Is the Application of HLAMatchmaker Relevant in Kidney Transplantation?

Abstract

HLAMatchmaker is a computer algorithm that determines HLA compatibility at the structural level. Last year, we published in Transplantation a study on triplet matching in two large kidney transplant databases (UNOS and Eurotransplant) of zero-HLA-DR mismatched kidney transplants (1). This study was designed to test the hypothesis that transplants with conventional HLA-A,B antigen mismatches but matched at the triplet level would be equally effective as the zero-HLA-A,B antigen mismatches. We found that up to two triplet mismatches in the UNOS database and up to four triplet mismatches in the Eurotransplant database had very similar graft survivals as the zero-HLA-A,B antigen mismatches. These findings suggest that the application of HLAMatchmaker will increase the number of well-matched donors and this strategy has been described elsewhere (2). Laux et al. reported in the March 27, 2004 issue of Transplantation that they were unable to find a statistically significant association between triplet matching and kidney graft survival using the international Collaborative Transplant Study (CTS) database (3) and concluded from their data that the application of HLAMatchmaker has no significant effect on kidney transplant survival. This article was deemed important enough to be accompanied by an invited commentary in the same journal issue (4). This study had a different design in that graft survival was analyzed in relation to the number of mismatched triplets. Up to six mismatched triplets were considered “good” matches and the “poor” matches were subdivided according larger numbers of mismatched triplets, mostly 7–9, 10–12, and ≥13 triplet mismatches. Data shown for the 1 HLA-A antigen, the 1 HLA-B antigen, and the 1 HLA-A + 1 HLA-B antigen mismatched groups did not reveal statistically significant correlations between triplet matching and kidney graft survival. Laux reported that their group of 4,455 zero-HLA-A, B antigen mismatches had a 5-year graft survival of 74.85%±0.78%. Another group of 6,172 0–6 triplet mismatches (which we presume, included the 4,455 zero-HLA-A, B antigen mismatches) showed 74.48%±0.70%, a practically identical value. Moreover, the 5-year graft survival of what the authors consider a “key” group of 1 HLA-A + 1 HLA-B antigen mismatches was highest for the 0–6 triplet mismatches. Especially, recent transplants performed between 1996 and 2001 showed a graft survival of 76.96%±4.95% for the 0–6 triplet mismatches. Most cases were first transplants done in Western Europe and their graft survival was 76.30%±3.11%. This result is quite comparable with the 76.8% rate we reported for the zero HLA-A, B antigen mismatches in Eurotransplant and similar percentages for the up to four triplet mismatches (1). We must conclude that these findings by Laux et al. are quite consistent with the concept that HLAMatchmaker can identify a group of HLA-A, B antigen mismatches that give similarly high graft survivals as the HLA-A, B antigen matched combinations. Another issue is the differential immunogenicity of the triplet mismatches, which was analyzed in the article by Laux et al. This assessment of triplet immunogenicity was based on preliminary data on antibody analyses (5) and must first be confirmed and extended before their role in graft survival can be analyzed. We agree with Laux and co-workers that there are problematic issues about the current application of HLAMatchmaker. Serological HLA typing results are often insufficient for accurate determination of triplet matches. High-resolution DNA typing provides a more precise assessment of structural HLA compatibility and should also consider the effect of HLA-C triplets. The most important clinical application of the HLAMatchmaker algorithm relates to humoral sensitization as the program is based on amino acid polymorphisms in antibody accessible sites of the HLA molecules. Being an excellent tool for the definition of acceptable mismatches for highly sensitized patients, it is routinely used in Eurotransplant. Rene J. Duquesnoy Division of Transplantation Pathology University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Frans H.J. Claas Department of Immunohematology Leiden University Medical Center Leiden, The Netherlands