*Purpose: It is becoming clear that de novo donor-specific antibodies (dnDSA) against HLA-DQ are the most prevalent and the leading cause of chronic antibody-mediated rejection and poor allograft outcome after kidney transplantation. A well-known problem with the most HLA matching approaches is that they don’t include systematic genotyping of HLA-DQ locus. Herein we evaluate the role of HLA-DQ matching at antigen, allele and haplotype levels to minimize the generation of HLA-DQ-dnDSA and improve graft outcome in kidney transplantation.

*Methods: All adult patients who underwent kidney transplantation between 2004 and 2013 at a single center, with available DNA samples were included in this study (N=926). Each transplant pair was retrospectively genotyped at the 2^nd field HLA level for HLA-DQA₁ and HLA-DQB₁.

*Results: The mean follow-up time of this kidney transplant cohort was 7.62 ± 3.78 years. 152 patients (16.4%) experienced graft failure during this period. HLA-DQ dnDSA occurred in 23 of 889 patients with antibody follow-up data within the first ten years. Figure 1 depicts the 10-year graft survival Kaplan-Meier curves according to the different levels of HLA-DQ MM. The 10-year survival rates were not statistically different between the groups with 0, 1 and 2 DQ antigen MM (80.4%, 77.7% and 74.3% respectively, p=0.27). In contrast, the different degrees of allele mismatches for the DQB₁ locus provided better risk stratification of the patients (82.8% with 0 DQB₁ MM, 78.6% with 1 DQB₁ MM and 70.0% with 2 DQB₁ MM, p=0.04). Next, we calculated the mismatches in the DQα/β pairs by considering DQA₁ at the 1^st and DQB₁ at the 2^nd field HLA genotyping level. The Kaplan-Meier curves showed that primarily the degree of mismatches for DQα/β haplotypes associated with the risk of graft failure after kidney transplantation (83.0% with 0 DQα/β MM, 78.7% with 1 DQα/β MM and 69.4% with 2 DQα/β MM, p=0.02). Finally, the patients with both matched DQα/β haplotypes had 100% DQ dnDSA-free survival compared to the decreased DQ dnDSA-free survival in patients with one (95.1%) or both (87.1%) mismatched DQα/β haplotypes (p=0.006).

*Conclusions: By comparing the HLA-DQ mismatches at antigen, allele and haplotype levels, we found that DQα/β haplotype mismatch analysis provides the best risk stratification of the kidney transplant patients. These findings indicate that adding DQα/β haplotype matching to the current antigen HLA-A, -B, or -DR matching algorithm will decrease de novo formation of HLA-DQ antibodies and improve graft survival after kidney transplantation.

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