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

Abstract

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...

The HLA‐DRB1*15 phenotype is associated with multiple red blood cell and HLA antibody responsiveness

“…47 Later studies confirmed this association in end-stage renal disease patients, only for DR2 in combination with HLA-A2 and -B44 and -B53 antigens. 48 Also, in hemophilia patients with FVIII inhibitor the OR of carrying a DRB1*15 allele was 2.0 compared to noninhibitor patients. 49 The higher PRA associated with higher DRB1*15 frequency is possibly female specific, as seen in multiple sclerosis and some other autoimmune diseases such as narcolepsy and Type 1 autoimmune hepatitis.…”

Association of HLA phenotypes of end-stage renal disease patients preparing for first transplantation with anti-HLA antibody status

“…Univariate analysis of the whole cohort concluded that nine HLA allelotypes (DR1,4,7; B8,12,40; A1,A2,A11) were associated with reduced risk of sensitization while five allelotypes (B42,53; A10,19,36) were associated with elevated risk of sensitization. 13 Fuller and Fuller demonstrated that 79% of anti-HLA-Bw4 antibody-producing patients expressed either DRB1*01 or DRB1*03 and concluded that these alleles might confer a high risk for both humoral allosensitization and renal allograft failure in case of HLA-Bw4 incompatibility. 21 On the other hand, another study showed that the presence of DR1 in the recipient was correlated with low immune response.…”

“…22 Although Heise et al concluded that DR1 and DR4 phenotypes were associated with low PRA and good graft survival, and DR3 with high PRA and poor graft survival, they drew attention to the point that it would be incorrect to infer DR1 phenotypes as poor responders to all HLA epitopes. 13 The results of this study do not fully confirm the results of the above-mentioned studies as we have found statistically significant frequency of HLA-A3 (p = 0.018), HLA-A66 (p = 0.04), and HLA-B18 (p = 0.006) antigens in PRA-positive patients and DRB1*07 (p = 0.02) having the highest frequency in patients with sensitizing event history but no anti-HLA development suggesting that DRB1*07 might be associated with low risk of anti-HLA antibody formation.…”

“…On the other side, the reason why some people do not produce antibodies despite foreign HLA exposure remains unclear. 13 The HLA typing of the recipient might influence the development of anti-HLA antibodies. Some HLA antigens appear to be more immunogenic than others.…”

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“…However, some researchers demonstrated correlations between PRA positivity and HLA antigens in highly sensitized patients. 11,12 In these studies, the antibodies were analyzed with single antigen bead array by using LUMINEX. A positive correlation between PRA and LSA could not be detected.…”