HLAMatchmaker: A molecularly based algorithm for histocompatibility determination. IV. An alternative strategy to increase the number of compatible donors for highly sensitized patients

Background. HLAMatchmaker is a computer algorithm that determines human leukocyte antigen (HLA) compatibility at the level of polymorphic amino acid triplets in antibody-accessible sequence positions. Recent studies have shown that HIA-DR-matched kidney transplant recipients with zero to two triplet mismatches had almost identical graft survival rates as those with zero HILA-AB,DR antigen mismatches. This report describes how HLAMatchmaker can be used to identify more compatible donors for highly sensitized patients. Methods. The HLAMatchmaker program was used to calculate the probability of finding a donor (PFD) with zero, one, or two triplet mismatches for 54 highly sensitized patients waiting for a kidney transplant and having panel reactive antibody (PRA) values greater than 85% and 50 randomly selected nonsensitized patients with PRA values less than 3%. Results. There was a wide variability for PFD values for the two patient cohorts. If only donors. with zero HLA-A,B mismatches were deemed acceptable for recipients, the median PFD of a zero-antigen mismatch was 0.046% for nonsensitized patients and 0.009% for highly sensitized patients (P=0.007). Half of the highly sensitized patients had a PFD below 0.01%, or,fewer than 1 in 10,000 donors would have zero antigen mismatches. Application of HLAMatchmaker identified additional HILA antigens with zero-triplet mismatches for 27 patients, resulting in a 1.8-fold increase in PFD. Considering additional antigens with one-triplet or two-triplet mismatches increased the PFD by an additional 3.8-fold and 13.7-fold, respectively. Acceptable antigen mismatches for 37 of the 54 highly sensitized patients Were identified by consistently negative reactions in serum screens, and their addition resulted in a 12.7-fold increase of the PFD to a median of 0.141%. Applying these acceptable antigens to the HLAMatchmaker algorithm identified additional antigens with zero or acceptable triplet mismatches and their inclusion increased the PFD by 3.3-fold to 0.347%. Conclusions. HLAMatchmaker offers a valuable strategy for identifying more suitably HLA-matched donors and has the potential for alleviating the problem of accumulation of highly sensitized, patients on the transplant waiting list.