Living Donation Has a Greater Impact on Renal Allograft Survival Than HLA Matching in Pediatric Renal Transplant Recipients

Marlais, Matko MRCPCH; Hudson, Alex MSc; Pankhurst, Laura MSc; Fuggle, Susan V. D.Phil.; Marks, Stephen D. MD

doi: 10.1097/TP.0000000000001159
Original Clinical Science-General

Background: Living donor (LD) kidney transplantation accounts for around half of all pediatric renal transplant recipients and results in improved renal allograft survival. The aim of this study was to determine the effect of HLA matching on deceased and LD renal allograft outcomes in pediatric recipients.

Methods: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant on all children who received a donation after brain death (DBD) or LD kidney-only transplant between 2000 and 2011. HLA-A, HLA-B and HLA-DR mismatches were categorized into 4 levels and 2 groups. Data were fully anonymized.

Results: One thousand three hundred seventy-eight pediatric renal transplant recipients were analyzed; 804 (58%) received a DBD donor kidney, 574 (42%) received an LD kidney. Five-year renal allograft survival was superior for children receiving a poorly HLA-matched LD kidney transplant (88%, 95% confidence interval [95% CI], 84-91%) compared with children receiving a well HLA-matched DBD kidney transplant (83%, 95% CI, 80-86%, log rank test P = 0.03). Five-year renal allograft survival was superior for children receiving an LD kidney with 1 or 2 HLA-DR mismatches (88%, 95% CI, 84-91%) compared with children receiving a DBD kidney with 0 HLA-DR mismatches (83%, 95% CI, 80-86%, log rank test P = 0.03).

Conclusions: In children, poorly HLA-matched LD renal transplant outcomes are not inferior when compared with well HLA-matched DBD renal transplants. It is difficult to justify preferentially waiting for an improved HLA-matched DBD kidney when a poorer HLA-matched LD kidney transplant is available.

This registry analysis involving 1,378 pediatric renal transplant recipients shows similar 5-year outcomes comparing poorly HLA matched living with well HLA matched deceased donor renal transplants, questioning current allocation algorithms and increasing the debate around waiting time versus risk of sensitization.

1 Institute of Child Health, University College London, London, United Kingdom.

2 NHS Blood and Transplant, Bristol, United Kingdom.

3 Nuffield Department of Surgical Sciences, Oxford Transplant Centre, Oxford University Hospitals, University of Oxford, Oxford, United Kingdom.

4 Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

Received 24 August 2015. Revision received 17 January 2016.

Accepted 21 January 2016.

This research study was supported by the National Institute for Health Research Biomedical Research Centre based at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.

The authors declare no conflicts of interest.

A.H., L.P., S.V.F., and S.D.M. conceived the study, all authors contributed to study methodology development. A.H. and L.P. collected the main study data. M.M., A.H., and L.P. collated the data and performed analytical work. S.V.F. and S.D.M. had oversight of this study. M.M. and S.D.M. wrote the first draft of the article with input from all authors. All authors have approved the final article submitted. S.D.M. acts as senior author and guarantor for this study.

Correspondence: Stephen D. Marks, Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, United Kingdom. (stephen.marks@gosh.nhs.uk).

Article Outline

Living donor (LD) kidney transplantation is now accepted as the treatment of choice for children with end-stage kidney disease with well-recognized advantages over deceased donor (DD) kidney transplantation, such as improved short- and long-term renal allograft survivals.1,2 One of the disadvantages to LD kidney transplantation is that often HLA matching is poorer than donation after brain death (DBD) kidney transplantation. In the United Kingdom, the 2006 National Kidney Allocation Scheme (NKAS) aims for a favorable match for DBD kidney transplants, which may in part account for this.

The NKAS prioritizes pediatric recipients for a good HLA match, and the result of this is that 90% of children receiving a DD kidney transplant in the United Kingdom have a good HLA match (NHS Blood and Transplant). In contrast to this, the Share-35 initiative in the United States places very little emphasis on HLA matching and instead aims to reduce waiting times for DD kidney transplantation in children,3,4 which has led to a reduction in the number of LD kidney transplants in children in the United States.3-5

Previous studies have reported that HLA matching has a smaller effect on short-term renal allograft outcomes in renal transplant recipients than previously thought,6 but the long-term effect is still unclear. Given the current estimated life of a transplant kidney of 10 to 15 years,2 young renal transplant recipients can expect more than 1 kidney transplant during their lives. The impact of poor HLA matching at the first transplant can make future transplantation more challenging due to HLA sensitization.7,8 In view of this, there may be an advantage to waiting for a well HLA-matched DD kidney transplant, if the only available LD kidney is poorly HLA-matched for the recipient, because this may reduce the risk of HLA sensitization for future retransplantation.

The aim of this study was to determine the effect of HLA matching on deceased and LD renal allograft outcomes in pediatric recipients.

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MATERIALS AND METHODS

Patient Characteristics

This was an observational retrospective national registry study of LD and DBD donor kidney transplantation. Data were collected for all first-time single-organ kidney transplants performed in pediatric (<18 years of age) recipients from January 1, 2000, to December 31, 2011. Donation after circulatory death kidney transplants and en-bloc transplants were excluded. Transplants where the HLA match group (see Table 1) or renal allograft survival were not known were excluded from the analysis.

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HLA Matching Classification

All pediatric renal transplant recipients included in this study had their HLA match classified according to the system in Table 1. There were 4 possible levels of match (based on the UK 2006 NKAS),1,9 and for analysis, these were grouped into 2 groups: a good HLA match (level 1 or level 2) and a poor HLA match (level 3 or level 4). Data were also separately analyzed for the number of HLA-A, HLA-B, and HLA-DR mismatches in each case to determine which HLAs may be responsible for any differences.

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Statistical Analysis

Differences in baseline characteristics were tested using χ2 test for categorical variables and analysis of variance for continuous variables. Kaplan-Meier estimates were used to estimate univariate posttransplant renal allograft survival by donor type (DBD and LD) and by HLA match level (as defined in Table 1). Renal allograft survival was analyzed by number of HLA-A, HLA-B, and HLA-DR mismatches separately in univariate analysis. Death-censored renal allograft survival was defined as time from renal transplantation to renal allograft failure.

A Cox proportional hazards risk-adjusted regression model was also used to explore the differences in renal allograft survival having accounted for explanatory variables. The following factors were tested as explanatory variables in the model: recipient age, recipient sex, recipient ethnicity (white/nonwhite), recipient blood group, dialysis status at transplant, primary renal disease (grouped), year of transplant, highly sensitized patient (calculated reaction frequency ≥85%), recipient waiting time, transplant center, cold ischemia time (CIT) (grouped), left/right kidney, donor age, donor sex, donor ethnicity (white/nonwhite), and donor blood group.

Out of the explanatory variables tested above, recipient age, transplant year, and left/right kidney were found to be significant at the 5% level. Therefore, these were included as covariates in the final Cox proportional hazards risk-adjusted model. Transplant year was grouped by 3-year periods to provide adequate adjustment without loss of power. The proportional hazards assumptions were assessed and deemed to have been met in the final model.

All statistical tests were 2-sided, and P values less than 0.05 were deemed to be statistically significant. Data were fully anonymized, and ethical principles were adhered to throughout the study, this study met the NHS Blood and Transplant ethical criteria, and separate ethical review was not required. Statistical analyses were performed in SAS version 9.4 (SAS Institute Inc. Cary, NC).

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RESULTS

Patient Characteristics

One thousand three hundred seventy-eight pediatric renal transplant recipients were analyzed, 804 (58%) received a DBD kidney transplant whereas 574 (42%) received an LD kidney transplant. Thirteen donation after circulatory death and/or en bloc transplants were performed during the study period and excluded from the analysis. There was a higher number and proportion of good HLA matches in the DBD group, as compared with the LD group. Table 2 shows the proportion of children with each level and group of HLA matching for each transplant type (DBD and LD). Table 3 shows the baseline characteristics for all transplants included in the analysis, split by HLA match group and transplant type.

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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).

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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).

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Risk-Adjusted Analysis

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.

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DISCUSSION

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.

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ACKNOWLEDGMENTS

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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