HLA phenotypes of ESRD patients are risk factors in the panel-reactive antibody (PRA) response

To determine whether recipient HLA phenotypes are correlated with an increased or decreased risk of alloantibody sensitization in end-stage renal disease (ESRD) candidates for first or repeat kidney transplantation; we analyzed 19440 kidney allograft recipients consisting of 13,216 Caucasians and 6224 non-Caucasians transplanted between 10/87 and 11/98 at South-Eastern Organ Procurement Foundation (SEOPF) member institutions. Relative risk values and 95% confidence limits were obtained using Wolfe's method. Logistic regression was used to adjust for covariates that influence sensitization, i.e. ethnicity, gender, age, pregnancies, transfusions, primary/repeat transplant and living versus cadaver donor. Univariate analysis of the entire cohort indicated that nine HLA allelotypes (DR1,4,7; B8,12,40; A1,2,11) were associated with a significantly reduced risk of sensitization, and five allelotypes (B42,B53; A 10,19,36) were associated with an increased risk of PRA responses. Corrected for the number of statistical comparisons, recipients with DR1, DR4, A1 or A2 were 15% less likely to be sensitized per allelotype. Recipients with B42, B53 or A36 were at increased risk of preformed antibodies, after correction of the P value, for an average of 38% increased risk per allelotype. In the multivariate analysis, HLA phenotypes identified as independent risk factors associated with protection against sensitization were DR1,4,7; B12(44,45); and A1,2, with an average reduced risk of 9% per allelotype. The only independent susceptibility allelotype was A36 with an increased risk of 29%. The A10 (25,26,34,66) group reached borderline significance. We also looked for HLA-DR,-B,-A combinations that could potentially represent protective or at risk haplotypes/genotypes. Stepwise logistic regression identified five combinations associated with protection: DR1-B35-A3; DR1-B35-A2; DR1-B44-A2; DR4-B44-A2; DR7-B57-A1 (RR range 0.83-0.63) with 27% average reduced risk per combination. Phenotype combinations associated with an increased risk of sensitization were: DR2-B44-A2; DR2B53-A2; DR3-B8-A1: DR3-B42-A30; DR6-B42-A30; DR11-B53-A30 (RR range 2.76-1.48) with an average increased risk of 70% per combination. This study provides strong evidence that HLA-linked genes influence the anti-HLA PRA response. The magnitude of the altered PRA response risk in DR-B-A combinations was approximately twice that of the allelotypes at individual loci. HLA-DR genes seemed to contribute most of the altered risk. The correlations between DR types and PRA responsiveness are consistent with the DR types previously regarded as predictors of kidney graft survival. The magnitude of increased PRA risk attributable to an allelotype or combination was approximately twice that associated with a decreased risk. We conclude that some HLA class II-linked genes modulate the PRA response in a clinically significant manner. This immune response gene (Ir) regulation probably operates through polymorphic HLA molecules in their physiologic roles of antigen processing and presentation to helper T cells.