraft 3(75) 1(25) 0.15

Totalnumberofdeaths 4(15.4)e 4(15.4)f 1.0

Returntodialysis 0(0) 4(15.4) 0.03

a Arterialthrombosis.

b Venousthrombosis(1),arterialthrombosis(2). c Deathfromliverdiseasewithfunctioninggraft.

d Deathfrominfection(1),deathfromischemicheartdisease(1),venousthrombosis(1),urinaryfistula(1). e Infection(2),liverdisease(1),cardiovasculardisease(1).

f Infection(2),ischemicheartdisease(2).

functionwassimilarinthetwogroups(PKT:Scr1.7±0.8mg/dl and GFR-MDRD 42.2±18.3ml/min/1.73m2; control: Scr

1.6±0.9mg/dl and GFR-MDRD 40.4±13.8ml/min/1.73m2).

Proteinuriawas0.6g/24hinthePKTgroupand0.3g/24hin thecontrolgroup (p=0.08)(Table3and Fig.4).Nopatients inthe PKTgroupandfourinthecontrolgroupreturned to dialysis(p=0.03).

Duringfollow-up,immunosuppressionconsistedofa com-binationoftacrolimus,mycophenolicacidandsteroidsin67% ofallpatients.Otherimmunosuppressiveregimensusedwere similar inthe two groups. Tacrolimus levels at the end of follow-upwere6.9±2.3inthePKTgroupand7.5±2.6ng/ml inthecontrolgroup(p=0.43).

CMVinfections andurinarytractinfectionsweresimilar inthetwogroups.Urologicalcomplicationsandtumor inci-denceswerealsosimilarinthetwogroups,whileaslightly highernumberofcardiovascularcomplicationsand periph-eralarterialdiseaseswereobservedinthePKTgroup(p=0.06)

(Table4).

Clinicalfactorsassociatedwithgraftsurvival

In the univariate analysis including age, time on dialysis, delayedgraftfunction,HLAincompatibility,belongingtoPKT group,diabetesmellitus,serum creatinineatmonth6, pro-teinuriaatmonth6,andthedifferenceinGFRbetweenmonth 6andendofstudy,onlythosebelongingtoPKTgroupwere associated with improved outcome (p=0.049). Multivariate logistic regression analysys was performed and the factor belongingtoPKTgroupdidnotreachstatisticalsignificance (HR=0.18;95%CI,0.03–1.02;p=0.053)(Table5).

Discussion

Theshortageoforgansisamajorhurdleinkidney transplanta-tion,andonesolutiontotheproblemistoextendtheageofthe donor.However,organsfromolderdonorsareoftendiscarded due to the macroscopic appearance ofthe parenchyma or

Table3–Evolutionofrenalfunctionandproteinuria.

Variable PKTgroup (N=24) Controlgroup (N=19) p-Value Serumcreatinine(mg/dl) 6months(PKT=24/CG=19patients) 1.7±0.7(0.9–3.9) 1.5±0.4(0.8–2.5) 0.23 12months(PKT=24/CG=19patients) 1.5±0.4(1–2.8) 1.5±0.5(0.9–3.1) 0.86

Endoffollowup(PKT=22/CG=18patients) 1.7±0.8(0.7–4.2) 1.6±0.9(0.8–5) 0.78 GFR(MDRD)(ml/min/1.73m2)

6months(PKT=24/CG=19patients) 39.5±14.6(15.2–73) 41.9±11.9(19.2–72.1) 0.58 12months(PKT=24/CG=19patients) 42.7±11.7(21.9–65) 41.7±11.2(14.7–58) 0.80 Endoffollowup(PKT=22/CG=18patients) 42.2±18.3(13.7–87) 40.4±13.8(8.4–72.1) 0.72 DeclineinGFR(6months–endoffollow-up)(ml/min/1.73m2peryear) +0.9±0.5(−5.9to12.8)

1.2(−2.9to3.8) +0.1±3.4(−6.9to5.3) 0(−2.1to2.5) 0.52 Proteinuria(g/24h) 6months(PKT=24/CG=19patients) 0.4(0.2–0.9) 0.4(0.2–0.6) 0.31 12months(PKT=24/CG=19patients) 0.5(0.2–1) 0.3(0.2–0.5) 0.09

Endoffollow-up(PKT=22/CG=18patients) 0.6(0.3–1) 0.3(0.2–0.4) 0.08

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Table4–Majorsurgicalandmedicalcomplications. Complication PKTgroup (N=26) N(%) Controlgroup (N=26) N(%) p-Value Infection 10(41.7) 9(47.4) 0.70 Urinarytract 3(30) 4(44.4) 0.45 CMV 3(30) 4(44.4) 0.45 Urologicalproblem 10(38.5) 10(38.5) 1.0 Urinaryfistula 2 4 Wounddehiscence 1 1 Seroma 3 2 Arterialstenosis 2 2 Ureterstenosis 2 1 Tumor 2(8.3)a 2(10.5)b 0.80 Cardiovasculardisease Hypertension 22(91.7) 17(89.5) 0.80 Diabetes 10(41.7) 7(36.8) 0.75 Dyslipemia 11(45.8) 11(57.9) 0.43

Ischemicheartdisease 7(29.2) 3(15.8) 0.30

Cerebrovascularaccident 1(4.2) 0 0.36

Chroniclimbischemia 4(16.7) 0 0.06

a Colon(1),Kaposi’ssarcoma(1). b Skin(1),Kaposi’ssarcoma(1).

Table5–Riskfactorsforgraftsurvival.

Factor Univariate analysis HR(95%CI) p-Value Multivariate analysis HR(95%CI) p-Value Age 1.1(0.90–1.40) 0.27 1.1(0.94–1.46) 0.14

Delayedgraftfunction 2.1(0.33–13.7) 0.42

HLAincompatibilities 1.5(0.73–3.27) 0.25 1.5(0.64–3.60) 0.33

PKTgroup 0.2(0.03–0.99) 0.049 0.18(0.03–1.02) 0.053

Acuterejection 0.9(0.39–2.06) 0.90

Serumcreatinineat6months 4.1(0.47–35.8) 0.39

Proteinuriaat6months 1.5(0.6–3.8) 0.42

majorvessels.Inaddition,alargenumberareoftendiscarded duetothelackofcompatiblerecipientsamongelderlypatients undergoingchronicdialysis.13Apossiblesolutiontoavoidthis wastage ofkidneys potentially suitable for transplantation couldbetheperformanceofPKTincarefullyselectedelderly patients. Patient and graft survival are longer forpatients undergoingPKTthanforthosetransplantedwhenreceiving dialysis,andtimespentondialysispriortotransplantation significantlyaffectsgraftandpatientoutcome.8,9 Inastudy of1849 kidney recipients, including 385 PKTs, patient sur-vivalat5yearswashigherinPKTthaninnon-PKTpatients. Withdeceaseddonors,patientsurvivalwas92.6%and76.6%, respectively(p=0.001),andwithlivingdonors,patientsurvival was93.3%and89.5%,respectively(p=0.02).Graftsurvivalwas alsohigheramongthePKTpatients.14 Severalotherstudies havealsoshownbetterresultswhenperformingPKTas com-paredtotransplantationaftertheonsetofchronicdialysis.

Nevertheless,nostudieshaveanalyzedtheperformanceof PKTinelderlypatientsusingkidneysfromelderlydeceased donors.ThispolicywouldgatherthebenefitslinkedtoPKT andtheuseofvalidorgansthatotherwisewouldbediscarded. OurpilotstudydemonstratesthatPKTinveryelderlypatients (meanage 74.3±2.9years)using kidneysfrom veryelderly deceaseddonors(meanage73.8±4.1years)offersexcellent

results.GraftsurvivalwassignificantlybetterinPKTpatients ascomparedtothatofacontrolgroupofelderlypatientswho receivedkidneysfrom elderlydeceaseddonorsafterhaving startedchronicdialysis.Therewere nodifferencesbetween bothgroupsregardingpatientsurvival.Byunivariateanalysis, belongingtoPKTgroupwastheonlyfactorassociatedwith an improvedoutcome,althoughit did notreach statistical significancebymultivariateanalysis(Table5).

The reasonfor improvedgraft survivalwith PKT isnot completely clear. Several studies have shown a negative impact of waiting time on dialysis, with a directly pro-portional relationship to the risk of graft loss and shorter patientsurvival.15Thetimeondialysisalsoinfluenceschronic allograft nephropathy.8 Theexact reasons forthisnegative effect remain unclear, but several potential explanations havebeenpostulated,suchasanincreaseofpersistent pro-inflammatoryandpro-atherogenicmolecules, malnutrition, immunesystemdisordersandinadequateclearanceoftoxic metabolites.16,17Thepreservationofresidualrenalfunction may influencetheimprovementinsurvival.Recentstudies havefoundnoclearevidenceonthisfactor.Ontheotherhand, differencesintherateofimmediateordelayedgraftfunction, orintherateofacuterejection,couldinfluencebetter out-comesofPKT.WefoundthatourelderlyPKTpatientshada

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0 10 20 30 40 50 60 70 80 90 100 60 48 36 24 12 0 Months % Preemptive Control 0.02 96 68 Death-censored

A

B

3 7 8 10 16 26 Control 4 8 12 14 20 26 Preemptive 0 10 20 30 40 50 60 70 80 90 100 60 48 36 24 12 0 Months % Preemptive Control 0.139 79 65 Non death censored

3 7 8 10 16 26 Control 4 8 12 14 20 26 Preemptive

Fig.2–Kaplan–Meierestimatesof(A)death-censoredgraft survivaland(B)non-death-censoredgraftsurvival.

0 10 20 30 40 50 60 70 80 90 100 60 48 36 24 12 0 Months % Preemptive Control 0.795 83 78 3 7 8 10 16 26 Control 4 8 12 14 20 26 Preemptive

Fig.3–Kaplan–Meierestimatesofpatientsurvival.

0 1 2 3 4 5 6 7 8 60 48 36 24 12 6 3 1 Basal Months

A

B

Serum creatinine (mg/dl) Preemptive Control 12 16 7 12 6 7 3 16 17 18 19 26 Control 4 21 24 24 24 26 Preemptive –10 0 10 20 30 40 50 60 70 60 48 36 24 12 6 3 1 Basal Months MDRD GFR (ml/min/1.73m2) Preemptive Control 12 16 7 12 6 7 3 16 17 18 19 26 Control 4 21 24 24 24 26 Preemptive

Fig.4–Renalfunctionovertimein26PKTpatientsand26 controls,shownas(A)medianScrlevelsand(B)median GFR.

significantlyhigherrateofimmediategraftfunction(92%vs 53%)andasignificantlylowerrateofdelayedgraftfunction (3.8%vs34.6%),ascomparedtocontrolpatients.Onthe con-trary,wefoundasignificantlyhigherrateofBPARamongour PKTpatients(23.1%vs3.8%inthecontrolgroup).Some stud-ieshaveshownasignificantlylowerrateofBPARwithinthe firstsixmonthspost-transplantationinPKTpatients.18,19In contrast,inanotherstudy of1463kidney transplantsmore patientsexperiencedanacuterejectionepisodeinthe PKT group,20whichtheauthorstentativelyattributedtopoordrug complianceortotheabsenceoftheimmunosuppressiveeffect of the uremic state.6 Although age was associated with a decreaseinthefunctionoftheimmunesystemandtherefore

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adecreaseintherateofacuterejection,howevertheimpact ofacuterejectionongraftlosshasbeenreportedtobemore pronouncedinelderlypatients,independentofgraftquality.21 However,inallthesestudiesgraftsurvivalwashigherinthe PKTgroup.20Althoughweshouldnotforgetthatthe informa-tioninthesestudiesisbiasedtowardpatientswhoreceiveda kidneytransplantfromlivingdonor.Thereislittleinformation intheliteratureontheincidenceofacuterejectionandits evo-lutioninolderpatientswhoreceivetheanticipatedrenalgraft fromcadaverorliving.Recentfindingsfromourgroupprovide newinformationinthe field ofimmunology (imbalanceof thedifferentlymphocytepopulations,immunoglobulinsand complement) in dialysis patients and its influence on the developmentofinfections.22,23Thesefindingsshouldleadto newlinesofresearchaimedatknowledgeand behaviorof lymphocytesubsetsinpatientswithadvancedchronic kid-neydiseaseanddialysispopulationanditspossibleinfluence onacuterejection.Takentogether,thesefindingssuggestthat PKTmayhavealong-termadvantageregardlessofacute rejec-tionepisodes.

SinceourstudyisthefirsttoanalyzePKTinveryelderly patientsusingveryelderlydonors,morestudiesarerequired toconfirmourresultsandtogaininsightsintotheinfluence ofuremiaandchronicdialysisintheriskofacuterejectionin thispopulation.

Ourstudy hasseveral limitations,including arelatively smallsamplesize.Itwasconductedatasinglecenter,and ourcriteriaforincludingpatients–GRF<15ml/minand25% progressioninrenalfailureover thepastyear24 mayrule outextrapolatingourfindingstoothercentersusing differ-entcriteria.Furthermore,wedidnotevaluateresidualrenal function, which may confer a survival benefit and which meritsinvestigationinfuturestudies.Nevertheless,although deceaseddonororgansare,forethicalreasons,reservedfor patientsondialysis,ourexperiencehasshownthatPKTcan be an option for patients with non-dialysis ESRD with no detrimenttodialysispatients onthewaiting list.This pol-icymay bothprovidenon-dialysiselderly patientswiththe opportunityforaPKT;withthepromiseofexcellentresults, andalsohelpovercomethe problemoforgan shortagesby usingkidneysdestinedtobediscardedduetoalackofelderly recipients. Thefocusofclinicians shouldbeon shortening transplantwaitingtimesforelderlypatientsusing preemp-tive transplantation whenever possible. The kidneys from deceasedveryolddonorscanbesuccessfullytransplantedin ESRDnon-dialysiselderlyrecipientwhentherearenotother veryoldcandidatesinthewaitinglist.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgements

This study has been supported by grants from REDINREN (RD012/0021)and AITER (Asociaciónpara laInvestigación y TratamientodelaEnfermedadRenal).

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