HLA matching and graft survival in kidney transplantation

INTRODUCTION

The evidence that antigens of the 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 to randomly matched cadaveric 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), 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.

RELATIVE IMPORTANCE OF HLA-A,-B, AND -DR

The simple assumption that each mismatch for HLA antigens has equal weight has not been borne out. The initial CTS analysis showed that the major impact comes from the DR and B antigens, with little additional effect from the A antigens [1,2]. The UK Transplant and Eurotransplant data are somewhat similar, with DR matching having a much greater effect than that of B or A [3,4]. Another study found that HLA-DR mismatches (and the number of rejection episodes) correlated with poor long-term survival [5]. Each antigen also appears to exert its effect at different times post-transplant, with the maximal effect of DR and B mismatching occurring within the first six months and two years post-transplant, respectively [6]

A related issue is whether specific HLA mismatch combinations are associated with decreased renal allograft survival [7,8]. A retrospective study addressed this issue by examining 2877 unrelated renal transplants with one mismatch of either HLA-A, -B, or -DR [7]. Seven unique combinations ("taboo" mismatches) of recipient HLA antigen and donor HLA antigen were associated with significant decreases in graft survival when compared to survival among transplant groups with either no mismatch or one indifferent mismatch. At five years, graft survival among the groups without a mismatch, with one indifferent mismatch, or with one taboo mismatch was 72, 69, and 50 percent, respectively. The mechanism by which "taboo" HLA mismatches may result in diminished allograft survival is unknown.

When trying to match a donor to a recipient, avoidance of mismatches is used in preference to matching of HLA antigens. This approach maximizes the number of patients offered well-matched grafts because the same antigen may be present twice. As an example, HLA-A2 is a common antigen and homozygosity is frequent. Such a patient can receive a graft with no mismatches; however, he or she cannot be matched for six HLA antigens, since only five are present.