Eplet mismatch analysis and allograft outcome across racially diverse groups in a pediatric transplant cohort: a single-center analysis

Abstract

HLA eplet mismatch load has been suggested as an improvement to HLA antigen mismatch determination for organ selection. Given that eplet mismatches are determined based on amino acid sequence difference among HLA alleles, and that the frequency of HLA alleles varies between racial groups, we investigated the correlation between eplet mismatch load and allograft outcomes in 110 pediatric kidney transplant recipients who received their first organ from a donor of the same race (SRT) versus a donor of a different race (DRT). Adjusted modified Poisson regression was used to assess the interaction between eplet mismatch load and race mismatch and its effect on outcome. Caucasians and living donor recipients had lower eplet mismatched loads against their donors compared with non-Caucasian and deceased donor recipients. Overall, for the entire population, the risk of de novo HLA-DSA development was significantly increased with higher eplet loads (p < 0.001). Compared with the SRT group, the DRT group had higher eplet loads when compared with their donor, for HLA class I but not HLA class II molecules; however, there was no significant difference in the incidence of de novo HLA-DSA between the 2 groups. The risk of rejection increased significantly for DRT compared with SRT, only when class I eplet load was ≥ 70 (p = 0.04). Together this data show that eplet mismatch load analysis is an effective tool for alloimmune risk assessment. If considered for donor selection, acceptable eplet mismatch loads determined from studies in homogenous populations may restrict transplantation across racially diverse donor and patient groups with no evidence of poor outcome. Therefore, an acceptable eplet mismatch load threshold must consider the heterogeneity of the transplant population.

Keywords: Donor; Eplet; Recipient.

Fig. 1

Comparison of crystal structures between HLA-A*01:01, HLA-A*02:01, and HLA-A*03:01. Theoretical structures were produced in HLA Fusion ™ Version 4.2. HLA-A*01:01 and HLA-A*03:01 have shared eplets. Eplets unique to HLA-A*01:01 but not present in HLA-A*03:01 are circled in black. Antibody verified eplets are listed as “YES” in table. HLA-A*02:01 is more distinct from HLA-A*:01:01 and HLA-A*03:01. Pink = alpha domain; blue = beta 2 microglobulin; brown = bound peptide; yellow = eplets

Fig. 2

Eplet load difference between SRT and DRT groups. HLA- class I eplet mismatch load (ABC) between donor and recipient in the DRT group (n = 29) was higher than that of SRT group (n = 70) (mean eplet load = 37 versus 28, respectively; 95% CI 2.4–15.3; p = 0.007). HLA-class II eplet load (include HLA-DRβ1/DRβ345/DQβ1/DPβ1) was higher in DRT compared with SRT (33 versus 25, respectively; 95% CI 0.8–15.8; p = 0.029). There was no significant difference in the mean eplet load at HLA-DRβ1 for DRT versus SRT (mean eplet loads 13 versus 14, respectively; p = 0.573)

Fig. 3

Relative risk of rejection with increasing class I eplet mismatch. After adjusting for donor and recipient age, gender, donor source, kidney allocation period, recipient diagnosis, and CPRA, the solid curve illustrates the increased association between eplet MM and race mismatch. Each point on the solid curve denotes the relative risk for rejection when comparing DRT and SRT at a certain class I eplet mismatch level. The dash lines denote the 95% confidence intervals. As the number of class I eplet mismatch increases, the association between the number of eplet mismatches and incidence of rejection increases. Number of patients with eplet load < 20, n = 21; 20–50 eplet load n = 70; eplet load > 50 n = 19