In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 9 ( 2020-9), p. 2193-2204
Abstract:
HLA matching for three HLA loci (HLA-A, HLA-B, and HLA-DR) at a low-resolution antigen level has been integral to algorithms for allocating donor kidneys for transplant since the 1970s. The authors used high-resolution genotyping of the 11 HLA loci and analysis of mismatches of HLA eplets—small patches of surface-exposed amino acids of the HLA molecule—to evaluate the effect of eplet mismatches on de novo formation of donor-specific HLA antibodies (DSAs) and kidney transplant outcome. They found that eplet mismatches in the HLA-DQ locus are most important for DSA formation, rejection, decline of graft function, and graft failure. Their findings suggest that molecular HLA-DQ matching might be more helpful than antigen matching for HLA-A, HLA-B, and HLA-DR when aiming to minimize formation of DSAs and improve outcomes after transplant. Background In kidney transplantation, evaluating mismatches of HLA eplets—small patches of surface-exposed amino acids of the HLA molecule—instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes. Methods To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches. Results De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell– or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch. Conclusions Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA 1 and DQB 1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2020010019
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
2029124-3
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