The number of patients undergoing treatment for end-stage renal disease (ESRD) continues to increase, whereas the growth in incident rate of ESRD is slowing (1). Much of the growth is attributable to a disproportionate increase in the number of older patients starting ESRD therapy (2). Consequently, the age of candidates awaiting kidney transplantation also has been increasing.
Kidney transplantation is the preferred treatment for most patients with ESRD because it has been found to be associated with greater longevity and better quality of life compared with dialysis (3). Previous studies have shown a significantly longer life expectancy among moderately older patients (older than 60 yr) with deceased donor kidney transplantation compared with moderately older patients on the waiting list (4). Also, compared with younger recipients, the relative risk of graft failure is not significantly different for recipients older and younger than the age of 65 after adjustment for comorbidities (4–6). Chronological age, in itself, is not a barrier to transplantation, and there is currently no age limit for access to transplantation in the United States. Moreover, a recent study showed that a survival benefit of transplant is observed in carefully selected individuals older than 75 yr of age (7). With the aging of the American population, further growth in the population of elderly patients with ESRD is anticipated.
In this study, we examined national data to assess the effect of deceased donor renal transplantation on mortality in transplant candidates on the waiting list who were at least 70 yr old at the time of listing. We also studied the impact of hypertension, diabetes, and glomerulonephritis on mortality rates among elderly patients on the waiting list and those with transplants. Finally, we assessed graft survival among elderly recipients of deceased donor and living donor transplants.
This study was approved by Health Resources and Services Administration's (HRSA's) Scientific Registry of Transplant Recipients (SRTR) project officer. HRSA has determined that this study satisfies the criteria for the IRB exemption described in the “Public Benefit and Service Program” provisions of 45 CFR 46.101(b)(5) and HRSA Circular 03.
Using national data submitted to the Organ Procurement and Transplantation Network by all U.S. kidney transplant centers, the Scientific Registry of Transplant Recipients identified 5667 elderly patients (ages 70 yr and older at the time of listing) initially wait-listed for a kidney from January 1, 1990 to December 31, 2004. Patients were excluded from the analysis if they received a transplant before the start of dialysis (n=230; deceased donor transplants=141; living donor transplants=89). Of these 5667 candidates, 2078 (36.7%) received a deceased donor transplant, 360 (6.4%) received a living donor transplant, 1849 (32.6%) died without transplant, and 1380 (24.4%) were alive but had not yet received a transplant by December 31, 2005.
Crude (unadjusted) mortality rates were computed as the number of deaths per 100 patient years at risk. Time-to-death was modeled using time-dependent Cox nonproportional hazard regression models with transplant as a time-dependent covariate. Candidates entered the study on either the date of kidney waiting list registration or the date of first dialysis therapy, whichever was later, and were followed through December 31, 2005. Time at risk was censored at living donor transplant. Mortality hazard ratios were computed for the transplant recipients compared with those on the waiting list and were adjusted for recipient age, sex, race, ethnicity, panel reactive antibody level, diagnosis, dialysis modality, donation service area, and time from initiation of dialysis until first placement on the waiting list. All analyses were performed using SAS software, version 9.1 (SAS Institute, Inc., Cary, NC). Statistical significance was identified by a P value of less than 0.05.
The annual number of new registrants on the kidney waiting list who are younger than the age of 50 yr has declined slightly since 1990, whereas the number of new registrants ages 50 to 69 yr has nearly doubled and the number of new elderly registrants ages 70 yr and older has increased more than fivefold during the past decade. The continued aging of the ESRD patient population has led to increasing numbers of prevalent elderly registrants on the waiting list, from 114 in 1990 to 2544 in 2004.
The number of transplants performed in the elderly patient population has shown a steady increase, from 27 transplants in 1990 to 297 transplants in 2005. Table 1 shows the characteristics of patients at the time of placement on the waiting list (n=5667) and at transplant (n=2438). Of the elderly patients on the waiting list and in the deceased donor transplant groups, 21% and 19%, respectively, were older than 75 yr of age. The majority of the elderly candidates on the waiting list were men (68%), as were the majority of transplant recipients (70%). Hypertension was the most common cause of ESRD, accounting for 30% of cases, and diabetes was the cause for 22% of the cases. Seventeen percent of patients who received a transplant had diabetes. Seventy percent of the waiting list patients were white, 8% were Hispanic, and 16% were black. Among those who received a deceased donor transplant, about 78% were white, 6% were Hispanic, and 12% were black.
Of the 2078 deceased donor transplant recipients, 688 (33%) received expanded criteria donor (ECD) kidneys. Such kidneys are procured from donors ages 60 yr or older or donors ages 50 to 59 yr with at least two of the following conditions: cerebrovascular accident as cause of death, serum creatinine >1.5 mg/dL, or a history of hypertension; these kidneys have a relative risk of graft loss greater than 1.70 compared with kidneys from a reference group of donors aged 10 to 39 yr without any of the other three conditions (8).
Significant differences in the comorbidities between patients on the waiting list and patients with transplants were noted with regard to hypertension, diabetes, and peripheral vascular disease. Patients can be placed on inactive status if they are temporarily not appropriate candidates for transplantation, for example, due to infection. Waiting list registrants who never received a transplant had a much greater inactive rate than those who received a transplant (12.5% vs. 1.9%, respectively). The inactive time rate is the number of days in “inactive status” during the time at risk while the patient was on the waiting list divided by the time at risk while the patient was on the waiting list.
The unadjusted death rates per 100 patient years at risk for waiting list patients and deceased donor transplant recipients were 15.8 and 13.2, respectively (Table 2). Death rates after deceased donor kidney transplant were lower than those for dialysis patients on the waiting list for all subgroups. The overall adjusted relative risk (RR) of death for transplant patients was 41% lower than that for wait-listed patients (RR=0.59; 95% confidence interval [CI] 0.53−0.65; P<0.0001). The relative mortality risk for transplant recipients versus dialysis patients on the waiting list varied with time after transplantation, as depicted graphically in Figure 1. The risk of death among transplant recipients during the first 45 days after transplant was 2.26 times as high as that among the patients on the waiting list and remained elevated until 125 days after transplant (time to equal risk). The long-term mortality risk (>18 months) was 56% lower for transplant recipients (RR=0.44; 95% CI 0.39−0.50; P<0.0001).
Figure 2 shows corresponding survival curves for elderly waiting list candidates and transplant recipients. Survival was lower in the transplant group for almost 2 yr (time to equal survival) and thereafter was greater than survival in the waiting list group. At 4 yr, adjusted survival of transplant recipients was 66% compared with 51% for waiting list candidates. Subgroup analyses showed a significant transplant survival benefit for both the group ages 70 to 74 yr (RR=0.58; 95% CI 0.52−0.65; P<0.0001) and the group ages 75 and older (RR=0.67; 95% CI 0.53−0.86; P=0.0012).
The relative mortality risk for elderly recipients with diabetic and hypertensive ESRD was 47% lower (RR=0.53; 95% CI 0.41−0.68; P<0.0001) and 44% lower (RR=0.56; 95% CI 0.45−0.68; P<0.0001), respectively, when compared with corresponding waiting list candidates. Transplant recipients with glomerulonephritis as the cause of their ESRD also had a lower mortality risk than their waiting list counterparts, but this was not statistically significant (RR=0.89; 95% CI 0.64−1.22; P=0.46). There was a kidney transplant survival benefit in all three subgroups of organ procurement organization waiting time (P<0.0001).
Elderly recipients of ECD kidneys also had a survival benefit compared with waiting list candidates (RR=0.75; 95% CI 0.65−0.86; P<0.0001). In addition, recipients of living donor kidney transplants had a survival benefit compared with the waiting list candidates (RR=0.43; 95% CI 0.33−0.57; P<0.0001).
Table 3 shows unadjusted graft survival at 1, 2, and 3 yr among elderly recipients of deceased donor and living donor transplants. One- and 3-yr graft survival rates after deceased donor transplant were 80.9% and 66.9%, respectively. The corresponding graft survival rates after living donor transplant were 90.1% and 79.3%, respectively. Death-censored graft survival was 90.4% at 1 yr and 85.2% at 3 yr for deceased donor transplant recipients (Table 4). For living donor transplant recipients, 1- and 3-yr death-censored graft survival rates were 95.8% and 93.1%, respectively.
This study is one of the largest to date to describe the survival benefit of kidney transplantation in ESRD patients older than the age of 70. Many reported studies have addressed this issue, but most are limited to single centers or small numbers of patients (4–6, 9–17). It is also interesting to note that the definition of “elderly” has shown an upward trend over time.
This analysis illuminates two notable patterns among deceased donor kidney transplant recipients older than 70 yr of age compared with their counterparts on the waiting list. First, among elderly candidates overall, survival rates after kidney transplantation are significantly greater than those achieved by candidates who remain on the waiting list and are supported by dialysis. Second, a significant benefit of transplantation was identified among elderly patients with a primary diagnosis of hypertension or diabetes. Those with a primary diagnosis of glomerulonephritis also showed a survival benefit with a relative risk of 0.89, but this risk was not statistically significant, possibly because of the small sample size. The survival benefit of transplantation over dialysis has previously been shown for diabetics, although not specifically for elderly patients with diabetes (18).
Among dialysis patients ages 70 yr and older, transplantation was associated with a 41% lower risk of death compared with the survival of comparable candidates on the waiting list. In a similar study from Queensland, Australia, but with a slightly younger patient population (the mean age of recipients was 65.8 yr), Johnson et al. (19) reported a 76% decrease in mortality risk for transplant patients compared with those who remained on the waiting list. The larger survival benefit reported in the Australian study may be attributed to the relatively younger age of the patients as well as the exclusion of patients older than 75 yr from that waiting list. Although Albrechtsen et al. (6) did not make a direct comparison with waiting list patients, they reported on a cohort of patients older than 70 yr whose survival after transplant was comparable with a cohort of recipients who were 55 to 70 yr old. Other studies, using broader age criteria, have demonstrated similar advantages of transplantation. Schaubel et al. (20) noted a 53% decrease in the probability of death after adjustment for age, etiology of ESRD, and the number of comorbidities. Oniscu et al. (21) noted a 65% lower risk of death more than 1 yr after transplantation, after adjusting for sex, age at listing, cause of ESRD, socioeconomic status, dialysis modality, and distance between patient homes and transplant centers. Wolfe et al. (18) noted a 61% lower risk of death among patients ages 60 to 64 yr, 18 months after transplantation compared with waiting list patients on dialysis.
Not all studies have found transplantation to confer a survival benefit for the elderly. In their report from the registry data of Catalonia, Bonal et al. (22) reported equivalent survival for dialysis and transplantation in patients ages 65 to 70 yr. Data from Finland suggest worse survival outcomes for patients older than 60 yr after renal transplantation compared with the waiting list cohort remaining on dialysis (23).
There has been a progressive increase in use of ECD kidneys, which accounted for 16% of all deceased donor transplants in 2003 (24). The subpopulation of patients who benefit from an ECD transplant has recently been described by Merion et al. (25). The use of ECD kidneys has been even more widespread in the elderly, with 688 ECD kidneys of 2078 (33%) deceased donor organs received by the elderly candidates in the present study. Elderly recipients of ECD kidneys had a significant 25% lower mortality risk compared with waiting list patients on dialysis.
Quality of life benefits have been demonstrated in older recipients after kidney transplantation, specifically with regard to overall general health and social functioning, with a pronounced benefit in mental health compared with the national norms (26).
Older age is associated with some advantages with respect to transplantation. For example, acute rejection is less common in older patients because of a less active immune system (27). Although the elderly do not appear to be at lower risk for infection or chronic graft rejection with standard immunosuppressive regimens, future regimens at modified doses may decrease infectious complication in this age group (28).
Previous studies have shown that, among kidney transplant recipients ages 60 yr and older, death with a functioning graft is the predominant cause of graft loss. Thus, if one decreases the risk of death in older transplant recipients with careful pretransplant evaluation, i.e., by stricter selection of healthier candidates, not only might those patients live longer with a functioning graft, but their survival would be greater. Once candidates have been listed for a transplant, being placed on “inactive” status on the waiting list serves as an additional selective mechanism for ensuring that elderly candidates are suitable for receipt of a transplant when an offer arrives. Our data, which show a significant difference in the “inactive” status rate between elderly patients still on the waiting list and those who received a transplant (12.5% vs. 1.9%; P<0.001), lend support to this hypothesis.
Allocating scarce donor resources to the elderly has raised concerns in some circles. The unadjusted probabilities of 10-yr patient survival for deceased donor first transplant recipients older than age 65 yr in the United States is 20.6%. This contrasts with 58.6% for patients aged 40 to 49 yr (29). Should there be an upper age limit for deceased donor kidney transplantation? The answer is complicated by many issues. First, elderly patients have the potential for additional quality years of life. The average 70-yr-old patient on dialysis in the United States lives another 3 yr, as opposed to 13.4 yr for a 70-yr-old in the general population (29). Transplantation provides better quality of life than dialysis for such patients. However, although kidney transplantation is more cost- effective than dialysis, it takes substantial time for the lower long-term cost to break even with the high initial cost. If it can be predicted for a specific patient that the potential for survival is severely limited by extrarenal disease, the expense of transplantation may not be justified.
Although some studies have suggested equivalent 1- and 5-yr adjusted patient survival rates among recipients older than 65 yr of age (9, 16) and even among those age 70 yr compared with younger recipients (18), it is important to recognize that such results suggest greater selectivity of elderly patients for transplantation. Long-term survival has not been equivalent between cohorts older and younger than age 60 (46% vs. 68%, respectively; P<0.001) (30). Our study does not suggest increased placement of the elderly on the waiting list and more transplants because less selectivity would be expected to yield a smaller benefit from transplant.
As with all registry-based observational studies, these results are subject to certain limitations. First of all, the comorbidities listed are collected at the entry of the observation period and not updated periodically. Second, although the analysis adjusts for the various comorbidities, an observational study cannot identify and measure all relevant covariates that may influence the outcome. Finally, registry-based studies demonstrate correlation; they do not imply causation. This would require a randomized controlled trial.
This large study demonstrates that elderly patients on the waiting list experience significant survival benefit with kidney transplantation. The benefit is observed among patients whose life expectancy is expected to exceed 1.8 yr and is most striking for patients with ESRD caused by diabetes and/or hypertension. Although a patient's risk of death at 45 days after transplantation was 2.26 times as great as the risk of those on the waiting list, this risk declined rapidly. By 125 days, the mortality risk for both groups was equal. Recipients of a living donor transplant show the greatest reduction in mortality risk. Deceased donor transplantation (both ECD and non-ECD) also confers a survival benefit. The recipients of ECD kidneys had a 25% reduction in mortality risk compared with those on the waiting list. The results depend on the selectivity used to identify those elderly candidates on the waiting list for transplant. These findings are especially important in the face of the growing number of elderly patients on renal replacement therapy.
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