Immune Monitoring and Tacrolimus (Tac) Withdrawal in Low Risk Recipients of Kidney Transplants - Results of CTOT09.

Withdrawal of Tac from kidney transplant recipients receiving standard immunosuppression may limit nephrotoxicity. CTOT-9 is a multicenter RCT designed to test if immune monitoring will allow safe withdrawal of Tac in low immune risk patients also treated with rATG, MMF, and pred. Enrollees were adult recipients of primary live donor kidney transplants with peak flow PRAs < 30%, no donor specific antibodies (DSA) and negative flow cytometry T & B cell cross matches. Patients free of acute rejection (AR), free of AR on a 6 mo protocol biopsy, absent DSA at 6 mo and without persistent BK viremia were randomized 1:2 to Tac maintenance (TM) or withdrawal (TW). Donor-specific interferon gamma producing PBMC quantified by ELISPOT and DSA were measured pretransplant and at intervals posttransplant. Urinary CXCL9 and CXCL10 ELISAs were performed at regular intervals with intensified frequency during and after TW. After randomization, persistent elevations of urinary chemokines or de novo DSA prompted biopsies. Tac was renewed in patients with DSAs or biopsy-proven AR. 47 patients were enrolled and 21 were randomized (7 TM,14 TW). 6/14 in the TW group developed AR, 5/6 after withdrawal completed, of which 3 also developed class II DSA. 2 patients developed isolated class II DSA. As a result, the DSMB halted the study. Analyses revealed a pre-specified threshold of urinary CXCL9 of >200 pg/ml between 11 and 108 d prior to AR in 4/6 TW patients. Urinary CXCL9 was not elevated in those developing new DSA alone. In TW patients with ELISPOT data, pretransplant donor reactive ELISPOTs (>40 cells/300K) were positive in 4/5 patients with AR and only 1/5 with out AR. Our results indicate that Tac withdrawal is associated with unacceptably high rates of adverse clinical and immunologic events even in low risk living donor recipients. Preliminary analysis suggests that pretransplant ELISPOT and urinary CXCL9 testing may predict cellular rejection episodes supporting its use in other minimization protocols.