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 allele-level 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.

Keywords: epitope; eplet; graft failure; human leukocyte antigens; immunogenicity; kidney transplantation.

Figure 1

Study flow diagram.

Figure 2

Human leukocyte antigen (HLA) Class I singleton and profiles of eplet mismatches associated with death-censored graft failure and their distribution in donor and recipient population. (a) Hazard ratios and 95% confidence intervals of HLA class I eplet mismatches associated with death-censored graft failure and their distribution in donor and recipient population. (b) HLA class I profiles and singleton eplet mismatches associated with death-censored graft failure and their distributions in donor and recipient populations. (c) Profile 20 associated with death-censored graft failure includes 5 antibody-verified (AbVer) and non-AbVer eplet mismatches that are also associated with graft loss. In the figure, nodes represent single eplet mismatches and edges pair together nodes of eplet mismatches that are co-represented in the studied population (Figure 5 provides detailed descriptions of profile visualization). ∗ Models were adjusted for recipient characteristics: age, sex, time on dialysis, insurance, and cause of end-stage renal disease; donor characteristics: age, sex, and donor type; transplant characteristics: donor-recipient weight ratio, transplant era, induction agent, calcineurin inhibitor type, and steroids for maintenance immunosuppression.

Figure 3

Selected human leukocyte antigen (HLA)-DQB1 and HLA-DRB1 singleton and profiles of eplet mismatches associated with death-censored graft failure (DCGF) and their distribution in donor and recipient populations. Hazard ratios and 95% confidence intervals of selected (a) HLA-DQB1 and (b) HLA-DRB1 eplet mismatches associated with DCGF and their distribution in donor and recipient populations. (c) HLA-DRB1/DQB1 profiles and singleton eplet mismatches associated with DCGF and their distribution in donor and recipient populations. Edges of eplet mismatch profiles also associated with DCGF are presented in red. (d) Profile 03, associated with DCGF, involves 12 antibody-verified (AbVer) and non-AbVer eplet mismatches that are also individually associated with death-censored graft failure. In the figure, nodes represent single eplet mismatches and edges pair together nodes of eplet mismatches that are significantly co-represented in the studied population (Figure 5 provides detailed descriptions of profile visualization). ∗ Models were adjusted for recipient characteristics: age, sex, time on dialysis, insurance, and cause of end-stage renal disease; donor characteristics: age, sex, and donor type; transplant characteristics: donor-recipient weight ratio, transplant era, induction agent, calcineurin inhibitor type, and steroids for maintenance immunosuppression.

Figure 4

Examples of eplet mismatch profiles. Eplet mismatch profiles include simultaneously occurring eplet mismatches. These eplet mismatch profiles were segregated by class such that any given profile includes only eplets from human leukocyte antigen (HLA) class I or class II loci. (a) Profile 64 includes eplet mismatches non-AbVer.62RN and non-AbVer.63NI that are shared by HLA-A and HLA-B alleles. (b) Profile 46 includes the eplet mismatches AbVer.73A and non-AbVer.77TY that are shared by HLA-DRB1 alleles and AbVer.46VY3 that is shared by HLA-DQB1 alleles. AbVer, antibody verified. ∗ Given the large number of donor alleles that could code for each of the eplets represented in the profile, most HLA types found in association with the eplet on the HLA Epitope Registry are presented at the allele-group (first-field) level, with only a few examples of allele-level types represented in the green and orange boxes.

Figure 5

Profiles and singleton eplet mismatches. (a) Nodes represent single eplet mismatches. Class I and II eplet mismatches are represented by circles and squares, respectively. The circumference of circles and squares representing antibody-verified eplet mismatches is bolded. Edges pair together nodes (of eplet mismatches) that are significantly co-represented in the studied population. (b) Eplet mismatches statistically significantly associated with death-censored graft failure are represented in red. (c) Eplet mismatch profiles statistically significantly associated with death-censored graft failure have red edges connecting between nodes of eplet mismatches. (d) Eplet mismatch profiles statistically significantly associated with death-censored graft failure with eplet mismatches that have been antibody-verified are represented by bolded circumference.