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.

Substituting imputation of HLA antigens for high-resolution HLA typing: Evaluation of a multiethnic population and implications for clinical decision making in transplantation

“…HLA typing in these registries has generally been recorded only for low‐resolution HLA‐A, ‐B, and ‐DR, which is not suitable for modern molecular mismatch analysis. Given the significance of the long‐term outcome data hosted by the SRTR, multiple peer‐reviewed studies have used either HaploStats and/or the HLA Matchmaker converter to impute low‐resolution HLA typing into high resolution 1‐5 . Unfortunately, as we have demonstrated, this approach introduces a significant level of error.…”

“…Duquesnoy's HLA Matchmaker converter programs, both of which suggest a patient's most likely high-resolution HLA type based on their low-resolution type and ethnicity. [1][2][3][4][5] HaploStats uses HLA haplotype frequency reference panels for 21 different ethnicities derived from volunteer potential bone marrow donors in the Be The Match/NMDP database. This software can be used to narrow the search for a potential stem cell donor; importantly, however, all potential prospective donors must undergo subsequent high-resolution confirmatory typing before any clinical intervention.…”

“…The most commonly used imputation programs are the National Marrow Donor Program's (NMDP) HaploStats and Rene Duquesnoy's HLA Matchmaker converter programs, both of which suggest a patient’s most likely high‐resolution HLA type based on their low‐resolution type and ethnicity 1‐5 . HaploStats uses HLA haplotype frequency reference panels for 21 different ethnicities derived from volunteer potential bone marrow donors in the Be The Match/NMDP database.…”

Humanized Mouse Models for Evaluation of PSC Immunogenicity

“…Over the past 60 years in the field of transplantation immunology, a number of in vitro and in vivo assays useful for hPSC immunogenicity studies have been developed and refined. Well‐established in vitro assays include the mixed lymphocyte reaction (MLR) (Morris et al., 2015) for assessment of the proliferative T cell response to alloantigens; the cross‐match assay for determination of donor‐specific antibody activity (Manna, Halpin, Campbell, & Hidalgo, 2015); and other highly specific HLA‐typing assays, such as sequencing‐based typing, which allow for highly refined donor:recipient matching (Philogene et al., 2020; Vazirabad et al., 2019). For example, these assays enable studies correlating the effects of HLA disparities with transplantation outcomes.…”

Secular Trends in Survival Outcomes of Kidney Transplantation for Children

“…observation was spent with a functioning transplant, and 608 youths (33.6%) received more than one transplant during a median follow-up time of 13.4 years (interquartile range [IQR], 5.5-24 years). Even with only 19% of the time of observation spent in dialysis, the median time to death was 10 years (IQR, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and median age at death was 24 years (IQR,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). As a pediatric provider, parents and caregivers frequently ask me what lies ahead for their child with ESKD.…”