How Old is Old for Transplantation?
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<ul><li><p>American Journal of Transplantation 2004; 4: 20672074Blackwell Munksgaard</p><p>Copyright C Blackwell Munksgaard 2004</p><p>doi: 10.1111/j.1600-6143.2004.00622.x</p><p>How Old is Old for Transplantation?</p><p>Gabriel C. Oniscua,, Helen Brownb</p><p>and John L. Forsythea</p><p>aTransplant Unit, The Royal Infirmary of Edinburgh, UK andbInformation and Statistics Division, Scottish NationalHealth Service, UKCorresponding author: Gabriel C. Oniscu,email@example.com</p><p>Elderly patients are the fastest growing group re-quiring renal transplantation. This study investigateswhether transplantation is worthwhile in the elderlyand whether there is evidence supporting an age limitfor transplantation.</p><p>One thousand ninety-five adults transplanted inScotland between 1 January 1989 and 31 December1999 were followed up to 11 years. Sociodemographic,comorbidity and transplant data were obtained fromthe national databases and patients notes. Patient andgraft survival, risk and causes of graft failure and pa-tient death were compared between four age groups(1849, 5059, 6064 and >65).</p><p>All groups had similar gender, social deprivation andrenal disease distribution. The incidence of comorbid-ity increased with age. The groups had comparableHLA matching, but patients aged 1849 years receivedtransplants from younger donors and with shorter coldischaemic times. Younger patients had more acute re-jection and less delayed graft function. Older patientshad a higher incidence of death with functioning graft.Patients over 65 years had an almost dialysis-free re-maining life, while the graft half-life was significantlyshorter than patient half-life in the youngest group.</p><p>Transplantation in elderly recipients is worthwhile de-spite a higher comorbidity. Careful selection ratherthan a fixed age limit should be used to ensure a sat-isfactory graft and patient survival.</p><p>Key words: Renal transplantation, elderly patients,outcome, comorbidity, survival, multivariate analysis,graft survival, clinical assessment</p><p>Received 13 March 2004, revised and accepted for pub-lication 22 July 2004</p><p>Introduction</p><p>The number of elderly patients accepted in renal replace-ment programmes is continuously increasing. In Scotland,</p><p>a country of five million people, the incidence of end stagerenal disease (ESRD) has risen dramatically from 61 permillion population (pmp) in 1990, to 109 pmp in 1999. Thepercentage of ESRD patients over 60 years has increasedfrom 42% in 1989, to 65% in 1999. In fact, patients agedover 65 years represented more than half of the total num-ber of new patients in 1999 (1). A similar trend was notedin the United States, where the number of patients over 65years requiring RRT doubled in the last decade (2), Australia(3), Japan, Canada and the rest of Europe (4).</p><p>On the basis of evidence that transplantation is safe andsuccessful (5,6) and survival with a transplant is better thanthat on dialysis (7,8) even in older patients, there is a gen-eral consensus that age per se should not represent abarrier to transplantation. And yet, many centers are stillreluctant to accept elderly patients onto the waiting list dueto their comorbid conditions (9) and shorter life expectancy.In addition, an increased age at the time of transplantationhas a significant impact on long-term graft survival (10) anddeath with a functioning graft is a common event duringthe follow-up (11).</p><p>Although in the United Kingdom there is no age limit foraccess to transplantation and the listing and transplanta-tion criteria are identical for all patients irrespective of theirage, only 7.2% of transplant recipients are aged over 65years (12). In the United States, where extended criteriadonors (ECD) are used increasingly in recent years, only9.9% of patients over 65 years are transplanted with non-ECD, while 22.9% receive an ECD kidney (13). In Scotland,where the UK national listing and transplantation criteria areapplied, significant inequities in access to the waiting listand renal transplantation according to patients age havebeen described (14). Only 26% of those aged 6064 yearsand respectively 8.5% of those over 65 years are on thewaiting list for transplantation within 3 years of startingRRT. After listing, only 43% of the 6064 years old pa-tients and respectively 29% of those over 65 years aretransplanted within 3 years. This is in stark contrast to over70% of patients aged 1849 years listed within 3 years ofstarting RRT. More than 60% of those listed in this agegroup received a transplant within 3 years.</p><p>In the context of the current organ shortage, there is acontinuous debate whether elderly patients should go ontothe national waiting lists, or they should be part of speciallydesigned schemes to which older or marginal kidneys arepreferentially allocated. Currently in the United Kingdom,there are no such schemes and the selection criteria for</p><p>2067</p></li><li><p>Oniscu et al.</p><p>the transplant waiting list and subsequent transplantationare identical for all patients irrespective of their age.</p><p>Therefore, the aim of this paper was to compare the resultsof kidney transplantation in different age groups and toinvestigate whether transplantation is worthwhile in theelderly or we should set an age limit for access onto thewaiting list.</p><p>Methods</p><p>All adult patients who started dialysis between 1 January 1989 and31 December 1999 and were transplanted with a cadaveric kidney (firstgraft) until 31 December 2000 (n = 1095) were grouped according to theirage at grafting (1849 years, 5059 years, 6064 years and >65 years). Thekidneys were distributed according to the national criteria set by the UKTransplant. They are based on closeness of HLA with three tiers (tier 1 =no HLA mismatch, tier 2 = one mismatch for HLA-A and/or HLA-B and nomismatches for HLA-DR, tier 3 = one or two HLA-DR mismatches and/ortwo mismatches for HLA-A and/or HLA-B). At each level, priority is given topediatric over adult recipients, highly sensitized over non-sensitized, localversus national recipients. If more than one recipient is identified, a pointscoring mechanism is used as a discriminator based on the following crite-ria: recipient age, donor/recipient age difference, waiting time, matchability,sensitization and balance of exchange between centers. Although the al-gorithm has been revised several times throughout this study, all criteriacontinued to apply to all patients, irrespective of their age.</p><p>The sociodemographic and extensive comorbidity data, as well as the levelof HLA matching, the length of the cold ischaemic time, patient and graft</p><p>Table 1: Comparison of baseline characteristics of transplanted patients according to the age at transplantation</p><p>1849 years 5059 years 6064 years >65 years(n = 686) (n = 252) (n = 82) (n = 75) p-value</p><p>Male:Female ratio 57.9:42.1 67.5:32.5 64.6:35.4 66.7:33.3 0.033a</p><p>Primary renal disease (%) 0.174Glomerulonephritis 28.7 30.2 23.2 34.7Interstitial nephritis 35.0 34.9 31.7 25.3Multisystem disease 11.2 13.5 17.1 18.7Diabetes 13.7 8.3 11.0 8.0Other 11.4 13.1 17.1 13.3</p><p>Deprivation category (%) 0.621 (least deprived) 5.0 5.2 6.1 4.02 12.0 13.1 14.6 18.73 22.6 21.8 23.2 30.74 26.1 26.6 29.3 29.35 15.3 16.3 15.9 6.76 12.6 11.5 8.5 9.37 (most deprived) 6.4 5.6 2.4 1.3</p><p>HD as 1st RRT (%) 56.5 59.9 62.2 58.6 0.785Median duration of pre-transplant dialysis (years) 1.3 1.33 1.62 1.92 0.031a,b</p><p>Number of switches between dialysis modalities (%) 0.034a</p><p>0 65.7 64.5 61.7 76.01 21.3 21.6 29.6 13.3>2 13.0 13.9 8.7 10.7</p><p>Listing center (%) </p></li><li><p>How Old is Old for Transplantation?</p><p>Table 2: Comparison of comorbidity characteristics of transplanted patients according to the age at transplantation</p><p>1849 years 5059 years 6064 years >65 years p-value</p><p>Peripheral vascular disease (%) 5.0 11.9 16.3 27.3 </p></li><li><p>Oniscu et al.</p><p>Patient survival following transplantation (years)</p><p>121086420</p><p>Cum</p><p>ulat</p><p>ive s</p><p>urviv</p><p>al1.2</p><p>1.0</p><p>.8</p><p>.6</p><p>.4</p><p>.2</p><p>Age groups</p><p>>65 years</p><p>6064 years</p><p>5059 years</p><p>1849 years</p><p>Age group 1 year 3 years 5 years 8 years </p><p>1849 5059 6064 >65 </p><p>98 92 87 91 </p><p>93 88 76 77 </p><p>91 81 59 66 </p><p>82 61 49 33 </p><p>Figure 1: Patient survival followingtransplantation (p < 0.0001, Log-ranktest).</p><p>recipients aged >65 years, but this was compensated bya higher proportion of tier 2 (010, 010 or 110 mismatches)grafts.</p><p>As expected, the donor age increased, the older the recip-ient, from 38 years in the younger recipients, to 48 yearsin those >65 years, but with a comparable gender distri-bution.</p><p>Younger patients (1849 years) were transplanted within ashorter cold ischaemic time (mean 1126 min), but had ahigher incidence of acute rejection episodes, while elderlypatients (>65 years) had a higher incidence of delayed graftfunction.</p><p>All patients had an excellent 1-year survival rate (Figure 1).There were no significant differences between the sur-vival curves in the first year post-transplantation, but asexpected, there were substantial differences in the long-term survival between those younger and those older than60 years. It was noted that up to 5 years post-transplant,those aged >65 years had a better survival than patientsaged 6064 years. At 8 years post-transplant, half of thepatients in the 6064 years old group were alive comparedwith one third in the >65 group.</p><p>Similar differences were noted for the graft survival(Figure 2), 60% of the transplants performed in patientsyounger than 60 years functioning at 8 years, in contrastwith only 3040% in those over 60 years. However, graftsurvival in patients aged >65 years was comparable withthat seen in the 5059 years group for the first 5 yearspost-transplant. When the two groups of elderly recipientswere compared, patients over 65 years had a better graftsurvival throughout the study period.</p><p>This advantage persisted when graft survival was censoredfor death with functioning graft (Figure 3). In fact, the oldergroup had the best graft survival at all time points, butoverall, the differences between the study groups werenot statistically significant (p = 0.2685, Log-rank test).</p><p>An examination of the crude death rate (Table 4) showeda fourfold increase from 2.4 per 100 years of patientfollow-up in the 1849 years group to 10.35 in those aged>65 years. This was further illustrated by the differencesin the proportion of patients from each group, dying withinthe study period. Patient half-life showed a significantreduction in the life expectancy, from 37 years in theyoungest group to less than 8 years in patients >65 years(p = 0.0001, chi-square). Nevertheless, it is important to</p><p>2070 American Journal of Transplantation 2004; 4: 20672074</p></li><li><p>How Old is Old for Transplantation?</p><p>Graft survival (years)</p><p>121086420</p><p>Cum</p><p>ulat</p><p>ive s</p><p>urviv</p><p>al</p><p>1.2</p><p>1.0</p><p>.8</p><p>.6</p><p>.4</p><p>.2</p><p>Age groups</p><p>>65 years</p><p>6064 years</p><p>5059 years</p><p>1849 years</p><p>Age group 1 year 3 years 5 years 8 years </p><p>1849 5059 6064 >65 </p><p>88 82 75 88 </p><p>78 76 62 76 </p><p>70 68 53 63 </p><p>60 55 43 31 Figure 2: Graft survival (p < 0.0001,</p><p>Log-rank test).</p><p>highlight that the death rate noted in patients over 60 yearswho were transplanted, was significantly lower than thatobserved in similar aged patients who were listed but re-mained on dialysis (16 per 100 years of patient follow-up).When the risk of death on dialysis on the waiting list wascompared with the risk of death following transplantation(not adjusted for graft failure), it was observed that despitean initial (30 days) higher risk of death following transplan-tation (RR = 1.52, CI = 0.211.81), patients over 60 yearshave a 70% lower risk of death (RR = 0.30, CI = 0.160.56)beyond a year post-transplant.</p><p>When the relative risk of death, adjusted for comorbidityconditions, was determined for all transplant recipients,those over 50 years had a largely increased risk of deathcompared with the baseline represented by those aged1849 years (Table 4). A similar tendency was observedfor graft failure, more than 40% of the grafts in the eldestgroup being lost throughout the 11 years of follow-up, alarge proportion of these due to death with functioninggraft. Despite a significant disproportion in the graft half-lifebetween the four groups, a kidney allograft transplanted inpatients under 60 years was likely to function for at least9 years (one quarter of the estimated patient half-life), while</p><p>patients over 65 years enjoyed an almost entire dialysis-free life following transplantation (graft half-life 6.96 andpatient half-life 7.88, respectively).</p><p>A comparison of the relative risk of graft failure adjustedfor the confounding comorbidity, showed no significant dif-ferences between the four groups of transplanted patients(p = 0.201, Cox regression analysis, Table 4).</p><p>The incidence of death with functioning graft was threetimes higher in patients aged >65 years compared withthose aged 1849 years, in contrast to immunological fail-ures, which had an entirely opposite trend and were mostfrequent in the youngest age group (Table 5). However, asignificant proportion of the causes of graft failure in the1849 years old group were unaccounted for.</p><p>Significant differences in the proportion of patients dyingdue to infection or vascular causes were noted betweenthe four groups (Table 6), but it is important to note thatthere was no difference in cardiac death between all agegroups. Nevertheless, between one in four and one in fivedeaths were not known in each group. If we considerthese unknown cases to represent sudden deaths, and</p><p>American Journal of Transplantation 2004; 4: 20672074 2071</p></li><li><p>Oniscu et al.</p><p>Graft survival censored for death with functioning graft (years)</p><p>121086420</p><p>Cum</p><p>ulat</p><p>ive s</p><p>urviv</p><p>al1.1</p><p>1.0</p><p>.9</p><p>.8</p><p>.7</p><p>.6</p><p>.5</p><p>Age groups</p><p>>65 years</p><p>6064 years</p><p>5059 years</p><p>1849 years</p><p>Age group 1 year 3 years 5 years 8 years </p><p>1849 5059 6064 >65 </p><p>89 88 82 93 </p><p>81 84 74 90 </p><p>75 78 72 81 </p><p>70 75 72 70 </p><p>Figure 3: Graft survival censored fordeath with functioning graft (p =0.2685, Log-rank test).</p><p>therefore have a cardiac origin, this would increase thecardiac causes of death to 50% of all kidney transplantsperformed in Scotland, irrespective of the recipient age.</p><p>Discussion</p><p>The demographics of ESRD demonstrate a constant in-crease in the age of new patients starting replacement</p><p>Table 4: Comparison of patient and graft outcome according to recipients age at transplantation</p><p>1849 years 5059 years 6064 years >65 years(n = 686) (n = 252) (n = 82) (n = 75) p-value</p><p>Crude death rate (per 100 years 2.4 5.55 10.04 10.35of patient follow-up)</p><p>Deaths (%) 10.3 24.6 35.4 40.0 </p></li><li><p>How Old is Old for Transplantation?</p><p>Table 5: Comparison of causes of graft failure according to recipients age at transplantation</p><p>1849 years 5059 years 6064 years >65 yearsCause of graft failure (n = 686) (n = 252) (n = 82) (n = 75) p-valueDeath with functioning graft (%) 20.6 43.0 47.2 61.3 65 years on renalreplacement therapy (1) and a higher risk of death on dialy-sis on the waiting list. It is also important to note that whilein the youngest group, the estimated graft half-life is nearly10 years, against an estimated patient half-life of 37 years,a 7 years graft half-life in the eldest group ensures adialysis-free life in the context of a half-life of 8 years, of-fe...</p></li></ul>
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