A MULTICENTER TRIAL OF FK506 (TACROLIMUS) THERAPY IN REFRACTORY ACUTERENAL-ALLOGRAFT REJECTION - A REPORT OF THE TACROLIMUS KIDNEY-TRANSPLANTATION RESCUE STUDY-GROUP

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection , Renal transplant recipients experiencing biopsy-proven recurrent acu te allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolle d, of whom 59 (81%) had previously received at least one course of ant ilymphocyte antibody as rejection therapy, One-year follow-up was avai lable in 93% of patients, Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic resp onses to tacrolimus included improvement in 78% of patients, stabiliza tion in 11%, and progressive deterioration in 11%, The risk of experie ncing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine less than or equal to 3.0 mg/dl, 3 %; 3.1-5 mg/dl, 16% (P<0.04); >5 mg/dl, 23% (P<0.02). Twelvemonth (fro m the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patie nts (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 10 1 days. Eleven episodes of recurrent rejection were treated (three pat ients underwent transplant nephrectomy), with resolution achieved in n ine patients, Antilymphocyte antibody therapy was not used to treat re current rejection, Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; m edian at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were do cumented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was d iagnosed in a single patient. Tacrolimus whole blood levels averaged 1 5.0-9.9 ng/ml at day 7 of tacrolimus therapy and 9.4+/-5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly obse rved adverse events were neurological and gastrointestinal. Seventy-fo ur percent of patients received tacrolimus for at least 1 year. Tacrol imus therapy was discontinued in 18% of patients for rejection (11% fo r progressive, unrelenting rejection, and 7% for recurrent rejection), Tacrolimus therapy was discontinued in 8% of patients due to adverse events, In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good l ongterm renal allograft function, (3) a low incidence of recurrent rej ection, and (4) an acceptable safety profile in renal allograft recipi ents experiencing refractory rejection.