Matching Older Kidneys with Older Patients Does Not Improve Allograft Survival

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1 J Am Soc Nephrol 13: , 2002 Matching Older Kidneys with Older Patients Does Not Improve Allograft Survival BERTRAM L. KASISKE* and JON SNYDER* *United States Renal Data System Coordinating Center, Minneapolis, Minnesota; and Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota. Abstract. Centers may restrict the use of some donor kidneys on the belief that overall graft survival is improved by giving older kidneys to older recipients and vice versa. The prevalence and the effect on graft survival (determined by death, return to dialysis, or retransplantation) of this practice among 74,297 first cadaver kidney transplantations in 1988 to 1998 was examined by using data from the United States Renal Data System. Giving older kidneys to older recipients is common; recipients 55 yr old received donor kidneys that were 55 yr old 46.2% more often than expected, but they received kidneys that were 18 to 29 yr old 33.6% less often than expected ( 2 P ). Both recipient and donor age have important effects on graft survival, although the effects of donor age are much stronger than those of recipient age. Compared with recipients 18 to 29 yr old, recipients 55 yr old were 25% (95% confidence interval, 15 to 35%, P ) more likely to have graft failure (adjusted for donor age and other risk factors). On the other hand, donor kidneys 55 yr old were 78% (95% confidence interval, 58 to 99%, P ) more likely to fail compared with kidneys 18 to 29 yr old. However, giving older kidneys to older recipients had little independent effect on graft survival, once the intrinsic effects of recipient and donor age were taken into account. For example, transplanting donor kidneys 55 yr old into recipients 55 yr old reduced the risk of graft failure only 6% (95% confidence interval, 18 to 8%, P ) after the independent effects of donor and recipient age per se were taken into account. Thus, giving older kidneys to older recipients is a common practice that does not improve overall graft survival. Received June 6, Accepted October 24, The data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government. Correspondence to Dr. Bertram L. Kasiske, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN Phone: ; Fax: ; kasis001@umn.edu / Journal of the American Society of Nephrology Copyright 2002 by the American Society of Nephrology With the organ donor shortage, transplantation centers and patients have been accepting a greater proportion of older kidneys in recent years than in the past. Unfortunately, graft survival (determined by death, return to dialysis, or retransplantation) of older kidneys is inferior to that of kidneys from younger adult donors (1 3). The poorer graft survival of older kidneys has been attributed to a greater susceptibility to ischemia reperfusion injury and delayed graft function, which in turn may make the allograft more susceptible to acute rejection and graft failure (4 6). It has also been suggested that older donor kidneys, with their reduced number of functioning nephrons, may be more susceptible to chronic hyperfiltration injury and acute rejection, both of which may contribute to chronic allograft nephropathy (7,8). Recipient age also affects graft survival. Older recipients are more likely to die with a functioning allograft than younger recipients, although death-censored graft failure, defined as a need for retransplantation or maintenance dialysis, is less common in older recipients compared with younger recipients (9,10). Because graft survival is reduced in older recipients, it can be reasoned that by preferentially transplanting older donor kidneys (which are also less likely to survive as long as younger donor kidneys) into older recipients, overall graft survival may be optimized (11). It has also been frequently suggested that older kidneys function longer in older recipients as a result of the reduced physiologic stress placed on the allograft by the older recipient (7,12 16). Thus, the hyperfiltration, or inadequate nephron dosing, hypothesis has provided a strong rationale for preferentially accepting older donor kidneys for older recipients and vice versa. The United Network for Organ Sharing (UNOS) allocation scheme does not take donor age into account. Therefore, any nonrandom differences in the numbers older kidneys given to older recipients should reflect the practice of centers refusing kidneys on the basis of their relative age with respect to the potential recipient s age. We examined this in a large number of transplantations performed in the United States. We also investigated whether graft survival is improved by preferentially transplanting older kidneys into older recipients. Methods Study Population This analysis was carried out using data from the United States Renal Data System collected by UNOS. We examined all first cadaver kidney transplantations performed between 1988 and Patients who had undergone multiple organ transplantations were excluded. There were 74,297 patients with complete data on donor and recipient age included. In addition, we conducted analyses on 64,939 patients

2 1068 Journal of the American Society of Nephrology J Am Soc Nephrol 13: , 2002 that had complete data on donor and recipient age and gender, recipient race, cold ischemia time, primary cause of kidney failure, HLA mismatches, and panel-reactive antibody titer. Analyses We first examined the distribution of transplantations by categories of donor and recipient age to determine whether there were more or less of the expected number of transplantations in each age category. This analysis assumed that the UNOS allocation of cadaver kidneys by donor and recipient age was random and that differences in the expected number of transplantations in one or more age categories would reflect differences in the acceptance rates of kidneys by transplantation centers. We then examined the effects of recipient and donor age on graft failure, death-censored graft failure, and death with a functioning graft by Cox proportional hazard analyses. The Cox analysis allowed us to determine the independent effects of different donor and recipient ages, and age combinations, on graft failure. In this analysis, a relative risk of 1.00 indicates that there is no effect of that age or age combination on graft failure compared with a reference group (we arbitrarily chose donor and recipient age 18 to 29 yr as the reference group), whereas a relative risk of 1.00 indicates a proportionally increased risk, and a relative risk of 1.00 indicates a proportionally decreased risk of graft failure. We used discrete categories of recipient and donor age to avoid any assumptions about the nature of the relationships between age and outcomes. Specifically, we did not assume that there would be a linear relationship between age (donor or recipient) and graft failure; rather, we allowed age categories to reveal whether the relationship between age and graft failure was J-shaped, U-shaped, or some other configuration. We based our selection of categories on the distribution of recipient and donor ages in the UNOS transplantation population so that there would be adequate numbers in each category. In addition to recipient and donor age, we included in the same Cox analyses different combinations of recipient and donor ages to examine whether any specific donor and recipient age combinations had effects on outcomes that were independent of recipient age, donor age, and other risk factors. In this analysis, we hypothesized that if giving older kidneys to older recipients decreased the rate of graft failure, then the combination of older kidneys with older recipients would have a lower risk of graft failure ( 1.00), independent of the intrinsic risks of older kidneys and older recipients. We also performed separate side-by-side comparisons of the risk of graft failure in different donor-recipient age combinations versus the risk of graft failure that would be expected from the intrinsic effects of donor and recipient age in any combination. In the first Cox analysis, we examined the effects of different donor and recipient age combinations, whereas in the second analysis, we examined the effects of donor age and recipient age separately (but not in combinations). This permitted a qualitative comparison of differences in graft failure attributable to specific combinations of donor and recipient ages versus the effects on graft failure of donor and recipient age per se. All analyses were performed by SAS statistical software, version 8.1 (SAS Institute, Cary, NC). All results were considered statistically significant at P Relative risk results of the Cox analysis are expressed with 95% confidence intervals. Failure of a 95% confidence interval to include 1.00 indicates a statistically significant difference in relative risk. Results The numbers of first cadaver kidney transplantation procedures have increased only slightly from 1988 to However, an increasing proportion of these transplantations have been performed in patients 55 yr old. Similar trends have been observed in cadaver donor age (Figure 1). The percentages of the total number of recipients and donors 55 yr old have increased from 17.5 to 32.2% and from 6.5 to 12.0% from 1988 and 1998, respectively. During this time, giving older kidneys to older recipients was a common practice (Table 1). For example, recipients 55 yr old received kidneys that were 55 yr old 46.2% more often than would have been expected if differences in recipient and donor age had not been a factor in deciding to transplant a kidney (Table 1). Recipients 55 yr old received kidneys that were 18 to 29 yr old 33.6% less often than expected (Table 1). The differences between observed and expected numbers of transplantations in the different recipient and donor categories were similar in 1988 and 1993 compared with 1994 and 1998 (data not shown). Both recipient and donor age have important effects on graft survival, although the effects of donor age are much stronger than those of recipient age (Figure 2). Compared with recipients 18 to 29 yr old, recipients 55 old were 25% more likely to have graft failure over a median survival of 3.95 yr (25 to 75% interquartile range, 1.85 to 6.09 yr). Interestingly, there was a similar, increased risk of graft failure for recipients 18 yr old. On the other hand, donor kidneys 55 old were 78% more likely to have graft failure compared with kidneys 18 to 29 yr old. There was also a J-shaped curve effect for donor age because donor kidneys 18 yr old were 17% more likely to have graft failure compared with donor kidneys 18 to 29 yr old (Table 2). Giving older kidneys to older recipients does not appear to have a major effect on graft survival independent of the effects of recipient and donor age per se (Table 2). Indeed, there did not appear to be any consistent interactions of specific recipient-donor age combinations. Among the 16 recipient-donor age categories included in the multivariate Cox proportional hazard analysis, only 4 were statistically significant. However, all of these effects were only marginally significant (0.05 P Figure 1. Changes in the numbers of first cadaveric kidney transplant recipients and donors by age from 1988 to 1998.

3 J Am Soc Nephrol 13: , 2002 Matching Older Kidneys with Older Patients 1069 Table 1. Donor and recipient age matching among first cadaveric kidney transplants 1988 to 1998 Donor Age (y) Number of Transplants (% Different from Expected for Random Age Allocation) for Recipient Age a 0to17yr 18to29yr 30to41yr 42to54yr 55 yr 0 to (89.7) 765 ( 2.6) 534 ( 8.8) 398 ( 36.4) 94 ( 74.5) 18 to (17.3) 2595 (6.2) 1819 ( 0.1) 1839 ( 5.5) 763 ( 33.6) 30 to (0.0) 5328 (5.6) 3897 (3.6) 4026 (0.2) 1947 ( 17.9) 42 to ( 5.9) 6442 (0.3) 4834 (1.0) 5295 (3.5) 3082 (2.1) ( 15.9) 4279 ( 9.1) 3380 ( 3.7) 3903 (4.0) 3235 (46.2) a In each cell is the number of transplantations, and in parentheses are the percentage deviations from expected [100 (observedexpected)/expected]. For example, for donors and recipients both 55 yr old, there were 3235 transplants, which was 46.2% more than expected if all kidneys had been allocated without regard to donor or recipient age. Figure 2. The relative risk for graft failure attributable to specific donor and recipient age combinations (A) versus relative risks from donor age and recipient age per se (B) in Cox proportional hazard analyses. (A) Analysis includes only the 24 recipient and donor age categories shown (n 74,297). The reference category (relative risk, 1.00) is for recipients and donors 18 to 29 yr old. Relative risks more than 1.00 indicate a proportionally greater risk of graft failure; relative risks 1.00 indicate a proportionally lower risk. (B) Analysis includes only the 4 recipient age categories (reference, 18 to 29 yr old) and 4 donor age categories (reference, 18 to 29 yr old); the relative risk in each of the 24 recipient and donor age categories was calculated on the basis of the additive effects of recipient and donor age. Differences in the relative risks between (A) and (B) should reflect the effects of combining donors and recipients in specific age categories. To the extent that (A) and (B) are similar, there is not likely to be an effect of combining donor and recipient ages in specific categories that are independent of the effects of recipient and donor age per se (B) ), and some could have been the result of chance. The strongest of these effects were the 2 interactions for recipient and donor age for recipients 18 yr old receiving donor kidneys 18 yr old and for recipients 18 yr old receiving donor kidneys 30 to 41 yr old (Table 2). Both of these effects partly reduced the otherwise higher relative risk of graft failure for recipients 18 yr old. However, there was no reciprocal adverse effect of giving older donor kidneys to younger recipients, and in fact, there was a NS trend for a similar reduction in the risk of graft failure for giving older donor kidneys to younger recipients. In other words, there did not appear to be any consistent pattern across all of the possible recipient-donor age combinations that would suggest that giving younger or older kidneys to younger or older recipients altered the risk of graft failure. Confirming the results of the multivariate Cox analysis was the fact that the unadjusted relative risks of several different combinations of recipient and donor age appeared to be qualitatively similar to what would be expected in these categories from the independent effects of recipient and donor age alone that is, without interactions from recipient and donor age mismatches (Figure 2). For example, for donor kidneys 55 yr old, the risk of graft failure was not higher or lower for recipients of different ages in a multivariate Cox proportional hazard analysis (Table 2). Similar results were obtained if the Cox analysis was limited to only patients that survived at least 1 yr or for 3 yr (data not shown). As was the case for graft survival, giving older kidneys to older recipients did not appear to have any major effects on patient survival, or death-censored graft survival, independent of the effects of recipient and donor age per se (Figures 3 and 4). The Cox proportional hazard analyses confirmed the qualitative comparisons of the effects of donor-recipient age combinations with the intrinsic risk from donor and recipient age for patient survival, and death-censored graft survival (data not shown). However, the effects of recipient age on death-censored graft failure and death with function were very different from each other (Figures 3 and 4). Specifically, older recipients were much more likely to die than their younger counterparts, whereas older recipients were less likely to return to dialysis (or to undergo retransplantation) compared with younger recipients. In contrast, the effects of donor age on death-censored graft failure and death with function were similar (Figures 3 and 4). In Cox analysis adjusted for the same risk factors shown in Table 2, recipients of kidneys 55 yr old were 72% (95% confidence interval, 52 to 94%) more likely to return to dialysis (or to require retransplantation) than recipients of kidneys 18 to 29 yr old (full model not shown). Similarly, recipients of kidneys 55 yr old were 80% (30 to 250%) more likely to die than recipients of kidneys 18 to 29 yr old (full model not shown). Discussion The results of this study imply that transplantation centers are more likely to accept older donor kidneys for older recipients (and younger kidneys for younger recipients) than would be expected if decisions to accept or reject a kidney were not

4 1070 Journal of the American Society of Nephrology J Am Soc Nephrol 13: , 2002 Table 2. Lack of independent effects of giving older kidneys to older recipients on graft survival Age (yr) Relative Risk for Graft Failure a (95% CI) P Value Recipient age 0 to (1.10 to 1.43) to 29 (reference) to (0.89 to 1.03) to (0.98 to 1.13) (1.15 to 1.35) Donor age 0 to (1.07 to 1.28) to 29 (reference) to (1.10 to 1.32) to (1.26 to 1.51) (1.58 to 1.99) Recipient and donor age 18 to 29 or 18 to 29 (reference) to 17 and 0 to (0.66 to 0.93) to 17 and 30 to (0.64 to 0.96) to 17 and 42 to (0.72 to 1.09) to17and (0.55 to 1.09) to 41 and 0 to (0.84 to 1.05) to 41 and 30 to (0.89 to 1.11) to 41 and 42 to (0.90 to 1.13) to 41 and (0.89 to 1.17) to 54 and 0 to (0.79 to 0.99) to 54 and 30 to (0.79 to 0.99) to 54 and 42 to (0.84 to 1.04) to 54 and (0.86 to 1.12) and 0 to (0.80 to 1.00) and 30 to (0.81 to 1.03) and 42 to (0.84 to 1.06) and (0.82 to 1.08) a A relative risk greater than or less than 1.00 indicates a proportionally greater or lesser risk of graft failure. For example, recipients aged 0 to 17 yr who receive kidneys from donors aged 0 to 17 yr would be 15% more likely to develop graft failure (1.26 recipient age effect 1.17 donor age effect 0.78 recipient-donor combination effect), compared with the reference group of recipients or donors aged 18 to 29 yr. All age effects were adjusted for donor and recipient gender, recipient race, cold ischemia time, kidney failure from type 1 or 2 diabetes, panel reactive antibody titer 5%, human leukocyte antigen mismatches (0 to 6), and transplant year (1988 to 1998). Included are data from 64,939 first cadaveric transplants with complete data. influenced by differences between the age of the recipient and donor. One reason for this might be a belief that overall graft survival is improved by giving older kidneys to older recipients. However, the results of this analysis suggest that giving older kidneys to older recipients has no effect on overall graft survival. There is a widely held belief that placing older donor kidneys in older recipients reduces the physiologic stress on the Figure 3. The relative risk for death-censored graft failure attributable to specific donor and recipient age combinations (A) versus relative risks from donor age and recipient age in any combination (B). For a full explanation, see Figure 2 caption. Figure 4. The relative risk for death with function attributable to specific donor and recipient age combinations (A) versus relative risks from donor age and recipient age in any combination (B). For a full explanation, see Figure 2 caption. allograft and thereby prolongs allograft survival (7,12 16). Most of the studies that have provided data to support this hypothesis have been single-center investigations of relatively small numbers of patients (12 14). However, two single-center studies failed to find an independent effect of donor and recipient age differences on graft survival (10,17). Studies from large registries have shown that older donor age is associated with reduced graft survival, but these studies have not systematically examined the effects of interactions between donor and recipient age, independently from the effects of donor and recipient age per se. For example, Busson and Benoit (16) showed that when the donor was more than 10 yr older than the recipient, graft survival was lower, but they did not report whether differences in donor and recipient age predicted graft survival better than (or independently of) recipient age and donor age alone. In comparing separate analyses of transplantations grouped by donor age, Hariharan et al. (18) found that older recipient age negatively affected graft survival in recipients of older donor kidneys, but not in recipients of younger donor kidneys. However, they did not report the effects of specific donor and recipient age combinations (interactions) in multivariate analysis that independently adjusted for the intrinsic effects of recipient and donor age (18). Thus, it is unclear from these studies whether giving older kidneys to older recipients improves graft survival. The results of our analysis suggest that it does not.

5 J Am Soc Nephrol 13: , 2002 Matching Older Kidneys with Older Patients 1071 It is theoretically possible that the current practice of giving older kidneys to older recipients has made it impossible to detect an effect of this age matching on graft survival. However, this seems unlikely for two reasons. First, the number of patients in the analysis we performed is large, making it improbable that even small effects would have been missed. Second, giving older kidneys to older recipients was not completely efficient; there were large numbers of younger recipients who received older donor kidneys and vice versa (Table 1). Four of the 16 recipient-donor age combinations examined appeared to have statistically significant effects on graft survival over and above the effects of recipient and donor age per se (Table 2). However, there did not appear to be any consistent pattern to these effects, raising the possibility that these were the result of chance. For example, the apparent reduction in the risk for recipients 18 yr old that received younger donor kidneys, although statistically significant, was similar in magnitude to the reduction in risk for recipients 18 yr old that received older donor kidneys (Table 2). Similarly, the apparent reduction in risk for recipients 42 to 54 yr old that received younger donor kidneys was comparable to the risk reduction for recipients 42 to 54 yr old that received older donor kidneys. Importantly, none of the interactions testing the hypothesis that giving older kidneys to older recipients improves graft survival was statistically significant. It is also apparent from the qualitative comparison of relative risks that most of the risk associated with different recipient-donor age combinations (Figure 2A) is attributable to the intrinsic effects of recipient and donor age (Figure 2B). There may be ethical reasons to give older kidneys to older recipients, even if outcomes are not improved. Society may decide that it is justifiable to give good kidneys to younger recipients and marginal kidneys to older recipients. To a large extent, donor age determines which kidneys are good and which are marginal. However, our analysis suggests that using differences in recipient and donor age to help decide whether to accept or reject a cadaver donor kidney does little to enhance overall graft survival. In other words, the total number of years that the population of kidney transplant recipients enjoys graft function is not affected by current differences between the ages of the recipients and donors. As we examined these data, we were interested in testing the hypothesis that the age of the host could modulate the rate of senescence of the transplanted kidney. To the extent that mechanisms of normal aging might be both intrinsic and extrinsic to the kidney, it is theoretically possible that the age of the kidney and the age of the host could interact to accelerate or slow the rate of graft failure attributable to senescence (19). Our results suggest that this is not the case in kidney transplant recipients. However, these results certainly cannot distinguish how much of the effects of aging are intrinsic or extrinsic to the kidney. It is possible that either intrinsic or extrinsic factors are alone responsible for the effects of aging on the kidney. It is also possible that both intrinsic and extrinsic factors are important and that both continue at a fixed, linear rate over time. Either of these pathophysiologic scenarios for renal senescence would be entirely consistent with the lack of any interaction between recipient and donor age on graft survival seen in this study. Of course, the use of nephrotoxic immunosuppressive medications, allograft rejection, and partial denervation of the kidney could all affect the natural, physiologic aging of the kidney (19). The effects of recipient age on death with function compared with death-censored graft failure were markedly different (Figures 3 and 4). Recipients 55 yr old were much more likely to die with a functioning allograft compared with younger recipients. However, what is even more remarkable is the fact that recipients 55 yr old were less likely than younger recipients to return to dialysis or to undergo retransplantation. Others have reported that older transplant recipients are more likely to die of infectious complications and less likely to have acute rejection compared with younger recipients (20). Taken together, these observations suggest that strong consideration should be given to reducing immunosuppression in older transplant recipients. Finally, like others, we noted a J-shaped curve relationship between both donor and recipient age and graft survival. Specifically, donors and recipients 18 yr of age had an increased risk of graft failure, compared with donors and recipients 18 to 29 yr old. Decreased graft survival for kidneys taken from children is well known (21 23) and is likely the result of technical complications associated with transplanting small kidneys. It is also known that children have decreased graft survival, which is attributable to both a heightened immune response and problems with medication compliance that lead to a higher incidence of acute rejection. In summary, giving older cadaver kidneys to older recipients is a common practice. Our analysis showed that although both recipient and donor age affect graft survival, giving older kidneys to older recipients does not. 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