*Purpose: Single-center studies demonstrate de-novo HLA-DQ donor-specific antibodies (DSA) are the most common and pathogenic DSA. However, HLA-DQ is not accounted for in many kidney allocation schemes. Data in the Scientific Registry of Transplant Recipients (SRTR) do not include DSA and are therefore not amenable to directly study DQ DSA and transplant outcomes. We conceived a new approach looking at patients in the SRTR who returned to the kidney wait list after graft failure with new unacceptable antigens (UA) corresponding to the HLA type of the failed organ. This approach enables assessment of the differential role of HLA-DQ mismatches on graft loss and recipient sensitization.

*Methods: Adult patients in the SRTR who received a primary kidney transplant from 1/1/2010 – 3/1/2020 and were relisted after graft loss were included if they had donor/recipient typing and UA data at the HLA-A, B, C, DR and DQ loci along with cPRA before transplant and after relisting. Multiple linear regression was used to evaluate: 1) the probability of developing a new HLA UA corresponding to a mismatched donor antigen, 2) the increase in cPRA at relisting given development of a new donor-specific HLA UA and 3) the magnitude of these effects for HLA-DQ as compared to other loci. Models evaluating probabilities of new UA controlled for the effect of each HLA locus. Models evaluating cPRA controlled for other UA, HLA mismatches and waitlist time.

*Results: 3,443 deceased donor and 1,424 living donor recipients were included. The probability of an HLA-DQ mismatch producing a donor-specific DQ UA was 25.2% for deceased donor recipients and 28.9% for living donor recipients, significantly greater than every other HLA locus (Fig. 1A-B, p<0.05). The mean cPRA increase with a new DQ UA was 23.5% in deceased donor recipients and 29.0% in living donor recipients, significantly greater than all other HLA loci (Fig. 1C-D, p<0.05) except for HLA-A in deceased donor recipients (23.1%).

*Conclusions: This is the first study applying registry data to quantify the differential impact of HLA mismatches on generation of DSA (assessed based on UA at relisting) and on the likelihood of receiving a second kidney (measured as increase in cPRA). HLA-DQ mismatches have the highest probability of producing donor-specific UA after graft failure and result in the largest cPRA increases. These findings provide renewed impetus for consideration of HLA-DQ matching in kidney allocation algorithms.

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