A prospective, randomized trial of FK-506 in renal transplantation - A comparison between double- and triple-drug therapy

Previous clinical evaluation of FK506 in renal transplantation has demonstrated equivalent patient and graft survival when compared with cyclosporine-based regimens. However, lower steroid and anti-hypertensive medication requirements and lower serum cholesterol levels have been seen in patients receiving FK506. In August, 1991, a prospective, randomized trial was begun, comparing FK506/prednisone with FK506/azathioprine/prednisone. Two-hundred-and-four adults were entered into this trial between August 1, 1991, and October 11, 1992. The mean recipient age was 43.8 ± 13.7 years, with a range of 17.6-78.0 years. Sixty-one (30%) recipients received a 2nd, 3rd or 4th transplant, while 35 (17%) had a PRA greater than 40% at the time of transplant. Thirty-three (16%) of the transplants were in recipients over 60 years of age, Thirteen percent of the kidneys were from living donors; 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4 ± 8.4 hours, and the mean donor age was 34 ± 2.10 years, with a range from 4 months to 75 years. With a mean follow-up of 9 ± 4 months, the 1-year actuarial patient survival is 93%; for the two-drug group it is 95%, and for the three-drug group it is 91% (p = NS). One-year actuarial graft survival is 86%, in the two-drug group it is 90%, while in the three-drug group it is 82% (p = NS). The mean serum creatinine and BUN are 1.85 ± 0.76 mg/dl and 30 ± 14 mg/dl; the values are not significantly different between the two- and three-drug groups. Rejection was seen in 45% of patients, 51% in the two-drug and 39% in the three-drug group (p = 0.09). In cadaveric recipients, more rejection was seen in the two-drug group (58%) than in the three-drug group (39%; p < 0.02: 24 (12%) of patients required OKT3 or ATGAM(®) for rejection: 24 (12%) had cytomegalovirus; an equal incidence was seen in both groups. New onset diabetes was seen in 14% of patients; there was a higher incidence in the two-drug (20%) than in the three-drug (8%) group (p < 0.03). The incidence of PTLD was 1% (2 patients). Crossover between the two limbs was seen commonly: 26/25%) of the patients in the two-drug group required the addition of azathioprine, while 46 (45%) of the patients in the three-drug group required discontinuation of azathioprine (usually because of a falling white blood cell count or hepatic dysfunction). Sixty-five (32%) patients are off steroids, while 88 (43%) patients are not taking any antihypertensive medications. The mean serum cholesterol is 193 ± 53 mg/dl. These data confirm earlier reports about the efficacy of FK506 in renal transplantation. The benefit of azathioprine is unclear, with no improvement in patient and graft survival and a higher crossover rate, but with less rejection in certain subgroups and less diabetes.