HLAMatchmaker-based strategy to identify acceptable HLA class I mismatches for highly sensitized kidney transplant candidates

Abstract

Abstract HLAMatchmaker determines HLA compatibility at the level of polymorphic amino acid triplets in antibody-accessible sequence positions. Recent studies have shown that among HLA-DR-matched kidney transplants, the HLA-A, B antigen mismatches which are compatible at the triplet level have almost identical graft survival rates as the zero-HLA-A, B antigen mismatches. This finding provides the basis of a new strategy to identify HLA-mismatched organs that have similar success rates as the zero-HLA-antigen mismatches. This report describes how in conjunction with the Acceptable Mismatch program in Eurotransplant, HLA-Matchmaker can expand the pool of potential donors for highly sensitized patients, for whom it is very difficult to find a compatible transplant. Sera from 35 highly sensitized kidney transplant candidates with an average PRA of 96% were screened by lymphocytotoxicity with HLA-typed panels that included cells that were selectively mismatched for one or two HLA antigens for each patient. Acceptable and unacceptable HLA-A, B antigen mismatches were determined from the serum reactivity with the cell panel. HLAMatchmaker analysis was applied to identify additional HLA class I antigens that were matched at the triplet level. For each patient, we calculated the probability of finding a donor (PFD) in the different match categories from HLA gene frequencies in the kidney donor population. The median PFD for a zero-antigen mismatch was 0.025%. Matching at the triplet level increased the median PFD to 0.037% (P=0.008). The median PFD was 0.058% for a 0-1-triplet mismatch and 0.226% for a 0-2-triplet mismatch. Serum screening identified acceptable antigen mismatches for 28 of 35 higly sensitized patients, and the median PFD increased to 0.307% for a zero/acceptable antigen mismatch. The application of HLAMatchmaker permitted for 33 patients (or 92%) the identification of additional antigens that were acceptable at the triplet level, and the median PFD for a zero/acceptable triplet mismatch went up to 0.425% Inclusion of one-triplet mismatches increased the median PFD to 1.112%. Validation studies have shown that patient sera reacted with none of the zero-triplet-mismatched antigens, 8–13% of the one-triplet mismatches, and 12–19% of the two-triplet mismatches. Although most antigens with one or two mismatched triplets appear acceptable to highly sensitized patients, a serum analysis must ascertain that the patient's antibodies do not recognize such mismatched triplets. HLAMatchmaker offers a useful strategy of identifying more donors with acceptable HLA mismatches and could alleviate the problum of accumulation of highly sensitized on the transplant waiting list.