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This was a randomized, open label comparative study conducted at 19 centers in, the U S Recipients of cadaveric kidney transplants were randomized to FK506 or CsA-based therapy. All patients also received antilymphocyte antibody induction, azathioprine and corticosteroids. Patients active in the trial at 2-year post-transplant were approached for a protocol biopsy. Biopsie were scored the Banff Classification in a blinded fashion by one pathologist. The objectives of the protocol biopsy were to assess the prevalence of chronic rejection at 2-years post-transplant and to explore predictive factors of graft survival. Results: A total of 144 patients (41.3% of patients active at 2 years) had a protocol biopsy performed; 79 FK506 and 65 CsA. Demographic characteristics, serum creatinine levels and the incidence of acute rejection in the first year post-transplant were comparable between patients who did or did not have a protocol bioppsy. Histologic evidence of acute rejection was low in both treatment groups. 8.9% in the FK506 group and 9.2% in the CsA group, all of the rcrejections were scored Grade I or Il. Chronic allograft nephropathy (CAN) was prevalent in both groups. 49 (62.0%) FK506 patients and 47 (72.3%) CsA patients (p=0.155). There were no differences between treatments in the mean acute and chronic lesion scores and the mean lesion activity. The proportion of patients who developed CAN was similar by patient age, race and sex, donor race and sex, the proportion of patients who experienced 1 nonfunction, cold ishemia time and number of HLA mismatches. CAN was found in 77.4% of patients who had acute rejection in the first year compared to 60.4% of patients who did not have rejection in the first year (p=0.045). This difference was most pronounced in CsA patients, 92.6% who cxperienced acute rejection in the first year developed CAN compared to 57.9% who did not have a rejection. The occurrence of CAN was also significantly higher in patients who experienced nephrotoxicity (decreased renal function excluding rejection as a cause; p<0.001) and CMV infection (p=0.038) in the first year. Conclusions: The rate of subclinical acute rejection was low at 2-years in both treatment groupsI suggesting that the FK506 and CsA dosing was therapeutically appropriate. Histologic evidence of CAN was prevalent but there were no apparent histopathologic differences between FK506 and CsA. While it is essential to reduce the occurrence and severity of acute rejerction, these results also suggest that It is equally "important to minimize episodes of drug nephrotoxicity and improve CMV prophylaxis to optmize longterm allograft survival.