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

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).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.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.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.