Peter Chang,* Jagbir Gill,* James Dong,* Caren Rose,* Howard Yan,* David Landsberg,* Edward H. Cole, and John S. Gill*

Transcription

1 Article Living Donor Age and Kidney Allograft Half-Life: Implications for Living Donor Paired Exchange Programs Peter Chang,* Jagbir Gill,* James Dong,* Caren Rose,* Howard Yan,* David Landsberg,* Edward H. Cole, and John S. Gill* Summary Background and objectives Living donor paired exchange programs assume that kidneys from living donors are of comparable quality and anticipated longevity. This study determined actual allograft t 1/2 within different recipient age groups (10-year increments) as a function of donor age (5-year increments), and juxtaposed these results against the probabilities of deceased donor transplantation, and exclusion from transplantation (death or removal from the wait-list). Design, setting, participants, & measurements Data from the US Renal Data System (transplant dates with follow-up through September 2007) were used to determine allograft t 1/2, whereas data from patients on the United Network for Organ Sharing waiting list between 2003 and 2005 (with follow-up through February 2010) were used to determine wait-list outcomes. Results With the exception of recipients aged years, who had the best outcomes with donors aged years, living donor age between 18 and 64 years had minimal effect on allograft t 1/2 (difference of 1 2yearswith no graded association). The probability of deceased donor transplantation after 3 years of wait-listing ranged from 21% to 66% by blood type and level of sensitization, whereas the probability of being excluded from transplantation ranged from 6% to 27% by age, race, and primary renal disease. *St. Paul s Hospital, University of British Columbia, Vancouver, Canada; and University Health Network, University of Toronto, Toronto, Canada Correspondence: Dr. John S. Gill, St. Paul s Hospital, University of British Columbia, Providence Building Ward 6a, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6. jgill@ providencehealth. bc.ca Conclusions With the exception of recipients aged years, living donor age between 18 and 64 years has minimal effect on allograft survival. Clin J Am Soc Nephrol 7: , doi: /CJN Introduction Innovative strategies are needed to increase opportunities for transplantation for patients with ESRD. Living donor paired exchange (LDPE) programs allow patients with an emotionally related but ABO- or HLA-incompatible living donor to receive a compatible living donor transplant in return for the donation of a kidney from their incompatible donor to another individual. LDPE programs assume excellent transplant outcomes from most living donors, and that most of the variability in living donor outcomes is attributable to recipient rather than donor factors. The available literature suggests that donor factors (i.e., donor age) that have a significant effect on deceased donor transplant outcomes have fewer effects on living donor transplant outcomes. We previously reported no significant increased risk of kidney allograft failure with the use of living donors aged #65 years (1). In LDPE, the likelihood that a given biologically incompatible donor and recipient pair will find a compatible match increases with the number of participants in the program (2). It has been suggested that ABO- and HLA-compatible donor and recipient pairs be offered the opportunity to participate in LDPE programs to facilitate more living donor transplants (3). Detailed information regarding the outcomes of living donor transplants in different donor and recipient age groups may help increase interest and participation of compatible donor and recipient pairs in LDPE programs. For example, if donor age is a significant determinant of transplant outcome, a biologically compatible but agediscrepant donor and recipient pair may pursue LDPE to obtain a younger living donor kidney for the recipient. Alternatively, demonstration that outcomes are similar with living donors of different ages may encourage ABO- and HLA-compatible donor and recipient pairs to participate in LDPE for altruistic reasons. The goals of this study were to provide information to inform clinical decision making related to LDPE, and to inform strategies to increase participation in LDPE. The specific study objectives were as follows: (1) to determine living donor transplant outcomes, including actual allograft t 1/2 in different donor and recipient age groups; (2) to determine the likelihood of deceased donor transplantation for wait-listed transplant candidates with different blood types and degrees of Vol 7 May, 2012 Copyright 2012 by the American Society of Nephrology 835

2 836 Clinical Journal of the American Society of Nephrology sensitization; and (3) to determine the risk of being excluded from transplantation (death or permanent removal from the wait-list) among wait-listed transplant candidates. Materials and Methods Data Source and Study Population Data from the US Renal Data System (USRDS) were used for determination of kidney transplant outcomes, whereas data from the Organ Procurement Transplantation Network/ United Network for Organ Sharing was used to determine wait-list outcomes. Living donor kidney transplant survival was determined among all adult ($18 years) first kidney only living donor recipients between January 1988 and December The time frame was restricted to allow determination of actual kidney allograft t 1/2. For the purposes of comparison, the allograft t 1/2 was also determined among adult recipients of a first standard criteria deceased donor kidney transplant during the same time period. Wait-list outcomes including patient survival for waitlisted transplant candidates and the likelihood of deceased donor transplantation were determined among adult patients listed for a deceased donor kidney only transplant between 2003 and The time frame was restricted to allow determination of wait-list outcomes during a 5-year time horizon. Analytical Methods Calculation of Allograft Half-Life. Actual allograft t 1/2 was determined as the time to 50% allograft loss from any cause, including death, among patients with allograft survival of at least 1 year using the Kaplan Meier method. These analyses were stratified by recipient age (in 10-year increments) and donor age (in 5-year increments). Within each donor age group, the t 1/2 was determined including patients from the most recent transplant years that permitted calculation of the time to 50% allograft loss (including death as a cause of allograft failure). Determination of the Donor Age Associated Risk of Kidney Allograft Failure. Within each recipient age group, the association of living donor age with allograft survival was determined using separate Cox multivariate regression models adjusted for differences in donor and recipient sex, donor and recipient race, transplant year, cause of ESRD, duration of pretransplant dialysis exposure, HLA match, panel reactive antibodies (PRAs), and use of induction immunosuppressant medications. The proportional hazards assumption for all confounding variables was tested for visually using log-negative-log survival plots. In these models, recipients were followed from date of transplant until death, return to dialysis, repeat transplant, or end of follow-up (September 2007). Probability of Deceased Donor Transplantation. The Kaplan Meier method was used to determine the proportion of patients who received a deceased donor transplant at 1, 3, and 5 years after wait-listing. In these analyses, patients were censored at the time of living donor transplantation, death, permanent removal from the wait-list, or end of follow-up (February 26, 2010). The probability of deceased donor transplantation was determined by blood group and level of sensitization (PRAs) at time of wait-listing. Probability of Being Excluded from Transplantation after Wait-Listing. The probability of the combined end-point of death on the wait-list or permanent removal from the waitlist was determined at 1, 3, and 5 years after wait-listing using the Kaplan Meier method with censoring of patients at time of transplantation from any donor source or end of followup. These analyses were stratified by patient age, race, and cause of ESRD. All analyses were performed using StataMP 11 software (StataCorp, College Station, TX). This study was performed with the approval of our local hospital research ethics board. Results Table 1 shows the number of transplant recipients in each living donor-recipient age group, whereas Table 2 shows the living donor-recipient population characteristics. Of note, there were relatively few patients transplanted with living donors aged $65 years. The major determinant of allograft t 1/2 was recipient age rather than donor age (Table 3). Among the recipient group aged years, there was more variation in allograft t 1/2 by donor age than in recipient groups aged 40 49, 50 59, and $60 years (Table 3). Among recipients aged years, the longest t 1/2 (16 years) was achieved with transplantation from donors aged years. Among recipients aged years, years, and $60 years, there was surprisingly little variation in allograft t 1/2 with increasing donor age. Even with living donors aged $65 years, actual allograft t 1/2 seemed to be relatively similar to those achieved with younger donors. The subgroup of recipients aged years who received a living donor transplant from donors aged $65 years (n=52) were anomalous. The actual allograft t 1/2 in this subgroup was significantly lower (8 years) than that observed for recipients of the same age group with donors aged,65 years (range, years). Similarly with the exception of this subgroup, the t 1/2 observed in every donorrecipient age group was equal to or greater than those observed with standard criteria deceased donor kidney transplants (Table 3). Subgroup analyses of diabetic and African American recipients were consistent with the overall findings (data not shown). However, there were limited numbers of recipients with donors aged $60 years in these patient subgroups and these analyses should be updated after there has been further experience with transplantation from these donors. Table 1. Number of transplants in different living donor-recipient age groups Donor Age (yr) Recipient Age (yr) , $ Standard criteria deceased donor 25,962 20,748 18,084 11,217

3 Clin J Am Soc Nephrol 7: , May, 2012 Effect of Living Donor Age on Allograft Half-Life, Chang et al. 837 Table 2. Characteristics of living donor transplant recipients (n=50,750) Characteristic Value Male 58 Race white 80 black 15 other (includes Asians and 5 Native Americans) Cause of ESRD diabetes 23 hypertension 14 polycystic kidney disease 9 GN 30 other 24 Duration of pretransplant dialysis exposure (yr) preemptive 21 median (range) 0.63 (0.08, 1.40) mean (6SD) 1.15 (1.88) Donor type living related 78 living unrelated (including 22 spousal donations) HLA mismatch a Panel reactive antibodies b $80 4 Use of induction immunosuppression c depleting antibody 29 nondepleting antibody 22 no induction 49 Data are percentages unless stated otherwise. a HLA was missing for 1% of recipients. b Panel reactive antibodies value was missing for 11% of recipients. c Induction immunosuppression was missing for 1% of recipients. Table 4 shows the multivariate adjusted risk of allograft loss with increasing donor age. Compared with the reference group of living donors aged years, most recipient age groups with living donors aged between 40 and 64 years had a small but statistically significant increased risk of allograft loss. In all recipient age groups, the greatest donor age-associated risk of allograft loss was among recipients of living donors aged $65 years. Probability of Deceased Donor Transplantation Wait-listed blood group AB patients have the highest likelihood of deceased donor transplantation, followed by patients with blood groups A, O, and B (Table 5). Within blood groups, the likelihood of transplantation was inversely related to the level of sensitization (PRAs). Within the various ABO and PRA patient groups, the probability of transplantation after 3 years of wait-listing varied from 21% to 66% and was,50% in most groups. Probability of Death or Permanent Removal from the Wait-List The probability of death or permanent removal from the wait-list was higher among older-aged patients. Within recipient age groups, patients of white race had a higher probability of death and wait-list removal (Table 6) than non-white patients. Within each recipient age group, patients with diabetes as the cause of ESRD had the highest probability of death or permanent removal from the wait-list, whereas patients with polycystic kidney disease had the lowest risk of this outcome (Table 7). Discussion This study documents that in most recipient age groups, living donor age has a clinically insignificant effect on the long-term outcome of living donor transplantation as measured by actual allograft t 1/2. With the exception of recipients aged years, who achieved the best outcome with donors aged years, near equivalent outcomes were achieved across a broad range of donor-recipient age groups. When juxtaposed against the probability of deceased donor transplantation, and being excluded from consideration of deceased donor transplantation due to death on the waitlist or permanent removal from the wait-list, these findings should prove useful in expanding participation in LDPE programs by ABO and/or HLA incompatible donor-recipient pairs. The information may also encourage participation of ABO- and HLA-compatible donor-recipient pairs in LDPE that could significantly increase the number of transplants performedinldpeprograms.finally, the information should prompt re-examination of LDPE matching algorithms that emphasize donor-recipient age matching. A frequent question posed by patients and donors considering participation in LDPE is whether they will receive a kidney of equal quality to the kidney that they collectively contribute to the paired exchange. A major determinant of transplant outcomes with deceased donors is donor age (4 6). However, despite increased acceptance of older living donors (7), few studies have examined transplant outcomes from older living donors (1,8,9). An age-related decline in donor renal function may reduce the duration of allograft survival. In addition, there may be an age-related predisposition to ischemic, drug-induced, and immunologic injury, as well as decreased capacity to recover from such insults. In a recent meta-analysis of 12 studies, 5-year patient survival was lower among recipients of kidneys from living donors aged $60 years (unadjusted relative risk of survival, 0.89; 95% confidence interval [95% CI], ) (8). However, the included studies were small and were from single centers, and there was significant heterogeneity between the studies. A recent study from Ontario, Canada, demonstrated similar allograft survival between recipients of older living donor kidneys aged $60 years and recipients of standard criteria deceased donor kidneys; however, this analysis was limited by relatively short follow-up of 4 years (10). In a previous analysis of patients captured in the USRDS between 1995 and 2003, we reported that the multivariate adjusted risk of allograft loss with living donors aged years was similar to that obtained with deceased donors aged,55 years, whereas recipients from living donors aged 65 69

4 838 Clinical Journal of the American Society of Nephrology Table 3. Allograft t 1/2 in different living donor-recipient age groups Donor Age (yr) n Transplant Yr Allograft Half Life per Recipient Age (yr) , $ SCD 71, SCD, standard criteria deceased donor. Table 4. Living donor age-related risk of kidney allograft failure Donor Age (yr) Recipient Age (yr) ( ) 0.97 ( ) 0.96 ( ) 1.14 ( ) ( ) 1.12 ( ) 0.88 ( ) 1.19 ( ) ( ) 1.27 ( ) 0.99 ( ) 1.20 ( ) ( ) 1.36 ( ) 1.17 ( ) 1.05 ( ) ( ) 1.20 ( ) 1.08 ( ) 1.22 ( ) $ ( ) 1.47 ( ) 1.76 ( ) 1.64 ( ) Separate multivariate Cox regression model for each recipient age group. Adjusted for differences in donor and recipient sex, donor and recipient race, transplant year, cause of ESRD, duration of pretransplant dialysis exposure, HLA match, panel reactive antibodies, and use of induction immunosuppressant medications. years (hazard ratio, 1.3; 95% CI, ) and.70 years (hazard ratio, 1.7; 95% CI, ) had a higher relative risk of allograft loss (1). This study extends our previous work and provides more clinically relevant information by providing the actual allograft t 1/2 in different donor-recipient age groups and by providing additional information regarding the likelihood of deceased donor transplantation, and the likelihood of being excluded from transplantation while waiting for a deceased donor transplant. Although results vary depending on the specific donor and recipient characteristics, the finding that donor age,65 years has minimal effect on allograft t 1/2 suggests that for the majority of patients, participation in LDPEfollowedbytransplantationfromevenanolder-aged living donor is likely a better option than continued waiting for a deceased donor transplant. There were relatively few living donors aged $60 years to permit detailed subgroup analyses, and there may be certain patient subgroups who tolerate dialysis relatively well in whom continued waiting on dialysis may be a reasonable consideration. The information provided in this study can be further supplemented with published information regarding the probability of finding a matchinaldpeprogramtoinformclinicaldecisionmaking (2,3,11,12). A formal decision analysis may provide additional useful information but is beyond the scope of this study. The results of this study can also be used to promote participation in LDPE of ABO- and HLA-compatible pairs. In our clinical practice, we have included ABO- and HLAcompatible donor-recipient pairs in LDPE to obtain a younger donor kidney for a recipient with a compatible older-aged donor while facilitating the transplant of a second ABO and/ or HLA incompatible pair. With the exception of recipients aged years, the results from this study suggest little advantage to pursuing a younger donor for recipients with an older-aged but compatible donor aged,65 years through participation in LDPE. Instead, the information in this study can be used to reassure ABO- and HLA-compatible pairs who may be considering participation in LDPE for purely altruistic reasons of an excellent outcome with transplantation from a broad age range of living donors aged,65 years. These results may also prompt re-examination of LDPE matching algorithms that are designed to minimize the age difference between the living donor kidneys transplanted to participants in LDPE. We are not aware of data regarding the frequency with which offers for transplantation are declined due to donor age disparity in LDPE programs. However, removal or relaxation of age-matching criteria could conceivably increase the number of transplants performed in LDPE programs. It is important to note that our results should not be interpreted as a dismissal of the importance of living donor age on transplant outcomes. As shown in Table 4, there was an increased risk of allograft failure with increasing donor

5 Clin J Am Soc Nephrol 7: , May, 2012 Effect of Living Donor Age on Allograft Half-Life, Chang et al. 839 Table 5. Probability of deceased donor transplantation within 3 years of wait-listing by ABO and PRA ABO A B AB O PRA (%) $ $ $ $80 Cumulative time on the wait-list (yr) PRA, panel reactive antibody. Table 6. Probability of death on the wait-list or removal from the wait-list by age and race Recipient Age (yr) Race White Black Other White Black Other White Black Other White Black Other Cumulative time on the wait-list (yr)

6 840 Clinical Journal of the American Society of Nephrology Table 7. Probability of death on the waiting list or removal from the waiting list by age and cause of ESRD Recipient Age (yr) DM HTN PKD GN Other DM HTN PKD GN Other DM HTN PKD GN Other DM HTN PKD GN Other Cause of ESRD Cumulative time on wait-list (yr) DM, diabetes mellitus; HTN, hypertension; PKD, polycystic kidney disease. age and these findings are consistent with those from a recent single center publication from the Mayo Clinic that showed an association between living donor age and the risk of death-censored graft loss (13). Analyses of death-censored graft loss provide an incomplete picture of transplant outcomes because the competing risk of death with a functioning graft is not accounted for. It is notable that the Mayo Clinic study did not show an association between living donor age and patient death. When interpreting our results, readers should consider the inherent limitations of observational studies based on registry data. The older-age donors included in this analysis were likely highly selected and may differ from living donors participating in LDPE programs today. To permit calculation of the true t 1/2, our analysis was necessarily limited to an older cohort of transplant recipients. However, we are not aware of significant recent advances in transplant care that would differentially affect the survival of transplants from living donors of different ages. Despite inclusion of all living donor transplants in the USRDS, there were still relatively few transplants in some of the donor age groups. For example, there were only 52 living donor recipients aged years with donors aged $65 years, and there was a total of only 561 transplants from donors aged $65 years. The probability of deceased donor transplantation and removal from the waiting list are aggregate results for the United States, and readers should consider regional variation from these national averages when applying these results to individual patients. We were unable to evaluate the effect of other important donor factors that may affect transplant survival and confound our results, including predonation kidney function, donor BP, and donor diabetes. Importantly, 54% of the living donors in our study did not have information regarding pre-donation GFR documented and thus we were unable to include donor GFR in our analysis. Recent work has shown that the post-transplant recipient GFR is lower with transplantation from older living donors. However, there was no association between living donor age and the change in GFR during the first post-transplant year, and only small differences of questionable clinical significancewerefoundin the rate of GFR decline after the first post-transplant year between recipients of older and younger living donor kidneys (13). Recent work has demonstrated an increased risk of acute rejection with transplantation of older deceased donor kidneys (14). However, recent studies also failed to show an increased risk of rejection among older living donors (13). In summary, with the exception of recipients years of age who do best with donors years of age, living donor age in ranging from 18 to 64 years has limited effects on long-term kidney allograft survival as measured by allograft t 1/2. More experience is needed to determine the comparative outcome of transplants from living donors $65 years of age relative to younger living donors. Our study results should encourage participation in LDPE programs and prompt reevaluation of LDPE matching algorithms that emphasize donor age. Acknowledgment P.C. is funded by the CIHR Training Program in Transplantation. Disclosures None.

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