A Multicenter Trial of Fk506 (Tacrolimus) Therapy in Refractory Acute Renal Allograft Rejection

Abstract

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 acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 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 observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for 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 long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

“…The mean tacrolimus dose is 96% higher in African American transplant recipients than in Caucasians or Asians (25,26). Maintenance of adequate levels of tacrolimus and cyclosporine is a critical issue in these patients (27,28). Since tacrolimus and cyclosporine average only 25-35% absorption after oral administration, the factors that lead to poor drug absorption and extensive phase I metabolism will ultimately influence drug exposure.…”

Immunosuppressive therapy after human lung transplantation

“…Tac has been successfully used in the treatment of intractable acute, and also chronic, rejection after kidney [85], liver [86] and heart transplantation [87].…”

Clinical outcome after conversion to FK 506 (tacrolimus) therapy for acute graft-versus-host disease resistant to cyclosporine or for cyclosporine-associated toxicities

“…The authors also report that all patients who received tacrolimus as first-line therapy showed a response. 26 In solid organ transplantation, where tacrolimus has been used as rescue therapy for graft rejection occurring on cyclosporine, preconversion prognostic factors associated with a favorable outcome include decreased severity of rejection [12][13][14]18 and a shorter time interval between transplant and conversion to tacrolimus. 14 As the median time of conversion to tacrolimus in these patients was day 49 after transplantation, and tacrolimus was tertiary therapy in most cases, it is not known if earlier conversion would improve response.…”

“…9 Tacrolimus is effective in preventing allograft rejection following liver transplantation 10,11 and as rescue therapy in treating graft rejection following renal, liver and pancreatic transplantation utilizing CSP-based immunosuppression. [12][13][14][15][16] In these settings, therapy has been successfully converted from CSP to tacrolimus when CSP toxicity occurred. [17][18][19] Clinical studies in marrow transplantation have shown that tacrolimus can prevent acute GVHD following matched sibling and unrelated donor transplants.…”