Human Leukocyte Antigen Mismatching and Graft Survival in Pediatric Heart Transplant Recipients in the United States, 1987-2012

Abstract

Background: The association between donor-recipient human leukocyte antigen (HLA) mismatches and graft loss is not well understood in pediatric heart recipients. Objectives: We aimed to examine the independent association between overall and class-specific donor-recipient allelic and structural HLA mismatching and long-term graft loss in pediatric heart transplant recipients. Methods: In this retrospective national cohort study of 4,851 heart transplant recipients 18 years of age or younger from 1987-2012, we used the Kaplan-Meier method and multivariate Cox proportional hazards regression to compare probabilities of death or re-transplantation (graft loss) by total and class-specific donor-recipient HLA-A, -B, and -DR allele mismatches. We used the HLA Matchmaker algorithm to compare probabilities of graft loss by level of class-specific HLA structural differences at the molecular level. Results: Recipients with 4-6 mismatches had an increased independent long-term risk of graft loss compared to those with 0-3 mismatches (adjusted HR: 1.21 [95% CI: 1.05-1.40]). Median times to graft loss were 10.3 (95% CI: 9.9-11.1) and 14.3 (95% CI: 11.3-17.1) years in the groups with 4-6 vs. 0-3 mismatches, respectively. Mismatches at class I loci (HLA-A and -B) were associated with progressively higher probabilities of graft loss while mismatches at the class II locus (HLA-DR) were not. Having 10 or more class I structural eplet mismatches was associated with higher probability of graft loss (HR: 1.24 [95% CI: 1.07-1.44]) while the corresponding number of class II eplet mismatches was not. On stratification by both allele and structural eplet mismatching, only those with both 4-6 allele mismatches and 10+ class I eplet mismatches had an increased probability of graft loss. Conclusions: Genotypic and structural-level HLA mismatching might identify recipients at increased risk of long-term graft loss who could benefit from intensified post-transplant surveillance and management. Further studies should elucidate the mechanisms by which HLA mismatches may impact graft survival.