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Clinical and Translational Research

Order of Donor Type in Pediatric Kidney Transplant Recipients Requiring Retransplantation

Van Arendonk, Kyle J.1; James, Nathan T.1; Orandi, Babak J.1; Garonzik-Wang, Jacqueline M.1; Smith, Jodi M.2; Colombani, Paul M.1; Segev, Dorry L.1,3,4

Author Information
doi: 10.1097/TP.0b013e31829acb10
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Abstract

Kidney transplantation (KT) is the treatment of choice for pediatric patients with end-stage renal disease (1, 2), but because of their longevity these recipients almost inevitably outlive their grafts and require a second transplant. For example, among 11- to 17-year-old recipients, 5-year patient survival is 95.9%, whereas 5-year graft survival is 68.4% (3). Similarly, a survey of pediatric recipients who had survived into adulthood found that over half had undergone retransplantation within a mean follow-up of 13.2 years (4).

Because graft survival in pediatric KT recipients is better with living-donor kidneys compared with deceased-donor kidneys (5–7), conventional counseling has been to use the “best donor first”: if a living donor is available, a living-donor transplant should be performed first to maximize the chance of success. If multiple living donors are available, the solution is self-evident, because subsequent transplants could also occur from living donors. However, if only one living donor is available, the most advantageous timing strategy for use of the living donor (as the first donor, or as the second donor should a first deceased-donor transplant fail) remains unclear. Beyond arguments regarding risks to the living donor, deceased-donor transplantation has become a quite viable option for pediatric candidates in the context of recent Share-35 prioritization, after which there has been a trend away from living donation among pediatric recipients (7–9). This age-based allocation priority often does not apply when these patients need a second transplant, as many are no longer pediatric patients at that time. Furthermore, given that retransplant patients are often sensitized (10, 11), choosing a living donor as the second donor makes possible the use of living-donor desensitization regimens (12, 13).

To better understand the relationship between donor type order and pediatric KT outcomes, we used national registry data to (a) compare the likelihood of retransplantation after failure of a first transplant according to first transplant donor type, (b) compare graft survival according to transplant number and donor type, and (c) compare the expected cumulative graft life of two transplants according to order of donor type.

RESULTS

Retransplantation: By First Transplant Donor Type

Of patients receiving their first KT before age 18 (n=14,799), 7589 (51.3%) patients received a first living-donor KT and 7210 (48.7%) patients received a first deceased-donor KT (Fig. 1). Among patients with failure of a first living-donor KT (n=2713), 59.2% underwent retransplantation and 10.6% died (before retransplantation) within 5 years after graft failure (Fig. 2). Median time to retransplantation after first living-donor graft failure was 1.3 years (interquartile range [IQR], 0.3–2.9). Of the 1663 patients who underwent retransplantation after first living-donor graft failure, 43.8% were retransplanted with another living-donor graft, whereas 56.2% were retransplanted with a deceased-donor graft (Fig. 1).

F1-11
FIGURE 1:
Donor type in first and second KT among primary pediatric KT recipients.
F2-11
FIGURE 2:
Patient survival and incidence of retransplantation after first graft loss, stratified by donor type of first transplant, among patients receiving a primary pediatric KT.

Among patients with failure of a first deceased-donor KT (n=3059), 42.5% underwent retransplantation and 13.3% died (before retransplantation) within 5 years after graft failure (Fig. 2). Median time to retransplantation after first deceased-donor graft failure was 2.0 years (IQR, 0.7–4.2). Of the 1418 patients who underwent retransplantation after first deceased-donor graft failure, 74.3% were retransplanted with another deceased-donor graft and 25.7% were retransplanted with a living-donor graft (Fig. 1).

Graft Survival: By Donor Type and Transplant Number

Death-censored graft survival (DCGS) of living-donor grafts was longer than deceased-donor grafts among first transplants (adjusted hazard ratio [aHR] for graft loss, 0.78; 95% confidence interval [CI], 0.73–0.84; P<0.001) as well as second transplants (aHR, 0.74; 95% CI, 0.64–0.84; P<0.001) (Fig. 3A). No statistically significant interaction was identified between donor type and transplant number (P=0.4), suggesting that the graft survival advantage associated withliving-donor grafts held similarly in first and second transplants.

F3-11
FIGURE 3:
A, DCGS, stratified by transplant number and donor type, among recipients of a primary pediatric KT. B, DCGS of second KT, stratified by order of donor type, among recipients of a primary pediatric KT who underwent retransplantation. C, cumulative graft life, by percentiles, of the first two transplants in the D+L and L+D groups. DD, two deceased-donor grafts; LD, living-donor graft followed by deceased-donor graft; DL, deceased-donor graft followed by living-donor graft; LL, two living-donor grafts; D+L, n th percentile of graft survival times for all first deceased-donor grafts added to n th percentile for second living-donor grafts among those with a preceding deceased-donor graft; L+D: n th percentile of graft survival times for all first living-donor grafts added to n th percentile for second deceased-donor grafts among those with a preceding living-donor graft.

Repeat Transplant Recipient Characteristics

Among patients who received two or more grafts, peakpanel-reactive antibody (PRA) was increased at second transplants compared with first transplants, and second transplants more frequently had zero human leukocyte antigen (HLA) mismatches (Table 1). Living-donor transplants were more frequently performed preemptively, and the median time between first graft failure and receipt of second transplant was longer for those receiving a deceased-donor second transplant compared with living-donor second transplant.

T1-11
TABLE 1:
Recipient, donor, and transplant characteristics among pediatric KT recipients (1987–2010) who underwent retransplantation, stratified by order of donor type and graft number

Second Graft Survival: By Order of Donor Type

DCGS of living-donor second grafts was similar after first deceased-donor (DL group) compared with first living-donor (LL group) transplantation (aHR, 1.00; 95% CI, 0.78–1.28; P=1.0) (Table 2, Fig. 3B). Likewise, DCGS of deceased-donor second grafts was also similar after first deceased-donor (DD group) compared with first living-donor (LD group) transplantation (aHR, 0.90; 95% CI, 0.78–1.03; P=0.1).

T2-11
TABLE 2:
Graft survival among pediatric KT recipients who underwent retransplantation, stratified by order of donor type and graft number

DCGS of living-donor second grafts was longer than deceased-donor second grafts after both first living-donor (LL vs. LD) (aHR, 0.68; 95% CI, 0.56–0.83; P<0.001) and first deceased-donor (DL vs. DD) (aHR, 0.77; 95% CI, 0.63–0.95; P=0.02) transplantation. This graft survival advantage of a living-donor second graft compared with deceased-donor second graft was similar regardless of first transplant donor type (P=0.4).

Cumulative Graft Life of Two Transplants

The cumulative graft lives, by percentiles, of D+L (first deceased-donor and second living-donor transplant, added by percentile to avoid biased selection of only those with failed first grafts) and L+D (first living-donor and second deceased-donor transplant, using similar methods) were generally similar (Fig. 3C). Cumulative graft lives of 7.9, 20.1, and 34.5 years for the D+L group (25th, 50th, and 70th percentiles, respectively) were comparable with 9.7, 21.0, and 33.5 years for the L+D group.

DISCUSSION

This national observational study examining the order of donor type in pediatric KT recipients revealed several important findings. First, the magnitude of improvement in graft survival among living-donor grafts compared with deceased-donor grafts was similar among first and second transplants, meaning the graft survival advantage of a living-donor KT compared with deceased-donor KT was not significantly attenuated among second transplants. Second, among pediatric KT recipients who underwent retransplantation, graft survival of a living-donor second graft was similar regardless of the first transplant donor type, suggesting that, on average, receiving a first deceased-donor KTdoes not negatively impact the graft survival of a living-donor second graft (more so than receiving a first living-donor KT). Finally, the cumulative graft life of two transplants, using percentiles for first and second graft survival among all pediatric KT recipients (including the first graft survival estimates, importantly, in those who have not yet required retransplantation), was similar regardless of the order of living-donor and deceased-donor transplantation.

Living-donor grafts have been repeatedly shown to have improved graft survival over deceased-donor grafts (5–7), including in the setting of retransplantation (14). Specifically in the pediatric population, kidneys from living donors under age 55 have been shown to provide superior graft survival compared with deceased-donor kidneys (5). Our study confirmed that living-donor grafts clearly provide superior graft survival compared with deceased-donor grafts among both first and second transplants. Given the improved outcomes of living-donor grafts, living-donor KT istypically encouraged for primary pediatric KT when available as well as for retransplants that may be required. The increased longevity of these grafts could, in the best-case scenario, allow some patients to avoid retransplantation altogether. Living kidney donation can also shorten or eliminate time on dialysis since transplantation can be scheduled in advance and does not require waiting for a high-quality deceased-donor organ to become available.

Despite these benefits of living-donor KT, most pediatric KT recipients eventually require retransplantation, and for this reason, a difficult decision must be made, in particular among those with only one living donor available—should an available living-donor graft be utilized for primary KT or alternatively “saved” for potential retransplantation? Implementation of the Share-35 allocation policy in 2005, in which grafts from deceased donors under age 35 are preferentially allocated to pediatric patients, has decreased pediatric waiting time for a deceased-donor graft and increased the use of deceased-donor KT in children (7–9). A concomitant decrease in the rate of pediatric living-donor KT after Share-35 has suggested that some pediatric candidates may in fact be waiting for deceased-donor grafts rather than utilizing available living donors (15).

The living-donor first approach is thought to avoid potential sensitization from a first deceased-donor graft that could negatively impact survival of a subsequent living-donor graft. In this study, both first deceased-donor and living-donor grafts did lead to increased sensitization. However, living-donor second graft survival was similar after a first deceased-donor or living-donor graft and still exhibited a significant improvement compared with deceased-donor second graft survival. Primary deceased-donor KT could also lead to such high sensitization that retransplantation becomes exceedingly difficult. Indeed, those recipients with first deceased-donor graft failure were less frequently retransplanted compared with those with first living-donor graft failure. The extent to which this difference may be due to sensitization, however, is unclear. Receipt of a first living-donor KT is likely a surrogate for availability of additional potential living donors as well as other factors associated with an increased likelihood of transplantation (16), independent of differences in sensitization. Finally, a recent study using Organ Procurement and Transplantation Network data found no association between the degree of HLA mismatch of a first deceased-donorgraft and the development of sensitization with high PRA at listing for retransplantation (17), and the extent to which sensitization will even hinder retransplantation in the future is unclear given recent advances in desensitization protocols (13).

Given the risk of death and other adverse outcomes known to be associated with prolonged dialysis, this study evaluated only the outcome of graft survival from the individual patient perspective (i.e., the perspective of a child who could undergo either living-donor or deceased-donor KT). We recognize that other outcomes (growth, long-term cardiovascular morbidity, etc.) and other perspectives (societal, etc.), although not the focus of this study, may be equally valid choices. In addition, although specific age groups within the pediatric population may have different risks and needs with regard to KT, we chose to evaluate the question of donor type order from the simplified view of a homogeneous pediatric population, all of whom face the similar question of how to best utilize a living-donor organ in the context of age-based priority for deceased-donor organs. We acknowledge that decisions regarding donor type order may be significantly affected by the age of the transplant candidate. Unfortunately, an in-depth analysis of precisely how this decision may vary across patient age was limited by inadequate sample sizes for the DL and LD subgroups across all age strata.

When examining donor type order from the chosen perspective, our findings suggest that the increasingly common decision to forego primary living-donor KT if a deceased-donor graft becomes available might be a reasonable one. The expected cumulative graft life in those receiving a living-donor graft after a deceased-donor graft wassimilar compared with those receiving the reverse donortype order. This finding may be due to the disproportionately high rate of graft failure seen among 17- to24-year-olds (18, 19). Given this high-risk age period, itcould theoretically be optimal to save one’s “best” graft—the living-donor graft—until after passage through late adolescence and early adulthood. However, the mean age at second transplantation in this study was still well within that age period shown to have the highest risk of graftloss.

An alternative explanation of our findings may be an exceptionally strong beneficial effect of undergoing preemptive retransplantation, enabled by the remaining availability of a living donor at that time. In addition, the benefit of a living-donor graft may be diminished in the setting of recurrent disease such as focal segmental glomerular sclerosis (20). Given the frequency of such diagnoses prone to recur in the pediatric population, the superiority of living-donor grafts may be somewhat attenuated in this population (although clearly still superior, as shown in this study), thus swaying the overall benefit toward receiving a high-quality deceased-donor organ first while still enjoying theadvantage of Share-35 status. Finally, differential improvements in deceased-donor and living-donor graft survivalover time (e.g., if changes in immunosupression have led to more dramatic improvements in deceased-donor compared with living-donor graft survival over time) could alsohave affected our findings, although likely minimized by the inclusion of transplant year in each of our multivariable models.

The results of this study must be interpreted carefully given the inherent limitations of applying observational data to clinical decision-making. First, a direct comparison of cumulative graft life in the DL and LD groups is a biased one due to the selection bias inherent in entering these cohorts and the exclusion from these groups of those patients with the longest first graft survival (who therefore have not yet required retransplantation). We avoided this bias through our comparison of the D+L and L+D groups, showing similar cumulative graft life between the two groups when examining all the available percentiles of graft survival times for first and second grafts.

Second, in addition to considering the expected cumulative graft life of two transplants, one must also consider the time that will be spent on dialysis after first graft failure and before retransplantation. The age-based allocation priority given by Share-35 often no longer applies at the time that retransplantation is required (as they may no longer be pediatric patients at that time), meaning that the waiting time for a deceased-donor transplant will likely be significantly longer as an adult (after loss of a first living-donor graft, for example) compared with as a pediatric patient(at the time of their first deceased-donor transplant). Indeed,the patients in this study who received a second living-donor KT did more frequently undergo preemptive retransplantation and generally spent less time back on dialysis after first graft loss. However, a close examination of waiting time between first and second KT is complex because some patients may wait for a deceased-donor kidney for various periods of time before proceeding with living-donor retransplantation, whereas others may undergo immediate living-donor retransplantation. In addition, organ allocation policies, including the precise delineation of how younger transplant candidates are provided preference for deceased-donor kidneys, have changed over time and may also continue to change in the future.

Finally, and perhaps most importantly, the direct application of these results to clinical decision-making requires an assumption that an available living donor’s health status at the time of primary KT will not change before graft failure and the need for retransplantation. “Saving” one’s available living donor for retransplantation induces an inherent risk that one’s living donor, healthy and eligible for donation at the time of primary KT, may develop health conditions over time or even die before graft failure, precluding donation when retransplantation is needed. This inability to determine the future availability of living donors makes the decision to forego primary living-donor KT a risky one. At the very least, the approach of living-donor retransplantation (instead of primary KT) would mean that one’s living donor will be older (perhaps 10–15 years or more) at the time of donation, which may negatively impact second transplant survival given the association between older living-donor age and KT outcomes (21). Although our study provides important data to guide pediatric KT candidates and their families who face this choice between primary living-donor KT or acceptance of an available deceased-donor KT, these results must be interpreted in the context of these other variables not accounted for in an observational study.

In conclusion, deceased-donor KT followed by living-donor retransplantation does not negatively impact the benefit of a living-donor graft used in the setting of retransplantation and appears to provide similar cumulative graft life compared with living-donor KT followed by deceased-donor retransplantation. These findings must be carefully interpreted within the confines of applying observational data to clinical decision-making but nonetheless suggest that the conventional living-donor first approach topediatric KT may not be the only acceptable timing strategyfor utilization of a pediatric candidate’s available living donor.

MATERIALS AND METHODS

Study Population

All kidney-only transplants completed between January 1987 and July 2010 in patients who received a KT before age 18 were identified in theScientific Registry of Transplant Recipients (SRTR), which includes dataon all donor, wait-listed candidates, and transplant recipients in the United States (22).

Outcome Ascertainment

DCGS was defined as the time between transplantation and either graft failure (marked by retransplantation or return to dialysis) or last follow-up with a functioning graft, censoring for death and administrative end of study. Death ascertainment was supplemented by linkage to the Social Security Death Master File; death and graft loss ascertainment were also supplemented by linkage to data from the Centers for Medicare and Medicaid Services. To assess whether differential patient survival after deceased-donor and living-donor KT could alter the results of the study, a sensitivity analysis examining all-cause graft loss (including death as a graft failure) rather than death-censored graft loss was performed, and inferences were unchanged.

Graft Survival: By Donor Type and Transplant Number

DCGS of all first and second grafts was compared, stratified by donor type. An interaction term between donor type and transplant number was used to test for modification of the living-donor graft survival advantage by graft number.

Second Graft Survival: By Order of Donor Type

DCGS of second grafts was compared according to the order of donor type of the first two transplants among patients undergoing retransplantation: those who received two deceased-donor transplants (DD group), those who received a deceased-donor followed by living-donor transplant (DL group), those who received living-donor followed by deceased-donor transplant (LD group), and those who received two living-donor transplants (LL group). An interaction term was used to test for modification by first transplant donor type of the graft survival advantage of a living-donor second transplant.

Cumulative Graft Life of Two Transplants

In examining graft survival among repeat transplant recipients, first grafts by definition have failed, making analysis of second grafts somewhat biased. In comparing donor type order, this bias is important because those in the LD group by definition have lost their living-donor graft, which on average has a longer potential graft survival than a deceased-donor graft, which those in the DL group have necessarily lost. Furthermore, those patients with the best primary living-donor graft survival (who therefore have not yet required retransplantation) are by design excluded from a direct comparison of cumulative graft life in DL and LD recipients because this comparison requires the first graft to have already been lost.

To account for this bias, the nth percentiles of graft survival times for “all” first living-donor grafts (regardless of graft outcome—survival or failure) were added to the nth percentiles of second deceased-donor grafts (among those with a preceding living-donor graft) (L+D group). Likewise, the nth percentiles of graft survival times among “all” first deceased-donor grafts (regardless of eventual graft outcome) were added to the nth percentiles of second living-donor grafts (among those with a preceding deceased-donor graft) (D+L group). These cumulative graft lives for the L+D and D+L groups were plotted on the x-axis against each particular nth percentile on the y-axis. For example, the x-axis value for the D+L group at the 40th percentile on the y-axis consisted of the 40th percentile of graft survival time for all first deceased-donor grafts added to the 40th percentile of graft survival time for all second living-donor grafts among those with a preceding deceased-donor graft. As such, this analysis represents what would have been expected to be the ultimate combined survival of both grafts, using information not only from patients who lost their first graft but also from patients who still have a functioning first graft, thereby addressingthe selection bias of a simpler direct comparison of DL and LDrecipients.

Statistical Analysis

Death and retransplantation after first graft failure were explored as time-dependent competing events using cumulative incidence functions through the stcompet Stata module (23). DCGS was compared using Kaplan–Meier survival estimates and multivariable Cox proportional hazards models adjusting for recipient (age, sex, race, insurance, diagnosis, dialysis history, and peak PRA), donor (age and race), and transplant (HLA mismatch and year) factors. All tests were two-sided with statistical significance set at α=0.05. Analyses were performed using Stata 12.1/SE (College Station, TX).

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Keywords:

Pediatric kidney transplantation; Donor selection; Graft survival; Donor type; Retransplantation

© 2013 by Lippincott Williams & Wilkins