Risk factors for graft loss and mortality after renal transplantation according to recipient age: a prospective multicentre study

O iginal A icle Risk ac o s o g a loss and mo ali y a e enal ansplan a ion acco ding o ecipien age: a p ospec i e mul icen e s udy Jose Ma ia Mo ales1, Robe o Ma cén2, Domingo del Cas illo3, Amado And es1, Miguel Gonzalez- Molina4, Fede ico Oppenheime 5, Daniel Se ón6, Sal ado Gil-Ve ne 7, Ilde onso Lamp ea e8, F ancisco Ja ie Gainza8, F ancisco Valdés9, Me cedes Cabello4, Fe nando Anaya10, Fe nando Escuin11, Manuel A ias12, Luis Palla dó13 and Jesus Bus aman e14 1 Depa men o Neph ology, Hospi al 12 de Oc ub e, Mad id, Spain, 2 Depa men o Neph ology, Hospi al Ramon y Cajal, Mad id, Spain, 3 Depa men o Neph ology, Hospi al Reina Sofia, Co doba, Spain, 4 Depa men o Neph ology, Hospi al Ca los Haya, Malaga, Spain, 5 Renal T ansplan Uni , Hospi al Clinic, Ba celona, Spain, 6 Depa men o Neph ology, Hospi al Vall d Heb on, Ba celona, Spain, 7 Depa men o Neph ology, Hospi al de Bell i ge, Ba celona, Spain, 8 Depa men o Neph ology, Hospi al de C uces, Ba akaldo, Spain, 9 Depa men o Neph ology, Hospi al Juan Canalejo, La Co uña, Spain, 10 Depa men o Neph ology, Hospi al G ego io Ma añón, Mad id, Spain, 11 Depa men o Neph ology, Hospi al La Paz, Mad id, Spain, 12 Depa men o Neph ology, Hospi al Ma qués de Valdecilla, San ande , Spain, 13 Depa men o Neph ology, Hospi al D Pese , Valencia, Spain and 14 Depa men o Neph ology, Hospi al Clinico, Valladolid, Spain Co espondence and o p in eques s o: P o . Jose Ma ia Mo ales; E-mail: jmo [email p o ec ed] Abs ac Backg ound. To desc ibe he causes o g a loss, pa ien dea h and su i al figu es in kidney ansplan pa ien s in Spain based on he ecipien ’s age. Me hods. The esul s a 5 yea s o pos - ansplan ca dio- ascula disease (CVD) pa ien s, aken om a da abase on CVD, we e p ospec i ely analysed, i.e. a o al o 2600 ansplan ed pa ien s du ing 2000–2002 in 14 Spanish enal ansplan uni s, mos o hem ecei ing hei o gan om cada e dono s. Pa ien s we e g ouped acco ding o he ecipien ’s age: G oup A: <40 yea s, G oup B: 40–60 yea s and G oup C: >60 yea s. The mos equen immunosupp essi e egimen included ac olimus, myco- phenola e mo e il and s e oids. Resul s. Pa ien s we e dis ibu ed as ollows: 25.85% in G oup A (>40 yea s), 50.9% in G oup B (40–60 yea s) and 23.19% in G oup C (>60). The 5-yea su i al o he di e en age g oups was 97.4, 90.8 and 77.7%, espec - i ely. Dea h-censo ed g a su i al was 88, 84.2 and 79.1%, espec i ely, and non dea h-censo ed g a su i al was 82.1, 80.3 and 64.7%, espec i ely. Ac oss all age g oups, CVD and in ec ions we e he mos equen cause o dea h. The main causes o g a loss we e ch onic allo- g a dys unc ion in pa ien s <40 yea s old and dea h wi h unc ioning g a in he wo emaining g oups. In he mul i- a ia e analysis o g a su i al, only ele a ed c ea inine le els and p o einu ia >1 g a 6 mon hs pos - ansplan a ion we e s a is ically significan in he h ee age g oups. The pa ien su i al mul i a ia e analysis did no achie e a s a - is ically significan common ac o in he h ee age g oups. Conclusions. Fi e-yea esul s show an excellen ecipien su i al and g a su i al, especially in he younges age g oup. Dea h wi h unc ioning g a is he leading cause o g a loss in pa ien s >40 yea s. Ea ly imp o emen o enal unc ion and p o einu ia oge he wi h s ic con ol o ca - dio ascula isk ac o s a e manda o y. Keywo ds: ca dio ascula mo ali y; g a su i al; pa ien su i al; enal unc ion; enal ansplan a ion In oduc ion Du ing he las wo decades, he in oduc ion o new im- munosupp essan s has been associa ed wi h a decline in he p e alence o acu e ejec ion and wi h an imp o e- men in 1-yea g a su i al [1–3]. Howe e , in con as o he sho - e m su i al, he long- e m ou come o bo h ansplan ecipien s and hei g a s has no imp o ed as expec ed [4]. The e o e, he op imiza ion o long- e m ou come has become inc easingly impo an . The demog aphic modifi- ca ion o he dono and he ecipien may help o explain he lack o imp o emen . Recipien cha ac e is ics a he ime o ansplan a ion ha e e ol ed in a ime-dependen manne and nowadays ecipien age is on he inc ease. This inc ease in ecipien age may ha e an impo an impac on g a loss, pa ien su i al and pa ien dea h as well as he possible isk ac o s in ol ed in su i al such as ca dio ascula isk ac o s, which a e he main cause o g a loss in he long e m [1,5]. Accu a ely de e min- ing he possible causes in ol ed in su i al is essen ial o e ec i e long- e m managemen o he pa ien . © The Au ho 2012. Published by Ox o d Uni e si y P ess on behal o ERA-EDTA. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by-nc/3.0/), which pe mi s non-comme cial euse, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Fo comme cial e-use, please con ac jou nals. pe [email protected]. Neph ol Dial T ansplan (2012) 27 (Supple 4): i 39–i 46 doi: 10.1093/nd /g s544 Downloaded om h ps://academic.oup.com/nd /a icle/27/suppl_4/i 39/1882932 by UNIVERSIDAD DE VALLADOLID. BIBLIOTECA use on 14 Decembe 2021 Thus, he aim o his s udy was o assess he g a and pa ien 5-yea su i al acco ding o ecipien age and de- e mine he possible causes in ol ed. Ma e ials and me hods Popula ion All ansplan ed pa ien s du ing 2000–2002 ac oss 14 enal ansplan uni s in Spain we e included in a da abase (Renal Fo um Da abase) ocused on ca dio ascula isk ac o s [6]. No exclusion c i e ia we e conside ed; so, his da abase ep esen s he ull eco d o hese hospi als in he fi s 3 yea s o he 21s cen u y and also includes pa ien s who a e pa icipa ing in clinical ials. Th ee age g oups we e es ablished acco d- ing o ecipien age: <40, 40–60 and >60 yea s old. Da abase and clinical a iables The ca dio ascula disease (CVD) da abase was ini ia ed in 2000. All pa icipa ing uni s egis e da a conce ning all he enal ansplan s pe - o med in each cen e. Da a collec ion is ca ied ou e e y 12 mon hs, ia a da abase p o ided o ha pu pose, in e e y cen e. These da a a e ans- e ed annually o an independen biome y uni ha me ges and analyse he esul s om he sugges ions made by a wo king g oup c ea ed wi hin he ‘Renal Fo um’ amewo k. The ‘Renal Fo um’g oup and he ‘Renal Fo um da abase’a e suppo ed by an un es ic ed g an om As ellas. The Renal Fo um da abase includes dono and pa icula ly ecipien cha ac e is ics: age, o iginal disease, ime on dialysis, se ology, immuno- logical da a and p e- ansplan ca dio ascula condi ion. In his way, body mass index (BMI), a e ial hype ension, hype lipidaemia, diabe es, smoking and p e- ansplan CVD we e specifically eco ded. Immuno- supp essi e ea men a he poin o ansplan a ion was also eco ded. A e su ge y, he equency and numbe o acu e ejec ions, incidence o acu e ubula nec osis (ATN), g a su i al and causes o g a loss and pa ien su i al as well as o mo ali y, enal unc ion and p o einu ia we e eco ded. Ca dio ascula e en s we e also eco ded, as well as modifica ions o immunosupp ession and he p esence o concomi an medica ions such as s a ins and angio ensin con e ing enzyme inhibi o s/angio ensin ecep o blocke s (ACEIs/ARBs). These da a we e annually collec ed. E hics This s udy (no in e en ion) was app o ed by all he depa men s o Ne- ph ology o he 14 hospi als assu ing da a confiden iali y. A blinded code was assigned o each pa icipa ing hospi al o ake in o conside a ion he cen e e ec . S a is ical me hods The objec i e was o analyse he 5-yea ollow-up da a o pa ien s a e kidney ansplan a ion, specifically: (i) Desc ip i e analysis o he a iables o in e es in he 5 yea s: absol- u e and ela i e equencies o he quali a i e a iables, and measu es o associa ion and dispe sion (a e age, medium s anda d de ia ion, minimum, and maximum) o he quan i a i e ones. (ii) S udy o he g a and pa ien su i al: numbe o losses and exi us, causes o g a loss and pa ien dea h, cu es o Kaplan–Meie . (iii) Measu ing whe he he e was a s a is ically significan ela ionship be ween pa ien cha ac e is ics and g oups defined o he 48-mon h s udy. Using he co esponding es s o independen da a: in he case o quan i a i e a iables, - es (i he e is no mali y) o he Mann–Whi ney (when we did no p une o assume no mali y in he da a). In he case o quali a i e a iables, χ 2 es . (i ) Mul i a ia e analysis ha allows he iden ifica ion o isk ac o s ela ed o g a loss and pa ien dea h. The Cox eg ession model o calcula e he a e o g a loss and dea h as a unc ion o ime (un il you see he e en o in e es ) and o ecas a iables. Resul s Du ing 2000–2002, 2822 enal ansplan a ions we e pe - o med ac oss 14 hospi als in Spain. We excluded om his analysis 222 double ansplan s: li e –kidney, pan- c eas–kidney and hea –kidney. The e o e, 2600 enal ansplan s, including double-kidney ansplan a ion in a single ecipien (2.5%), we e he subjec o his s udy. Dono , su ge y and ecipien cha ac e is ics a e shown in Table 1. The mean ecipien age was 49.7 ± 13.7 and 12.5% we e hype immunized. The main cause o ch onic enal ailu e (CRF) in pa ien s <60 yea s was ch onic glo- me uloneph i is and he main cause o CRF in pa ien s >60 yea s was adul polycys ic kidney disease. HLA-DR misma ching was 0.9 ± 0.6 and HLA-A and -B, 2.6 ± 1. SBP, hype choles e olaemia, diabe es Type II, BMI, ATN and p o einu ia inc eased significan ly wi h age. Only 9.2% o he pa ien s who ecei ed a kidney ans- plan we e diagnosed wi h diabe es melli us: 4.0% (<40), 9.9% (40–60), 13.3% (>60); he e was a low p opo ion o obesi y and nea ly 15% had CVD. Me abolic synd ome p e alence inc eased significan ly wi h age, bu only 17.8% we e diagnosed wi h p e- ansplan me abolic syn- d ome. I can be no ed ha he incidence o acu e ejec ion in he fi s 6 and 12 mon hs was 14.4 and 16.6%, espec - i ely. Acu e ejec ion in he fi s 6 mon hs dec eased sig- nifican ly by age. The mean dono age was 46.9 ± 17, 63% we e male, and he mos equen cause o dea h was s oke. Cold ischaemia ime inc eased significan ly by age. In hese yea s, enal ansplan a ion om li ing dono s was anec- do ic (0.38%). Ini ial and 5-yea immunosupp esion is ep esen ed in Table 2. The mos equen combina ion egimen was based on ac olimus and mycophenola e mo e il wi h o wi hou monoclonal an ibodies an i-in e leukin 2 ecep o o hymo- globuline. In e es ingly, 24% ecei ed an ibodies as ini ial he apy. Pa ien s on ac olimus- o cyclospo ine-based im- munosupp esion a baseline we e 63.5 and 32.6%, espec - i ely. The mos impo an concomi an medica ions we e s a ins, ACEIs o ARA, inc easing om 23, 5.4 and 9.5% a 6 mon hs o 46, 9.5 and 29% a 48 mon hs, espec i ely. Fi e-yea g a su i al Dea h-censo ed g a su i al was 88, 84.2 and 79.1%, espec i ely (Figu e 1), and non-dea h-censo ed g a su - i al was 82.1, 80.3 and 64.7%, espec i ely (Figu e 2). The main causes o g a loss we e ch onic allog a ne- ph opa hy in <40-yea -old pa ien s and dea h wi h unc- ioning g a in he wo emaining g oups (Table 3). Risk ac o s o g a loss a e shown in Table 4. Mul i- a ia e analysis showed ha independen p edic o s o dea h-censo ed g a su i al in he h ee age g oups we e ele a ed se um c ea inine le els and p o einu ia >1 g a 6 mon hs pos - ansplan a ion. Figu e 3shows he e ol- u ion o p o einu ia and glome ula fil a ion by age g oup. Diabe es was also a isk ac o in hose younge han 40 yea s, and olde dono s was a isk ac o in ecipi- en s aged 40–60 yea s. Fi e-yea pa ien su i al CVD (33.9%) was he mos common cause o dea h ac oss all age g oups ollowed by in ec ion (22.9%). i 40 J.M. Mo ales e al. Downloaded om h ps://academic.oup.com/nd /a icle/27/suppl_4/i 39/1882932 by UNIVERSIDAD DE VALLADOLID. BIBLIOTECA use on 14 Decembe 2021 Ca dio ascula e en s by age g oup we e dis ibu ed as ollows: <40 (29 CV e en s), 40–60 (189 CV e en s) and >60 (136 CV e en s). S oke was he main CV cause o dea h in ecipien s younge han 40 yea s old and ischae- mic hea disease in olde han 60 yea s. Malignancies we e he hi d cause o dea h in hese pa ien s (Table 5). Table 1. Recipien and dono baseline cha ac e is ics Recipien baseline cha ac e is ics To al <40 40–60 >60 P- alue Age a ansplan a ion —25.85% 50.96% 23.19% Sex (male) 60% Cause o ch onic enal ailu e Ch onic glome uloneph i is 26.2% 34.9% 26.5% 15.8% 0.001 Adul polycys ic kidney disease 15.3% 4.2% 20.4% 16.5% In e s i ial neph opa hy 13.4% 19.6% 10.5% 12.8% Neph oangioscle osis 6.9% 2.5% 6.4% 12.6% Diabe es 6.6% 3.1% 7.1% 9.3% Unknown o igin 19.8% 16.4% 19.5% 24.1% O he s 11.9% 19.3% 9.6% 8.8% Time on dialysis (mon hs) 39.3 ± 46.7 Type o dialysis Haemodialysis 81% Pe i oneal dialysis 15% Bo h 2.7% P edialysis 0.9% Hype immunized pa ien s *PRA his o ical o cu en ≥50% 10.1% 11.2% 11.2% 6.5% 0.05 P io ansplan s No 84% 76.7% 84.1% 91.8% Yes 16% 23.3% 15.9% 8.2% Type o ansplan Double 2.4% 0.1% 0.8% 8.5% Simple 97.6% 99.9% 99.2% 91.5% Incompa ibili ies HLA-DR HLA-AB 0.9 ± 0.6/2.6 ± 1 HLA-DR + HLA-AB 3.34 ± 1.1 3.42 ± 1.16 3.56 ± 1.18 0.01 Immunosup ession Cyclospo ine 33.8% 19.4% 31.5% 56.9% 0.001 Tac olimus 6.2% 80.6% 68.5% 43.1% Ca dio ascula s a us BMI –23.11 ± 4.0 25.45 ± 4.2 26.25 ± 3.9 0.001 A e ial hype ension 75% 71.9% 76.0% 76.2% n.s. SBP (mmHg)-6 mon hs 130.4 137.9 144.2 0.001 DBP (mmHg)-6 mon hs 78.9 80.1 77.8 0.001 ACEI/ARB-6 mon hs 14.8% 16.8% 14.6% 12.9% n.s. ACEI/ARB-12 mon hs 20.7% 19.0% 23.0% 17.4% 0.05 Diabe es melli us 9.2% 4.0% 9.9% 13.3% 0.001 Type I 3.5% 2.8% 4.2% 2.7% 0.001 Type II 5.7% 1.2% 5.8% 10.6% 0.001 Dyslipidaemia 22.6% 0.001 Hype choles e olaemia 9.3% 5.5% 10.0% 12.1% Hype iglice idaemia 6.1% 6.4% 5.8% 6.3% Bo h 7.2% 5.1% 8.4% 7.0% Smoke Non-smoke o ex-smoke >5 yea s 76.0% 76.1% 72.6% 83.4% 0.001 Smoke o ex-smoke <5 yea s 24% 23.9% 27.4% 16.6% Alcohol Yes 5.6% 3.9% 7.0% 4.5% 0.01 Me abolic Synd ome 17.8% 8.1% 19.9% 24.1% 0.001 ATN 28.6% 24.4% 28.6% 33.3% 0.01 Rejec ion (6 mon hs) 14.4% 17.4% 13.7% 12.6% 0.05 Rejec ion (12 mon hs) 16.6% 19.4% 15.9% 14.8% n.s. P o einu ia (6 mon hs) >1 g/day 5.7% 3.8% 5.9% 7.6% 0.05 P o einu ia (g/day) 0.4 ± 0.68 0.25 ± 0.52 0.31 ± 0.58 0.40 ± 0.76 0.01 Hepa i is C 16.0% 18.8% 15.7% 13.1% n.s. Dono cha ac e is ics Dono age (yea s) 46.9 ± 17 34.2 ± 14 46.2 ± 15 60.1 ± 14 0.001 Male 62.7% 65.4 62.5% 60.0% n.s. Causes o dea h 0.001 Acu e ce eb o ascula acciden 56.0% 39.8% 57.6% 70.0% C aneoencephalic auma ism 34.7% 51.0% 31.4% 24.1% Hypoxia 4.6% 4.3% 5.8% 2.5% O he s 4.7% 4.9% 5.2% 3.4% Cold ischaemia ime (h) 19 ± 6 17.76 ± 5.6 18.76 ± 5.4 19.18 ± 5.6 0.001 Risk ac o s o g a loss and mo ali y i 41 Downloaded om h ps://academic.oup.com/nd /a icle/27/suppl_4/i 39/1882932 by UNIVERSIDAD DE VALLADOLID. BIBLIOTECA use on 14 Decembe 2021 The 5-yea ecipien su i al o he a ious age g oups was 97.4, 90.8 and 77.7%, espec i ely (Figu e 4). The pa ien s’su i al mul i a ia e analysis did no show a s a - is ically significan common ac o in he h ee g oups, bu he use o ACEI/ARB was a significan isk ac o in pa ien s olde han 60 yea s and diabe es eached s a is i- cal significance in he 40–60 age g oup (Table 6). Discussion In his s udy, we analysed he mos impo an 5-yea esul s o enal ansplan a ion om deceased dono s in he mode n immunosupp essi e e a in Spain. Fi e-yea esul s show an excellen ecipien su i al and g a su - i al, especially in he younges age g oup. Conside ing ha all ansplan pa ien s (e en e ansplan s, hype im- munized, and hose olde han 70 yea s) we e included, dono and ecipien ages ha e inc eased and he deg ee o HLA ma ching has wo sened; he su i al a es ob ained confi m a clea imp o emen in he long- e m manage- men o enal- ansplan pa ien s and ha new immuno- supp essi e egimens coun e ac subop imal ea u es o dono s and ecipien s. Compa ed wi h o he la ge na ional and in e na ional egis ies ocused on long- e m esul s in enal ansplan [7–10], ou esul s sugges an imp o e- men in long- e m g a su i al and sligh ly be e long- e m pa ien su i al a es. O in e es , his finding con- fi ms p e ious obse a ions o a s udy ca ied ou in Spanish ansplan pa ien s who had a unc ioning allo- g a 1 yea a e ansplan a ion [11]. In his s udy, long- e m g a su i al in Spanish kidney ansplan ecipien s is mo e han double o ha compa ed wi h he USA, bu simila dea h-censo ed g a su i al a e obse ed in Spanish and US ecipien s [11]. P e- ansplan medical ca e, co-mo bidi ies, such as CVD, and hei managemen in each coun y’s heal h sys em a e possible explana ions o he di e ences be ween he wo coun ies. Con a y o p e ious s udies ca ied ou in Spain [7], acu e ejec ion is no an independen ac o o allog a loss and dea h wi h unc ioning g a is he leading cause Table 2. Immunosup ession (baseline and 60 mon hs la e ) D ug <40 (%) 40–60 (%) >60 (%) Basal 60 mon hs Basal 60 mon hs Basal 60 mon hs S e oids 97.3 76.8 97.2 72.5 97.7 68.4 Cyclospo ine 19.4 13.5 30.5 22.7 50.7 41.5 Tac olimus 80.6 76.6 69.5 66.7 39.3 43.9 Mycophenola e mo e il 88.4 77.9 86.0 76.8 87.9 68.0 O he s (m-TORi Aza hiop ine) 9.3 12.7 9.4 11.9 11.2 13.2 An ibody induc ion 20.4 23.8 30.3 Fig. 1. Fi e-yea g a su i al by age g oup (non-dea h-censo ed). Fig. 2. Fi e-yea g a su i al by age g oup (dea h-censo ed). Table 3. Causes o g a loss by age g oup (5 yea s) Causes <40 (%) 40–60 (%) >60 (%) To al (%) Acu e ejec ion 16.1 13.4 9.5 12.6 U opa hy 1.6 0.4 1.0 0.9 Vascula 0.8 2.1 2.5 2.0 De no o GN 1.6 0.0 0.5 0.5 Recu en GN 5.6 1.7 0.5 2.1 Exi us wi h a unc ioning g a 7.3 30.5 37.5 27.9 Ch onic allog a neph opa hy 30.6 20.1 21.0 22.7 Venous h ombosis 9.7 8.4 3.5 6.9 A e ial h ombosis 5.6 4.6 4.0 4.6 A e ial + enous h ombosis 1.6 0.8 1.0 1.1 P ima y non- unc ion 1.6 4.2 6.0 4.3 Recu en disease 3.2 0.4 1.0 1.2 Su ge y p oblems 0.0 2.9 1.0 1.6 O he s 5.6 3.8 7.5 5.5 i 42 J.M. Mo ales e al. Downloaded om h ps://academic.oup.com/nd /a icle/27/suppl_4/i 39/1882932 by UNIVERSIDAD DE VALLADOLID. BIBLIOTECA use on 14 Decembe 2021 o g a loss in pa ien s >40 yea s. O e he las wo decades, he e has been an associa ion obse ed be ween he in oduc ion o new immunosupp essan s, especially ac olimus and MMF, and a significan educ ion in he incidence o acu e ejec ion [1,2]. As acu e ejec ion esul s in a unc ional and s uc u al damage o he g a , i has been assumed ha a dec ease in i s incidence should esul in an imp o emen o la e g a ou come. Howe e , his assump ion has no been p e iously con- fi med in epidemiological s udies. Mo eo e , in his s udy, he mean dono and ecipien age is highe compa ed wi h o he s udies [12], bu he use o new immunosupp es- san s could coun e balance he majo p opo ion o ejec- ion episodes and subsequen incomple e eco e y o enal unc ion associa ed wi h senescen issue [13]. Renal g a dys unc ion is he esul o bo h immuno- logical and non-immunological insul s. Some au ho s conside ha he p esence o he isk ac o s in ol ed in he me abolic synd ome induces a p ominen isk o g a loss bu , in his s udy, componen s o me abolic synd ome do no appea o con ibu e g ea ly o ch onic g a dys unc ion and only AH, sys olic blood p essu e and dia- be es we e significan ly in ol ed in he uni a ia e analy- sis. Diabe es is a isk ac o o g a loss in ecipien s younge han 40 yea s old, bu i did no each s a is ical significance a olde ages. The combina ion o TAC + MMF, which o e s an accep able ca dio ascula isk p ofile [14], and is ecei ed by mo e han 60% o pa ien s, could also be impo an o explain hese esul s [6]. Howe e , no el CVD ac o s as ele a ed c ea inine le els and p o einu ia >1 g a 6 mon hs pos - ansplan a ion we e isk ac o s associa ed wi h a poo 5-yea g a su i al in all age g oups. A p esen , di e en s udies [15–17]ha e shown ha he p esence o p o einu ia, compa ed wi h i s absence, is associa ed wi h an inc eased isk o g a loss, pa ien dea h and ca dio ascula isk [18]. Likewise, he le el o p o einu ia is a key ac o in he p ognosis o enal g a ailu e [19]. Che uku i e al.[20] and a ecen s udy in he enal- ansplan popula ion demons a ed ha he g oup wi h mo e han 1 g/day a 3 mon hs showed a g a ailu e ela i e isk o 16.0 (95% CI, 3.5–72; P < 0.001) which ep- esen s mo e han wice he isk o hose pa ien s wi h a p o- einu ia be ween 0.15 and 0.5. So, he use o d ugs dec easing he le el o p o einu ia, such as ACEI and ARB, and immunosupp essi e d ugs wi hou his dele e ious e ec a e s ongly ecommended in hese pa ien s. Ou esul s also highligh ha c ea inine le el had a sig- nifican ela ionship wi h g a su i al a e. This finding co obo a es p e ious obse a ions which es ablished ha wi h e e y 1 mg/dL inc ease in c ea inine le el, HR o g a loss inc eases by 1.8 uni s [21]. Renal unc ion wi hin he fi s yea a e ansplan a ion has been shown o be an impo an pa ame e influencing long- e m g a su i al [22]. Mo eo e , a 5-yea ollow-up o a la ge US pi o al egis a ion ial, which ocused on he long- e m ou come o ac olimus- e sus cyclospo ine-based immu- nosupp ession [23], showed ha du ing he 5-yea ollow- up, he mean se um c ea inine le els based on in en - o- ea analysis we e always lowe in he ac olimus g oup han in he cyclospo ine g oup. Thus, he combina ion o ac olimus + MMF, which o e s an accep able isk p ofile Table 4. Risk ac o s o g a loss (5 yea s) Uni a ia e analysis (P- alue) Mul i a ia e analysis (all ages) Mul i a ia e analysis by age g oup HR (95% IC) P- alue <40 HR (95% IC) P- alue 40–60 HR (95% IC) P- alue >60 HR (95% IC) P- alue Recipien aged ≤0.001 ———— Dono aged ≤0.001 ——1.02 (1.0–1.05) ≤0.05 — Hype immunized ≤0.05 ———— AH ≤0.05 ——— Diabe es ≤0.001 —4.85 (1.9–11.8) ≤0.001 —— AT N ≤0.001 ———— Acu e ejec ion a 12 mon hs ≤0.001 —— — Time on dialysis ≤0.05 ——— Se um c ea inine: 6 mon hs ≤0.001 3.18 (1.6–6.2) ≤0.001 9.34 (3.5–25.0) ≤0.001 3.12 (1.6–7.6) ≤0.01 3.18 (1.6–6.2) ≤0.001 P o einu ia: 6 mon hs >1 g ≤0.001 3.91 (1.8–8.4) ≤0.001 4.66 (2.1–10.6) ≤0.001 4.10 (2.1–8.2) ≤0.001 3.91 (1.8–8.4) ≤0.001 Sys olic a e ial hype ension a 6 mon hs ≤0.001 ———— SBP a 6 mon hs Hepa i is C ≤0.001 ———— Risk ac o s o g a loss and mo ali y i 43 Downloaded om h ps://academic.oup.com/nd /a icle/27/suppl_4/i 39/1882932 by UNIVERSIDAD DE VALLADOLID. BIBLIOTECA use on 14 Decembe 2021 and i is ecei ed by mo e han 60% o pa ien s, could also be an impo an ac o o explain hese esul s. The low a e o mo ali y in hese 5 yea s can be ex- plained by he ac ha ou popula ion is Caucasian, wi h a low a e o diabe ic pa ien s and low p opo ion o pa ien s wi h p e- ansplan CVD, and he e o e, hei ca dio ascula isk is lowe han ha o p e- ansplan Ame ican [24] o No h Eu opean [25] popula ions. Finally, pa ien s wi h g a unc ion ha e a high long- e m su i al. In ec ions and CVD ha e been epo ed as he p edominan causes o dea h. P e en ion o s oke is manda o y in pa ien s younge han 40 yea s. A en ion o a he oscle o ic isk ac o s may be he mos impo an challenge o u he imp o e he longe i y o pa ien s wi h success ul enal ansplan s. To a oid dea hs om in ec ion, pa icula ly common du ing he fi s yea a e ansplan a ion, he e a e ou impo an aspec s o con- side : pa ien selec ion, p ophylac ic measu es, ea ly diag- nosis and e ec i e ea men . Specific diagnos ic es s and e ec i e ea men a e now a ailable o all he commonly encoun e ed in ec ions and should be implemen ed ea lie a he han la e . Reduc ion o discon inua ion o immunosupp ession in he p esence o se ious in ec ion is also ecommended [26]. Conclusions Ou esul s show an excellen long- e m ecipien su i al and g a su i al wi h ecen immunosupp essi e egi- mens, especially in he younges age g oup. Dea h wi h unc ioning g a is he leading cause o g a loss in pa ien s >40 yea s. As he incidence o acu e ejec ion has been p og essi ely educed by ecen immunosupp essi e egimens, he assessmen o o he isk ac o s o g a loss is becoming inc easingly impo an . No el CVD isk ac o s, such as enal unc ion and p o einu ia 6 mon hs a e ansplan a ion, can be ega ded as a iables p edic - ing long- e m enal g a su i al, and hei assessmen p o ides a use ul ool o p edic ing long- e m ou come. Fig. 3. P o einu ia a 6 and 60 mon hs and glome ula fil a ion (modifica ion o die in enal disease) a 6, 12, 24, 36, 48 and 60 mon hs by age g oup. Table 5. Causes o dea h by age g oup (5 yea s) Causes <40 (%) 40–60 (%) >60 (%) To al (%) In ec ion 25.0 20.8 24.5 22.9 Ca dio ascula disease 33.9 35.6 31.0 33.9 Ce eb o ascula acciden 18.8 8.9 7.3 8.8 Ischaemic hea disease 6.3 7.9 8.2 7.9 O he hea causes 12.5 11.9 8.2 10.1 Sudden dea h 6.3 6.9 7.3 7.0 Li e disease 0.0 1.0 4.5 2.6 Neoplasias 12.5 13.9 11.8 12.8 Acciden al 0.0 1.0 0.0 0.4 Unce ain 0.0 5.0 4.5 4.4 O he 12.5 16.8 17.3 16.7 Unknown 6.3 5.9 6.4 6.2 Fig. 4. Fi e-yea pa ien su i al by age g oup. i 44 J.M. Mo ales e al. Downloaded om h ps://academic.oup.com/nd /a icle/27/suppl_4/i 39/1882932 by UNIVERSIDAD DE VALLADOLID. BIBLIOTECA use on 14 Decembe 2021 The choice o immunosupp essi e egimen emains c i i- cal o p e en ing ejec ion and main aining a good enal unc ion and low le els o p o einu ia. Thus, ea ly im- p o emen o enal unc ion and p o einu ia oge he wi h s ic con ol o ca dio ascula isk ac o s, especially in younge pa ien s a e manda o y. Conflic o in e es s a emen . The esul s p esen ed in his pape ha e no been published p e iously in whole o pa , excep in abs ac o ma . Re e ences 1. Pascual M, The u a h T, Kawai T e al. S a egies o imp o e long- e m ou comes a e enal ansplan a ion. N Engl J Med 2002; 346: 580 2. Wood o e R, Yao GL, Meads C e al. Clinical and cos -e ec i eness o newe immunosupp essi e egimens in enal ansplan a ion. A sys- ema ic e iew and modelling s udy. Heal h Technol Assess 2005; 9: 1 3. Ha iha an S, Johnson CP, B esnahan BA e al. Imp o ed g a su i- al a e enal ansplan a ion in he Uni ed S a es, 1998 o 1996. N Engl J Med 2000; 342: 605 4. Meie -K iesche HU, Schold JD, S ini as TR e al. Lack o imp o e- men in enal allog a su i al despi e a ma ked dec ease o acu e ejec ion a es o e he mos ecen e a. Am J T ansplan 2004; 4: 378 5. Foley RN, Pa ey PS, Samak MJ. Clinical epidemiology o ca dio- ascula disease in ch onic enal disease. Am J Kidney Dis 1998; 32 (Suppl 3):112–119 6. Mo ales JM, Ma cen R, And es A e al. Renal ansplan a ion in he mode n immunosupp essi e e a in Spain: ou -yea esul s om a mul icen e da abase ocus on pos - ansplan ca dio ascula disease. Kidney In 2008; 74 (Suppl 111): S94–S99 7. Mo eso F, Alonso A, Gen il MA e al. o he Spanish La e Allog a Dys unc ion S udy G oup. Imp o emen in la e eal allog a su i- al be ween 1990 and 2002 in Spain: esul s om a mul icen e case-con ol s udy. T ansplan In 2010; 23: 907–913 8. Cecka JM. The OPTN/UNOS enal ansplan egis y. Clin T anspl 2005: 1–16 9. Te aoka S, Nomo o K, Kikuchi K e al. Ou comes o kidney ans- plan s om non-hea -bea ing deceased dono s as epo ed o he Japan O gan T ansplan Ne wo k om Ap il 1995–Decembe 2003: a mul i-cen e epo . Clin T anspl 2004: 91–102 10. Fab izii V, Ko a ik J, Bodingbaue M e al. Long- e m pa ien and g a su i al in he Eu o ansplan senio p og am: a single-cen e expe ience. T ansplan a ion 2005; 80: 582–9 11. Ojo AO, Mo ales JM, González-Molina M e al. Compa ison o he long- e m ou comes o kidney ansplan a ion: USA e sus Spain. Neph ol Dial T ansplan 2012; doi:10.1093/nd /g s287 12. Se on D, A ias M, Campis ol JM e al. o he Spanish Ch onic Al- log a S udy G oup. La e enal allog a ailu e be ween 1990 and 1998 in Spain: a changing scena io. T ansplan a ion 2003; 76: 1588–1594 13. de Fij e JW, Malla MJ, Doxiadis II e al. Inc eased immunogeni- ci y and cause o g a loss o old dono kidneys. J Am Soc Neph ol 2001; 12: 1538 14. Mo ales JM, Dominguez-Gil B. Impac o Tac olimus and Myco- phenola e Mo e il combina ion on ca dio ascula isk p ofile a e kidney ansplan a ion. J Am Soc Neph ol 2006; 17(Suppl 3): s296–s303 15. Roodna JI, Mulde PGH, Van Riemsdijk IC e al. Ischemia imes and dono se um c ea inine in ela ion o enal g a ailu e. T ans- plan a ion 2003; 75: 799–804 16. Ibis A, Al unoglu A, Akgüll A e al. Ea ly onse p o einu ia a e enal ansplan a ion: a ma ke o allog a dys unc ion. T asplan P oc 2007; 39: 938–940 17. Sancho A, Ga ela E, A ila A e al. Risk ac o s and p ognosis o p o einu ia in enal ansplan ecipien s. T ansplan P oc 2007; 39: 2145–2147 18. Fe nandez G, Plaza JJ, Sanchez-Plumed J e al. P o einu ia: a new ma ke o long- e m g a and pa ien su i al in kidney ansplan- a ion. Neph ol Dial T ansplan 2004; 19(Suppl 3): 47–51 19. Yildiz A, E koç R, Se e MS e al. The p ognos ic impo ance o se e i y and ype o pos - ansplan p o einu ia. Clin T anspl 1999; 13: 241–244 20. Che uku i A, Welbe y-Smi h MP, Ta e sall JE e al. The clinical significance o ea ly p o einu ia a e enal ansplan a ion. T ans- plan a ion 2010; 89: 200–207 Table 6. Risk ac o s o pa ien dea h (o e all and by age g oup) Uni a ia e analysis (P- alue) Mul i a ia e analysis Mul i a ia e analysis by age g oup HR (95% IC) P- alue HR (95% IC) P- alue 40–60 HR (95% IC) P- alue >60 HR (95% IC) P- alue Recipien aged ≤0.001 ——— — Dono aged ≤0.001 ——— — BMI ≤0.05 ——— — Diabe es ≤0.001 ——2.15 (1.08–4.27) ≤0.05 — AT N ≤0.05 ——— — Glucose a 6 mon hs ≤0.001 ——— — Se um c ea inine a 6 mon hs ≤0.01 ——— — SBP a 6 mon hs ≤0.05 — Hepa i is C ≤0.05 ——— — Cold ischaemia ≤0.01 ——— — Cyclospo ine ( e sus ac olimus) ≤0.001 ——— — Ca dio ascula disease p e-Tx ≤0.001 ——— — ACEI/ARB ≤0.05 ——— 2.32 (1.30–4.14) ≤0.01 HR, haza ds a io. Risk ac o s o g a loss and mo ali y i 45 Downloaded om h ps://academic.oup.com/nd /a icle/27/suppl_4/i 39/1882932 by UNIVERSIDAD DE VALLADOLID. BIBLIOTECA use on 14 Decembe 2021 21. Rayhill SC, D’Alessand o AM, Odo ico JS e al. Simul aneous pan- c eas–kidney ansplan a ion and li ing ela ed dono enal ans- plan a ion in pa ien s wi h diabe es: is he e a di e ence in su i al? Ann Su g 2000; 231: 417–423 22. Ha iha an S, McB ide MA, Che ikh WS e al. Pos - ansplan enal unc ion in he fi s yea p edic s long- e m kidney ansplan su i- al. Kidney In 2002; 62: 311–318 23. Vincen i F, Jensik SC, Filo RS e al. A long- e m compa ison o ac olimus (FK506) and cyclospo ine in kidney ansplan a ion: e i- dence o imp o ed allog a su i al a fi e yea s. T ansplan a ion 2002; 73: 775–782 24. Kim SJ, Schaubel DE, Fen on SA e al. Mo ali y a e kidney ans- plan a ion: a compa ison be ween he Uni ed S a es and Canada. Am J T ansplan 2006; 6: 109–114 25. Lindholm A, Alb ech sen D, F odin L e al. Ischemic hea disease: majo cause o dea h and g a loss al e enal ansplan a ion. T ans- plan a ion 1995; 60: 451–457 26. B iggs D. Causes o dea h a e enal ansplan a ion. Neph ol Dial T ansplan 2001; 16: 1545–1549 Recei ed o publica ion: 7.8.12; Accep ed in e ised o m: 18.10.12 i 46 J.M. Mo ales e al. Downloaded om h ps://academic.oup.com/nd /a icle/27/suppl_4/i 39/1882932 by UNIVERSIDAD DE VALLADOLID. BIBLIOTECA use on 14 Decembe 2021