On Path to Informing Hierarchy of Eplet Mismatches as Determinants of Kidney Transplant Loss

Abstract

Introduction: To mitigate risks related to human leukocyte antigen (HLA) incompatibility, we assessed whether certain structurally defined HLA targets present in donors but absent from recipients, known as eplet mismatches (EMM), are associated with death-censored graft failure (DCGF).Methods: We studied a cohort of 118,313 American 0% panel reactive antibodies (PRA) first kidney transplant recipients (2000 to 2015) from the Scientific Registry of Transplant Recipients. Imputed allelelevel donor and recipient HLA-A, -B, -C, -DRB1, and -DQB1 genotypes were converted to the repertoire of EMM. We fit survival models for each EMM with significance thresholds corrected for false discovery rate and validated those in an independent PRA > 0% cohort. We conducted network-based analyses to model relationships among EMM and developed models to select the subset of EMM most predictive of DCGF.Results: Of 412 EMM observed, 119 class I and 118 class II EMM were associated with DCGF. Network analysis showed that although 210 eplets formed profiles of 2 to 12 simultaneously occurring EMMs, 202 were singleton EMMs that were not involved in any profile. A variable selection procedure identified 55 single HLA class I and II EMMs in 70% of the dataset; of those, 15 EMMs (9 singleton and 6 involved in profiles) were predictive of DCGF in the remaining dataset. Conclusion:Our analysis distinguished increasingly smaller subsets of EMMs associated with increased risk of DCGF. Validation of these EMMs as important predictors of transplant outcomes (in contrast to acceptable EMMs) in datasets with measured allele-level genotypes will support their role as immunodominant EMMs worthy of consideration in organ allocation schemes.

A Comprehensive Evaluation of the Antibody-Verified Status of Eplets Listed in the HLA Epitope Registry

“…The rationale for this explicit and precise definition of eplets and reactivity patterns also follows from the need to define the most immunogenic eplets in transplantation (56). Multiple studies have tried to identify the most immunogenic eplet mismatches (16,(57)(58)(59), which is a crucial step in making eplet-matching in transplantation clinically applicable. Currently, these studies are limited by the use of different versions of the HLA Epitope Registry and/or HLAMatchmaker and consequently the different eplet definitions that are used in the analyses.…”

“…However, as eplets have been theoretically defined, their clinical relevance needs to be validated by antibody verification (8,15). Although antibody-verified eplet mismatches have been demonstrated to correlate with DSA formation and graft survival (13,14), recent reports also indicated that there are still clinically relevant eplets which have not been antibodyverified yet (13,16).…”

HLA Eplet Mismatches in Kidney Transplantation: More Than Just Adding Things Up

“…Imputation of 2 field HLA typing is an unavoidable necessity when collating a dataset of sufficient size and with adequate duration of follow-up to address the question of the clinical relevance of individual eplet mismatches, yet this will inevitably impact the reliability of attributing the observed associations to specific eplets, particularly when the authors were unable to determine mismatches at -DRB3/4/5, -DQA, -DPA, and DPB. Mohammadhasanzadeh and colleagues 7 readily acknowledge this limitation of their work and conclude that although their findings require validation from diverse populations with allele-level genotypes before they can be used in prioritizing donor-recipient matching that avoid higher-risk eplet mismatches, they offer a short list of candidate eplet mismatches that could be studied to understand the properties that confer an increased risk of graft failure.…”

“…In modeling the complex interrelatedness of eplet mismatches through network analysis, they highlight important limitations in simply adding the number of individual eplet mismatches in risk stratification when antibody formation may be targeted at the most immunogenic eplet of a larger eplet cluster or group. Ultimately, in demonstrating a hierarchy of risk associated with specific eplet mismatches, Mohammadhasanzadeh and colleagues 7 question the validity of quantitative eplet mismatch loads as a tool for assessing risk at the time of organ allocation, where each eplet mismatch is considered to hold equal weight.…”

“…In this issue of Kidney International Reports, Mohammadhasanzadeh 6 and colleagues use a data driven approach in a large registry cohort to add further insights into to differential clinical implications of specific eplet mismatches. The association between HLA eplet mismatch and death censored graft survival was examined in a retrospective cohort of 118,313 unsensitized, first kidney transplant receipts from the United States Scientific Registry of Transplant Recipients (SRTR).…”