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HLA matching and graft survival in kidney transplantation

Daniel C Brennan, MD, FACP
Section Editor
Barbara Murphy, MB, BAO, BCh, FRCPI
Deputy Editor
Albert Q Lam, MD


The evidence that antigens of the human leukocyte antigen (HLA) system provide the major barrier to acceptance of renal transplants was first obtained with living-related-donor transplants. Graft survival was superior in sibling pairs having both the same serologically defined HLA antigens and a nonreactive in vitro mixed lymphocyte proliferative response when compared with randomly matched, deceased donors treated with the same immunosuppressive drugs, principally azathioprine and prednisone. (The mixed lymphocyte response [MLR] is an in vitro estimate of incompatibility in which the degree of proliferation of the recipient lymphocytes to donor lymphocytes is measured.) There was an intermediate level of graft survival in haploidentical parent-to-child or sibling-to-sibling transplants in which one but not both of the haplotypes matched.

The most valuable databases now in existence are those representing pooling of information from a large number of collaborating centers. Although such pooled data may suffer from variations in protocols and undocumented selection factors, the power of univariate analyses becomes compelling when thousands of patients are included. These large databases include the United Network for Organ Sharing (UNOS), the Collaborative Transplant Study (CTS), the Scientific Registry of Transplant Recipients (SRTR), the American Southeast Organ Procurement Foundation (SEOPF), the United Kingdom Transplant Service, Eurotransplant, the Australian New Zealand Data (ANZDATA), and others.

The methods used to test for HLA antigens and antibodies have changed over time and become more sophisticated. Historically, serology and cellular-based assays such as the complement-dependent cellular lymphocytotoxicity (CDC) assay were used to determine HLA antigens and anti-HLA antibodies. Antigens are now molecularly defined through DNA analysis, providing allelic-level definition of the antigens, and anti-HLA antibodies can now be detected using flow cytometry, solid-phase immunoassays, and single-antigen bead assays such as Luminex [1,2]. These assays can also be used to detect non-HLA antibodies [3].


The simple assumption that each mismatch for HLA antigens has equal weight has not been borne out. The initial Collaborative Transplant Study (CTS) analysis showed that the major impact comes from the DR and B antigens, with little additional effect from the A antigens [4,5]. The UK Transplant and Eurotransplant data are somewhat similar, with DR matching having a much greater effect than that of B or A [6,7]. Another study found that HLA-DR mismatches (and the number of rejection episodes) correlated with poor long-term survival [8]. Each antigen also appears to exert its effect at different times posttransplant, with the maximal effect of DR and B mismatching occurring within the first six months and two years posttransplant, respectively [9].

An analysis of the United Network for Organ Sharing (UNOS) registry of patients transplanted between January 1, 1987 and December 31, 2013 confirms the importance of minimizing mismatches and maximizing matches [10]. In this study of 189,141 first adult kidney-alone transplants, there was a 13 percent higher risk with one HLA mismatch (hazard ratio [HR] 1.13, 95% CI 1.06-1.21) and a 64 percent higher risk with six HLA mismatches (HR 1.64, 95% CI 1.56-1.73), with increasing risk for each level of mismatch. In contradistinction to previous studies, these results were independent of locus.

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Literature review current through: Nov 2017. | This topic last updated: Aug 31, 2016.
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