Renal Allograft Survival Analysis by HLA Match Group
Five-year renal allograft survival by donor type and HLA match group is shown in Figure 1. This shows renal allograft survival after well and poorly HLA-matched DBD kidney transplants and survival after well and poorly HLA-matched LD kidney transplants. Five-year renal allograft survival was shown to be superior for children receiving a poorly HLA-matched LD kidney transplant at 88% (95% confidence interval [95% CI], 84%-91%) compared with those receiving a well HLA-matched DBD kidney transplant, 83% (95% CI, 80%-86%; log rank test P = 0.03).
For both forms of donor graft, there was no statistical evidence to suggest a significant difference in renal allograft survival in children who received a good HLA match compared with those that received a poor HLA match (DBD donor P = 0.08, LD P = 0.47, respectively using log rank test).
Renal Allograft Survival Analysis by Number of HLA-A/-B/-DR Mismatches
Figures 2–4 show the whole renal allograft survival analysis split into number of HLA-A, HLA-B, and HLA-DR mismatches, respectively. Figure 2 shows 5-year renal allograft survival by HLA-A mismatch count and donor type, showing that there is no significant difference between renal allograft survival in children receiving an LD kidney with 1 or 2 HLA-A mismatches (renal allograft survival, 89%; 95% CI, 86-92%) compared with children receiving a DBD kidney with 0 HLA-A mismatches (renal allograft survival, 86%; 95% CI, 80-90%; log rank test P = 0.22).
Similarly, Figure 3 shows 5-year renal allograft survival by HLA-B mismatch count and donor type. There is no significant difference between renal allograft survival in children receiving an LD kidney with 1 or 2 HLA-B mismatches (renal allograft survival, 89%; 95% CI, 85-91%) compared with children receiving a DBD kidney with 0 HLA-B mismatches (renal allograft survival, 85%; 95% CI, 78-90%; log rank test P = 0.26).
Figure 4 shows 5-year renal allograft survival by HLA-DR mismatch count and donor type. In contrast, 5-year renal allograft survival was superior for children receiving an LD kidney with 1 or 2 HLA-DR mismatches at 88% (95% CI, 84-91%) compared with those receiving a DBD kidney with 0 HLA-DR mismatches at 83% (95% CI, 80-86%; log rank test P = 0.03).
Table 4 shows the results of the Cox proportional hazards regression model. Model 1 shows the univariate effects of donor type and HLA match group. Model 2 shows the risk adjusting factors, not including HLA match group and donor type. It is clear that renal allograft survival has improved over time in this study; this is partly explained by improved immunosuppression, but also the fact that the UK 2006 NKAS has improved the proportion of well HLA-matched renal allografts for children. Before 2006, it was possible for a child to receive a level 4 HLA-matched DBD kidney transplant. Consequently, a higher proportion of well-matched DBD kidney transplants has been performed in an era of improved survival results. To truly compare the outcomes of poorly matched LD transplants and well-matched DBD kidney transplants, transplant year must be accounted for. Other covariates that were shown to be significant in model 2 are right/left kidney and recipient age.
Model 3 in Table 4 shows the adjusted Cox model, accounting for the covariates above. This shows that children who receive a poorly matched LD kidney transplant have a lower risk of renal allograft failure than children who receive a well-matched DBD kidney transplant, although this did not reach statistical significance (hazard ratio, 0.77; 95% CI, 0.53-1.11). Therefore, this risk-adjusted analysis does not find a significant difference in renal allograft survival between well HLA-matched DBD kidney transplants and poorly HLA-matched LD kidney transplants in children.
This study is one of the only studies comparing children receiving well HLA-matched DBD kidneys with children receiving poorly HLA-matched LD kidneys, and the first to assess the effect of HLA-A, HLA-B, and HLA-DR on renal allograft survival in this context. We have demonstrated that children receiving a transplant kidney from a poorly HLA-matched LD donor do not have inferior 5-year renal allograft survival compared with children receiving a transplant kidney from a well HLA-matched DBD donor. Therefore, it is difficult to justify preferentially waiting for a well HLA-matched DBD kidney if there is an LD kidney available for transplantation, regardless of the level of HLA matching in the LD kidney.
This study adds to the evidence that already exists confirming the benefits of LD kidney transplantation above DBD kidney transplantation.1,2,10 The study by Foster et al10 has similarities with our study, reporting that in kidney transplant recipients younger than 21 years, LD transplants have superior survival over DD transplants, regardless of HLA matching. Our study also supports the body of evidence that suggests that with current modes of immunosuppression, HLA matching has a diminished effect on short-term renal allograft outcomes6 as demonstrated by the fact that HLA match group did not affect 5-year renal allograft survival in LD or DBD pediatric kidney transplants in this study.
The main limitation to this study is that it is limited to 5-year renal allograft outcomes, and the long-term effect of poorly HLA-matched transplantation in these young recipients is not assessed. There have been studies that have looked at sensitization and ease of retransplantation in young renal transplant recipients, and there is evidence that poor HLA matching at first transplant may make it more difficult for retransplantation to occur when it is necessary.7,8 This is particularly important in children where subsequent retransplantation may be required throughout life. Therefore, any changes in kidney allocation systems must be made with caution and full consideration of the wider literature on this topic.
This issue is one of the driving factors in the UK 2006 NKAS, where well HLA-matched DBD kidneys are prioritized for younger recipients to try and avoid sensitization and issues with retransplantation in the future.9 However, in other countries, such as the United States with the Share-35 initiative, allocation schemes are focused toward a shorter wait to transplantation for young recipients at the expense of HLA matching.5,7
There are a number of reasons for the improved renal allograft survival of LD kidney grafts in children compared with DBD kidney grafts, and these have been documented in the literature.2,10 One of the key issues with DBD kidney grafts is logistical, and a longer CIT with this type of transplantation can lead to delayed graft function and primary nonfunction.10 This study was conducted in the United Kingdom, which is a relatively small country geographically. Therefore, we expect the results of this study to be exaggerated in larger countries where DBD kidneys are required to travel larger distances to reach recipients with the resultant longer CIT. We would therefore expect that the superior renal allograft survival in LD kidney transplantation in children would be reproduced and accentuated in other larger countries.
The results of our study emphasize the importance of living donation in renal transplantation, and we should aim to achieve this for children, wherever possible. A concerning trend that has emerged from the USA Share-35 initiative is a reduction in the number of pediatric LD kidney transplants and an increase in pediatric DBD kidney transplants.3-5 The problems associated with this transition may be offset in part by improvements in access and waiting times for pediatric kidney transplantation that have been achieved by Share-35, but the long-term effects of Share-35 are not yet clear and will emerge over time. As more countries modify their kidney allocation schemes in view of recent evidence and in particular as countries deemphasize the importance of HLA matching, it is imperative that the benefits of living donation are not understated and that we do not continue to see falls in LD kidney transplantation for children.
The ultimate goal is clearly to achieve well HLA-matched LD kidney transplants for children, because these have the best renal allograft survival outcomes and produce the best long-term outcomes for patients. Current data show that LD transplantation often occurs with suboptimal matching as the pool of donors is narrow. This could be improved with paired kidney matching schemes, which are now legal in a number of countries, including the United States and the United Kingdom where the National Living Donor Kidney Sharing Schemes are active. This coupled with increases in altruistic donation could enable more well HLA-matched LD kidney transplants to take place.11-13 In the United Kingdom, 33 pairs with a pediatric recipient have been registered since 2008, 8 of which have been in their first matching run in 2015 (up until the third matching run in 2015). Thirteen pediatric recipients have received a transplant from an altruistic donor and 4 have received a transplant through being on the end of an altruistic donor chain [NHS Blood and Transplant].
We have demonstrated the importance of living donation in pediatric kidney transplantation in this study and have shown that HLA matching does not appear to affect 5-year renal allograft survival in pediatric kidney transplantation. This evidence calls into question kidney allocation schemes, which increase the number of DBD kidney transplants for children, at the expense of reduced numbers of LD kidney transplants for children. Any changes to transplantation practice must be made with caution, as further research is required to assess the impact of kidney waiting time on patient outcomes and the potential long-term consequences of poor HLA matching with implications for retransplantation in this young population.
The authors are grateful to all the transplant centers in the United Kingdom who contributed data on which this article is based.
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