Epitope Mismatch Predicts De Novo DSA After CNI Withdrawal in Low-Risk Kidney Transplant Recipients.

Abstract

De novo donor specific antibody (dnDSA) correlates with kidney transplant (KTx) loss, and is predicted by early acute rejection (AR) and non-adherence. CTOT-09, a multi-centre randomized prospective trial, hypothesized that immune quiescence at 6 months (mo) in “low risk” patients (pts) treated with rabbit-ATG, tacrolimus (Tac), mycophenolate mofetil and prednisone can identify pts who may be safely withdrawn from Tac with careful immunologic monitoring. We further hypothesized that Class II epitope mismatch (mm) load in CTOT-09 would predict dnDSA development after Tac withdrawal. Enrollees were adult recipients of primary live donor KTx with peak flow PRA<30%, no DSA and a negative flow crossmatch prior to KTx. Pts free of AR in the first 6 mo, no AR on a 6 mo protocol biopsy, and no dnDSA at 6 mo were randomized 1:2 to Tac maintenance (TM) or withdrawal (TW). DSA testing by flow beads was performed every 3 mo post-KTx. Donor-recipient HLA epitope mm was determined using HLA Matchmaker (V3.0). 21 of 47 enrollees qualified for randomization (7 TM, 14 TW). DQ dnDSA developed in 1/7 TM pts (at 24 mo). In contrast, DQ dnDSA developed in 5/14 TW pts and were detected earlier (at 10.4±1.5 mo). DQ epitope mm loads were not significantly different but trended higher in the TM pts (28±20 vs 19±16, p=0.13). A predefined and published threshold of >16 DQ epitope mm load was significantly associated with the development of DQ dnDSA in the TW pts (all 5 who developed DQ dnDSA had epitope mm loads >16 as compared to only 3/9 in those who did not, p=0.03). 2 of 14 TW pts with DQ dnDSA also developed DR dnDSA. There were no Class I dnDSA in any pts. In summary, Tac withdrawal is associated with a high rate of DQ dnDSA that occurs early and cannot be predicted by immune quiescence at 6 mo, even in low risk pts. Rather, high levels of HLA DQ epitope mm is significantly associated with DQ dnDSA development supporting the concept that minimizing/withdrawing Tac should be restricted to KTx pts with low epitope mm loads.