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 Availableonlinexxx 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.PKTimprovesgraftandpatientsurvivalcomparedtootherrenalreplacement therapyoptions.ThereisnoinformationaboutPKTinelderlypatientsreceivingkidneys fromelderlydeceaseddonors.

Methods:From2007to2012,weperformedaprospectiveobservationalstudycomparing26 elderlypatientsreceivingPKTwithacontrolgroupof26elderlypatientsreceivingaﬁrst transplantafterpriordialysis.

Results:Meanageofrecipientswas74.3±2.9yearsandmean ageofdonorswas73.8±

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±11.7vs41.7±11.2ml/min,p-value=0.72).Patient survival wassimilarinthetwogroups.

∗_{Corresponding}_author.

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

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

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Conclusions:Elderlypatientswithendstageofrenaldiseasenon-dialysismaybeneﬁtfrom PKTelderlydeceaseddonorswhosekidneysweretobediscardedfortherearenotpatients inthewaitinglist.

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 ñonesdedonantesancianos fa-llecidossedesechanporquenohayreceptoresdeunaedadsimilar.Además,amenudose desechaungrannúmerodeórganosacausadelafaltadereceptorescompatiblesentrelos pacientesancianosendiálisiscrónica.Unaposiblesoluciónparaevitarquesedesperdicien estosri ñonesquepuedenserapropiadosparauntrasplanteseríallevaracabountrasplante renalprediálisis(TRP)enpacientesancianoscuidadosamenteseleccionados.ElTRPmejora lasupervivenciadelórganotrasplantadoydelpaciente,encomparaciónconotrasopciones deterapiasustitutivarenal.NodisponemosdeinformaciónacercadelTRPenpacientes ancianosalosquesetrasplantanri ñonesdedonantesancianosfallecidos.

Métodos:De2007a2012llevamosacabounestudioprospectivoobservacionalenelquese compararon26pacientesancianosquerecibieronunTRPconungrupodecontrolformado por26pacientesancianosalosquesepracticóunprimertrasplantedespuésdeunadiálisis previa.

Resultados:Lamediadeedaddelosreceptoresfuede74,3±2,9a ñosyladelosdonantes de73,8±4,1a ños. La inmunosupresióndeinducciónfue similaren los dosgruposde tratamiento.Lasupervivenciadelórgano,concensuraparaelanálisisestadísticoalamuerte delpaciente,fuedel96%enelgrupodeTRPydel68%enelgrupodecontrol(p=0,02), 5a ñosdespuésdeltrasplante.Hubounafuncióninmediataytardíadelri ñóntrasplantado 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:Enlospacientes ancianoscon unaenfermedadrenalterminal no dializa-dos,puederesultarbeneﬁciosounTRPdedonantesancianosfallecidoscuyosri ˜nonesse desecharíansinohubierapacientesenlistadeespera.

Introduction

Inrecentyears,thenumberofpatientsolderthan65years withendstagerenaldisease(ESRD)hasincreased1_and_is_now thefastestgrowingpatientpopulationrequiringrenal replace-menttherapyinbothEuropeandtheUnitedStates.Kidney transplantationimproveslifeexpectancyandqualityoflifein patientsofallageswithESRD2,3_and_is_an_attractive_option_for elderlypatients,inwhomitconferslowermortalityratesand

improvedqualityoflifecomparedto dialysis.4,5 _However,_a vastmajorityofkidneytransplantsinelderlypatientsare per-formedafteraperiodofchronicdialysis,andinthoseelderly patientsinwhomapreemptivekidneytransplant(PKT)is per-formedtheorgancomesfromalivingdonor.Noexperience aboutPKTusingkidneys fromelderlydeceaseddonorshas sofarbeenreported.Thislackofinformationisimportant becausePKTistheidealtreatmentforpatientswithadvanced chronickidneydisease(CKD).NotonlydoesPKTobviatethe

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need for vascular accessor the placementof a peritoneal catheter, thusreducing the cost of dialysis andimproving thequality oflife ofthe patient,6 _but_more_importantly, _it alsoextendsthesurvivalofpatientscomparedtoother ther-apeutic optionsandattainssuperioroutcomesin terms of bothgraftandpatientsurvivalthantransplantationafterprior dialysis.7,8_In_fact,_time_spent_on_dialysis_prior_to transplan-tation has been shown to be one of the most signiﬁcant factors affectingtheoutcomeof kidneytransplantation.9,10 Ontheotherhand,theonsetofchronicdialysis(buildingof asuccessfulvascularaccessforhemodialysis,orperitoneal catheterplacement)ismorechallenginginelderlypatients, thusreinforcingthetheoreticaladvantagesofPKTinthese patients.

Theshortageoforgansisalimitingfactorforkidney trans-plantationinallagerangesandhasledtotheuseofexpanded criteria donors, including those aged over 60 years.4,11 _In Spain,50%of donorsareolder than60andupto 25%are olderthan70.Kidneytransplantationwithexpandedcriteria donororganshasbeenassociatedwithlongersurvivalthan dialysis,3_but_data_are_limited_on_elderly_patients._Although graftsurvivalisgenerallypoorerwitholderthanwithyounger donors,whenkidneysareselectedbasedonrenalfunction, macroscopicexaminationandhistologicalinformation, excel-lentresultscanstillbeattained.12_In_spite_of_the_shortage_of organs,asigniﬁcantnumberofkidneysfromolderdeceased donors are not used because of donor hypertension, dia-betesorrenalfailure,macroscopicormicroscopicalterations in thekidney,or importantly,the lackof asuitable recipi-ent. Inaprevious study,we found that morethan 50%of kidneys fromolder donors werediscarded mainlybecause therewasnopotentiallycompatiblerecipientonthewaiting list.13

Inorderto avoidthewastingof kidneys fromdeceased elderlydonorsduetothelackofcompatiblerecipientsamong elderly patientsundergoing chronicdialysis, we created in January2007awaitinglistofpredialysiselderlypatientsto receive these kidneys. Herewe reportour experience with this cohort of elderlypatients receivingPKTs fromelderly 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 wereage >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 deOctubre, and all patients gavetheir signed informedconsent.

Thecontrolgroupcomprisedanadditional26patientsaged >65yearswhoreceivedaﬁrstkidneytransplantaftertheonset of chronic dialysis. Thirteen (50%)of thecontrols received pairedkidneysfromthesamedonorsasthePKTpatients;the remainingrecipientswereselectedascontrolsbecausetheir transplantswereperformedimmediatelybeforeorafterthe PKTpatients.

Thefollowingdonorvariableswererecorded:age,gender, ABO bloodgroup,BMI, history of hypertensionordiabetes 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 andproteinuriawererecorded weeklyduringthefirst month,everythreemonthsduringthefirstyear,andannually thereafter.

Mainoutcomesweregraftsurvival andpatient survival. 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-calvariableswereexpressedasfrequenciesorpercentages. Student’sttestortheMann–WhitneyUtestwasusedto com-parecontinuousvariables.Qualitativevariableswereanalyzed with thechi-squared testwithYates’ correctionorFisher’s exacttest.Graftandpatientsurvival werecalculatedusing theKaplan–Meier methodandcomparedwith thelog-rank test.Univariateandmultivariateregressionanalyses(witha backwardstepwiseprocedure)wereperformedwiththeCox proportionalhazardsmodeltoobtainhazardratios(HRs)with their95%conﬁdenceintervals(CIs).Allfactorswithp<0.05 in theunivariateanalysisandallclinicallyrelevantfactors with p<0.2in theunivariateanalysiswereincludedinthe multivariatemodel.Signiﬁcancewassetatp<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, theinterval between onset of chronic 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.Median donor agewas 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)in bothgroups.Median esti-matedGFRwas90.4±19.6ml/min/1.73m2 _in_the_PKT_group and94.2±24.3ml/min/1.73m2 _in_the_control_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 _Numbers_reﬂect_mean_and_SD.

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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

The actuarial1-, 3-, and5-yeargraft survivalrates (death-censored)were96%,96%and96%inthePKTgroupand76%, 68%and68%inthecontrolgroup(p=0.02) (Fig.2).Primary non-function was observed in one patient (arterial throm-bosis) in thePKT group andin three in the controlgroup (twocasesofarterialthrombosisandoneofvenous throm-bosis) (Table 2). Early graft loss (less than three months) occurredin onepatientinthePKTgroup(deathfromliver failure with functioning graft) and in four patients in the controlgroup (onedeathwithgraftthrombosis, onedeath fromsepsis, onedeathfromheart attack,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 graftfunction was observed in one patient (3.8%) in thePKT groupandin nine (34.6%)in thecontrolgroup (p=0.005).Sixpatients(23.1%)inthePKTgroupexperienced BPAR:fourwithacutecellularrejectionandtwowithacute humoral rejection.One patient(3.8%) in the controlgroup 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 _Arterial_thrombosis.

b _Venous_thrombosis_(1),_arterial_thrombosis_(2). c _Death_from_liver_disease_with_functioning_graft.

d_Death_from_infection_(1),_death_from_ischemic_heart_disease_(1),_venous_thrombosis_(1),_urinary_ﬁstula_(1). e _Infection_(2),_liver_disease_(1),_{cardiovascular}_disease_(1).

f _Infection_(2),_ischemic_heart_disease_(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 thecontrol group(p=0.08)(Table3 andFig.4).Nopatients inthePKTgroupandfourinthecontrolgroupreturnedto dialysis(p=0.03).

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

CMVinfectionsandurinarytractinfectionsweresimilar inthetwogroups.Urologicalcomplicationsandtumor inci-denceswerealsosimilarinthetwogroups,whileaslightly highernumberofcardiovascularcomplicationsand periph-eralarterialdiseaseswereobservedinthePKTgroup(p=0.06) (Table4).

Clinicalfactorsassociatedwithgraftsurvival

Inthe univariate analysis including age, time on dialysis, delayedgraftfunction,HLAincompatibility,belongingtoPKT group,diabetesmellitus,serumcreatinineatmonth6, pro-teinuriaatmonth6,andthedifferenceinGFRbetweenmonth 6andendofstudy,onlythosebelongingtoPKTgroupwere associated with improved outcome (p=0.049). Multivariate logisticregression 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 themacroscopic appearanceof the 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/1.73m2_per_year) _+0.9_±_0.5₍₋_5.9_to_12.8)

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’s_sarcoma_(1). b _Skin_(1),_Kaposi’s_sarcoma_(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.13_A_possible_solution_to_avoid_this wastage of kidneyspotentially suitablefor transplantation couldbetheperformanceofPKTincarefullyselectedelderly patients. Patient and graftsurvival are longer for patients undergoingPKTthanforthosetransplantedwhenreceiving dialysis,andtimespentondialysispriortotransplantation signiﬁcantlyaffectsgraftandpatientoutcome.8,9_In_a_study of 1849 kidneyrecipients, including385 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_Several_other_studies havealsoshownbetterresultswhenperformingPKTas com-paredtotransplantationaftertheonsetofchronicdialysis.

Nevertheless,nostudieshaveanalyzedtheperformanceof PKTinelderlypatientsusingkidneysfromelderlydeceased donors.ThispolicywouldgatherthebeneﬁtslinkedtoPKT andtheuseofvalidorgansthatotherwisewouldbediscarded. OurpilotstudydemonstratesthatPKTinveryelderlypatients (meanage74.3±2.9 years)usingkidneysfromveryelderly deceaseddonors(meanage73.8±4.1years)offersexcellent

results.GraftsurvivalwassigniﬁcantlybetterinPKTpatients ascomparedtothatofacontrolgroupofelderlypatientswho receivedkidneysfromelderlydeceaseddonorsafterhaving startedchronicdialysis.Therewerenodifferencesbetween bothgroupsregardingpatientsurvival.Byunivariateanalysis, belongingtoPKTgroupwastheonlyfactorassociatedwith an improved outcome,althoughit didnot reach statistical signiﬁcancebymultivariateanalysis(Table5).

Thereason for improved graftsurvival with PKTis not completely clear. Several studies have shown a negative impact of waiting time on dialysis, with a directly pro-portional relationship to the risk of graftloss and shorter patientsurvival.15_The_time_on_dialysis_also_influences_chronic allograft nephropathy.8 _The_exact _reasons _for_this_negative effect remain unclear, but several potential explanations havebeenpostulated,suchasanincreaseofpersistent pro-inflammatoryandpro-atherogenicmolecules,malnutrition, immunesystemdisordersandinadequateclearanceoftoxic metabolites.16,17_The_preservation_of_residual_renal_function mayinfluencetheimprovement insurvival.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.18,19_In contrast,inanotherstudyof 1463kidney transplantsmore patientsexperiencedanacuterejectionepisodeinthePKT group,20_which_the_authors_tentatively_attributed_to_poor_drug complianceortotheabsenceoftheimmunosuppressiveeffect of theuremic state.6 _Although _age _was _associated _with _a decreaseinthefunctionoftheimmunesystemandtherefore

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adecreaseintherateofacuterejection,howevertheimpact ofacuterejectionongraftlosshasbeenreportedtobemore pronouncedinelderlypatients,independentofgraftquality.21 However,inallthesestudiesgraftsurvivalwashigherinthe PKTgroup.20_Although_we_should_not_forget_that_the informa-tioninthesestudiesisbiasedtowardpatientswhoreceiveda kidneytransplantfromlivingdonor.Thereislittleinformation intheliteratureontheincidenceofacuterejectionandits evo-lutioninolderpatientswhoreceivetheanticipatedrenalgraft fromcadaverorliving.Recentfindingsfromourgroupprovide new informationin thefieldofimmunology(imbalance of thedifferentlymphocytepopulations,immunoglobulinsand complement) in dialysis patients and its influence onthe developmentofinfections.22,23_These_findings_should_lead_to newlines ofresearchaimedatknowledgeandbehaviorof lymphocytesubsetsin patientswithadvancedchronic kid-neydiseaseanddialysispopulationanditspossibleinfluence onacuterejection.Takentogether,thesefindingssuggestthat PKTmayhavealong-termadvantageregardlessofacute rejec-tionepisodes.

SinceourstudyisthefirsttoanalyzePKTinveryelderly patientsusingveryelderlydonors,morestudiesarerequired toconfirmourresultsandtogaininsightsintotheinfluence ofuremiaandchronicdialysisintheriskofacuterejectionin thispopulation.

Our studyhas severallimitations, includingarelatively smallsamplesize.Itwasconductedatasinglecenter,and ourcriteriaforincludingpatients–GRF<15ml/minand25% progressioninrenalfailureoverthepastyear24_–_may_rule 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 detriment todialysispatientsonthewaitinglist.This pol-icymaybothprovidenon-dialysiselderlypatientswiththe opportunityforaPKT;withthepromiseofexcellentresults, andalsohelpovercome theproblemoforganshortagesby usingkidneysdestinedtobediscardedduetoalackofelderly recipients.Thefocusof cliniciansshould beonshortening 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 fromREDINREN (RD012/0021) andAITER (Asociaciónparala Investigacióny TratamientodelaEnfermedadRenal).

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