The Hidden Benefit of CREG Matching.

Abstract

Matching for crossreactive groups (CREGs) of HLA antigens has been proposed to increase equity in the distribution of deceased donor organs among racial groups and to improve graft survival. Mixed results have been reported for the effect on graft survival; however, CREG matching may reduce the extent of sensitization following graft failure. We examined sera from 704 patients who were shown to be sensitized after renal transplantation and assessed the frequencies of antibodies to mismatches at the HLA-A, -B, -DR, and -DQ loci. Sera were tested using multiplexed bead assays with purified HLA antigen targets. Patients were categorized by whether or not a mismatched antigen was a CREG match. At each locus, the frequency of an antibody to a mismatched antigen was significantly less when the mismatch was a CREG match than when it was not (A: 38 v. 62%, P=0.000004; B: 33 v. 55%, P=0.00004; DR: 40 v. 65%, P=0.0003; DQ: 46 v 71%, P=0.02). However, there was great variability when mismatches were considered by individual specificity with the extent of reduction in antibody frequency ranging from 0 to 72% for different crossreactive antigens. Also, the impact of various CREG matches within a crossreactive group was highly variable and was, in some cases, directional. E.g., there was a 53% reduction in frequency of antibody to B8 when the patient had a B7 in their phenotype but no reduction in antibody frequency in the converse situation, i.e., when the patient was a B8 and the mismatch was a B7. In contrast to the protective effect of B7 is that a B7 mismatch when the patient does not have a B8 in their phenotype, results in antibody to B8 with nearly the same frequency as does a mismatch for B8. There are programs that calculate the number of amino acid differences between two alleles but CREG matching can be done manually and without the need for typing at the allele level. Since most transplants will have HLA mismatches, selecting donors with mismatches that are crossreactive with the patient's own antigens (i.e. CREG mismatches) may be important for patients, such as pediatric patients, who are likely to need retransplantation. However, the variability in the impact of CREG mismatches on sensitization must be considered in the donor selection process.