Human leukocyte antigen eplet mismatches and long‐term clinical outcomes in pediatric renal transplantation: A pragmatic, registry‐based study

Abstract

Background HLA epitope‐based matching offers the potential to improve immunological risk prediction and management in children receiving renal allografts; however, studies demonstrating the association between systems for defining epitope mismatches and clinical end‐points are lacking in this population. Methods We conducted a pragmatic, retrospective, registry‐based study of pediatric recipients of primary renal allografts in Victoria, Australia between 1990 and 2014 to determine the association between HLA EpMM and clinical outcomes including graft failure, re‐transplantation and dnDSA formation. Results A total of 196 patients were included in the analysis with a median age of 11 years. Median follow‐up period was 15 years during which time 108 (55%) primary grafts failed and 72 patients were re‐transplanted. HLA class I but not class II EpMM was a significant predictor of graft failure on univariate analysis but not in adjusted models. EpMM was associated with reduced likelihood of re‐transplantation in univariate but not adjusted analysis. Within the limitations of the study, class‐specific EpMM was a strong predictor of dnDSA formation. Associations were stronger when considering only the subset of antibody‐verified EpMM. Conclusion Associations between HLA EpMM and clinical outcomes in pediatric renal allograft recipients seen on univariate analysis were attenuated following adjustment for confounders. These findings are inconclusive but suggest that HLA EpMM may provide one tool for assessing long‐term risk in this population while highlighting the need for further clinical studies.

Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation

“…We elected to not formally evaluate HLAMatchmaker as we have previously shown that eplet load correlates highly with AAMS (R 2 = 0.95 and 0.96 for HLA-DQ and DR, respectively) (11). Eplet scores were utilised in other paediatric studies (encompassing 59-196 patients) which reported associations with Class I and Class II DSA, although association with graft function was not examined (32)(33)(34). For molecular mismatch assessment using netMHCIIpan, recipient HLA-DQ, DRB1 and DRB3/4/5 molecules were used to examine donor peptide presentation.…”

Impact of de novo donor‐specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function

“…Moreover, HLA eplet incompatibility, which has been suggested as an improvement to HLA antigen mismatch determination, could identify acceptable mismatches among antigens that may appear to be foreign for the host immune system 7,20,21 7,20,21 …”

“…7,8,18,19 Moreover, HLA eplet incompatibility, which has been suggested as an improvement to HLA antigen mismatch determination, could identify acceptable mismatches among antigens that may appear to be foreign for the host immune system. 7,20,21 The superiority of HLA eplet mismatch load to traditional HLA mismatching in the recognition of pediatric patients at risk of dnDSA development has not been elucidated yet. 7,20,21 Although dnDSA appearance may increase the risk of AMR, their impact on long-term allograft prognosis has been currently put into question.…”

“…7,20,21 The superiority of HLA eplet mismatch load to traditional HLA mismatching in the recognition of pediatric patients at risk of dnDSA development has not been elucidated yet. 7,20,21 Although dnDSA appearance may increase the risk of AMR, their impact on long-term allograft prognosis has been currently put into question. In detail, the recently published adult studies have indicated that dnDSA development constitutes a predominant risk factor for poor allograft outcome, particularly when combined with rejection episodes.…”

Pediatric Kidney Transplantation—Can We Do Better? The Promise and Limitations of Epitope/Eplet Matching

“…In adult kidney transplantation there is a growing body of literature showing increased risk for DSA formation, ABMR, and allograft failure with increasing eplet/epitope mismatch score (13,16,51,52). In children, there is less published literature, however, most research implementing EMM in pediatric KT has focused on eplet load, an enumeration of eplets mismatched between the donor and recipient (48,53,54). Eplet load has been linked to adverse allograft outcomes including acute rejection, allograft loss, and transplant glomerulopathy (50,51,55).…”