HLA-A, -B, and -DR Zero-Mismatched Kidneys Shipped to the University of Wisconsin, Madison, 1993–2006: Superior Graft Survival Despite Longer Preservation Time

In the first 20 years of clinical kidney transplantation (1962–1982), immunosuppression and organ preservation options were limited, and the field was dominated by transplants from living-related donors. During this time, it was discovered that similar to animal models of kidney transplantation, major histocompatibility complex human leukocyte antigen (HLA) haplotype matching mattered. Transplants between HLA-identical siblings, mismatched for minor H (nonmajor histocompatibility complex) antigens only, fared much better than a one haplotype or full (two haplotypes) HLA-mismatched donor-recipient combination and were more likely to survive even after cessation of all immunosuppression (1). The origin of the HLA-0 mismatched (HLA-0MM) national kidney sharing program in the United States dates from the mid- 1980s, a time of a great expansion of kidney transplants from deceased donors. In rare cases, the accident victim or other brain-injured donor happened to be matched with the recipient for both alleles of HLA-A, -B, and -DR based on serologic typing available at that time. Studies of such transplants showed outcomes superior to that of any other kind of kidney transplant from a deceased donor (2, 3). Nonetheless, at the time of the introduction of the United Network for Organ Sharing (UNOS) program of mandated sharing between transplant centers of six HLA antigen-matched kidneys in 1987, there was a concern that the increase in preservation time for kidneys being transported out of one organ procurement organization (OPO) and into another would negate the advantages gained by having an HLA-matched kidney donor (4). In addition to the uncertainties about cold storage, there were also uncertainties about the accuracy of typing procedures used to establish HLA match between two unrelated individuals. For example, before the introduction of DNA-based typing in 1992 (5), serologic methods used for typing HLA class II alleles HLA-DQ and -DR were only 75% reliable, as was the accuracy of assigning homozygosity for any HLA-A or -B allele based on the appearance of a “blank” in a class I HLA typing (6). Despite these technical drawbacks, however, the mandated sharing of six HLA antigen-“matched” kidneys produced encouraging results (7, 8). In 1995, UNOS mandated the sharing of all HLA-0MM kidneys, a decision which allowed a “blank” (e.g., A2-, B7-, and DR4-) to be considered as evidence of homozygosity for the purposes of the sharing program. This new confidence was based on significant advances in accuracy of HLA typing made possible by the polymerase chain reaction technique with sequence-specific primer (5) and other DNA-based approaches (9). Between 1995 and 1998, the UNOS registry showed 36% of all kidneys transplanted in the United States being shared between OPOs, with 15.6% being shared as HLA-0MM kidneys and 20.4% as paybacks (10). Stegall et al. (10) compared the survival of mandatorily shared, 0MM cadaver kidneys during this period with that of payback kidney transplants (>0MM). They found a consistent 5% to 7% increase in graft survival beginning at 12 months and extending to 4 years posttransplant. This difference in graft survival was largely due to a 10% lower incidence of transplant rejection, particularly in patients with low (0%–9%) or intermediate (10%–79%) panel reactive antibodies (PRA). These results showing a graft survival benefit of 0MM shipped kidneys were confirmed in a separate study of paired donor kidney transplants (11). It should be noted that the most highly sensitized patients, those with antibodies reactive to 80% or more of a random panel of blood donors, did not enjoy a significant graft survival benefit from the 0MM sharing program (10). Nonetheless, in June 2008, the UNOS board, citing their desire to “increase efficiency in kidney matching by focusing mandatory regional and national sharing of zero-antigen mismatched kidneys for adult candidates who are harder to match because of their highly sensitized immune response,” approved a proposal to limit mandatory sharing of 0MM kidneys to pediatric patients and those with a PRA more than or equal to 20% (12). The purpose of this study was to evaluate the experience of a single center with the 0MM shipped kidney program in the era of molecular HLA typing. Single-center studies of graft survival have been of great value, because many variables such as organ preservation method, induction and maintenance immunosuppression regimen, and recipient demographics are similar for all transplants. Because the national program of mandated 0MM kidney sharing has now been terminated, except for pediatric and highly sensitized patients, it is particularly opportune at this juncture to determine what its impact has been at individual transplant centers.