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Tacrolimus (Prograf-FK506) has been used since 1989 as a primary immunosuppressive agent in adult and pediatric renal transplant recipients at our institution.1,2 This report will summarize our experience with it over the past six years and will demonstrate its overall efficacy and superiority.
The early studies with tacrolimus, from 1989 through 1991, included a pilot series, a small randomized trial, and a larger nonrandomized group.1,3,4 When the outcome of these patients was compared with that in a roughly concurrent (although somewhat less challenging) group of cyclosporine (CyA)-treated patients, equivalent patient and graft survival rates were seen. However, improved secondary outcomes were noted in the tacrolimus-treated patients, including lower steroid and antihypertensive medication requirements, and lower serum cholesterol levels.4 This led to a second prospective, randomized trial, between August, 1991 and December, 1993, comparing two tacrolimus-based regimens, with and without azathioprine.5–8 Earlier analyses of this trial (by intention to treat, without patient censoring) demonstrated excellent outcomes with tacrolimus overall, but with unclear benefit for azathioprine. The most recent analysis, with a mean follow-up of 33 ± 10 months, showed a one- and three-year actuarial patient survival of 95% and 92%, with no significant difference between the two groups (Table 1). Overall one- and three-year actuarial graft survival was 89% and 80%, with worse results in the tacrolimus/azathioprine/prednisone group than in the tacrolimus/prednisone group. Overall one- and three-year actuarial graft survival in first cadaver recipients was 91% and 82%, without a statistically significant difference between the two groups. The projected half-life of first cadaver kidneys was 11.9 ± 2.5 years.
Sixty-nine percent of successfully transplanted patients have been taken off steroids, and 38% are off antihypertensive medications. The mean serum creatinine is 1.9 ± 1.5 mg/dL. There are no differences between the double and triple drug groups in these parameters. The incidence of rejection was 50%, and steroid-resistant rejection was seen in 11% of cases. There was a slightly lower, but not statistically different, incidence of rejection in the azathioprine group (45% vs 55% overall, and 8% vs 14% steroid resistance). There was also a substantial crossover between the two groups, more from triple to double therapy than vice versa.
Subsequent to completion of the second randomized trial, a third randomized trial was begun in December, 1993, evaluating the role of one week of low-dose cyclophosphamide in tacrolimus-treated recipients. Analysis of this trial is currently in progress, and a fourth randomized trial, comparing tacrolimus/prednisone and tacrolimus/prednisone/mycophenolate mofetil, has just begun.
Between December, 1989 and December, 1993, 43 pediatric patients received kidneys under tacrolimus-based immunosuppression (concomitant or previous liver recipients were excluded from this analysis).2 With a mean follow-up of 25 ± 14 months, overall one- and three-year actuarial patient survival was 100% (Table 2). Overall one- and three-year actuarial graft survival was 98% and 85%. Sixty-two percent of the successfully transplanted children have been weaned off steroids, and 62% are not taking anti-hypertensive medications. The mean serum creatinine is 1.2 ± 0.6 mg/dL. The incidence of rejection was 58%, and the incidence of steroid resistant rejection was 7%. An additional 26 children were transplanted between January, 1994 and July, 1995, with 100% patient and graft survival.
The overall experience with tacrolimus in our renal transplant patients has been gratifying. Better short-term graft survival, longer projected half-lives, and a remarkable ability to wean from steroids in a majority of patients have been the most notable observations. Based on these findings, we believe that tacrolimus is a superior immunosuppressive agent in renal transplant recipients and is, at present, the drug of choice. The prolongation of cadaver kidney half-life in patients treated with tacrolimus is similar to that reported by Gjertson, Cecka, and Terasaki in a collection of cases compiled in the United Network for Organ Sharing (UNOS) Scientific Registry from 24 American renal transplant centers.9 Ongoing work is continuing to evaluate the role of new third agents and other modalities (eg bone marrow augmentation)10,11 in an effort to improve further the outcomes after transplantation.