Histopathological findings in well functioning, long-term renal allografts. One hundred and twenty-eight patients with a first cadaveric kidney allograft participated in a prospective, randomized, clinical trial comparing triple treatment, consisting of initial low-dose cyclosporine (CsA), azathioprine (Aza) and methylprednisolone (MP), with all possible combinations of two immunosuppressive drugs. A protocol core biopsy was performed on all patients with a functioning graft two years after transplantation. The histological findings were evaluated blindly and correlated to possible risk factors for renal allograft damage. The most common histological features were diffuse fibrosis in 62% of biopsies, tubular atrophy in 64% and diffuse inflammation in 30%. Two other important findings were glomerulosclerosis (43%) and vascular intimai proliferation (36%). The histological findings were scored mostly mild. A total of 77% (69 of 89) of patients had normal or only slightly increased serum creatinine. Decreased graft function was related to increased interstitial fibrosis, inflammation, glomerulosclerosis, mesangial matrix increase of glomeruli, intimai proliferation of vessels and tubular atrophy. These findings are characteristic, but not pathognomonic, of chronic renal allograft rejection both in experimental models and in humans. Possible risk factors were correlated to graft histology. Donor age correlated strongly with mesangial matrix increase, intimai proliferation, and tubular atrophy; there was no correlation with interstitial changes. The number of acute rejections and cold ischaemia time did not correlate with any one of the histological findings at two years following transplantation. Cyclosporine dose and concentration had a negative correlation to interstitial inflammation. A “chronic allograft damage index” was eventually created for the comparison of the four different treatment groups. The index consisted of those tubular, glomerular, vascular and interstitial changes which correlated best with decreasing graft function. The “chronic allograft damage index” was significantly lower in the group that received triple therapy than in the three other treatment groups with double-drug immunosuppressive therapy (Aza plus CsA, Aza plus MP, CsA plus MP). Our results indicate that triple drug therapy is more efficacious than any of the double drug regimens in the prevention of chronic changes. Furthermore, our results demonstrate that even renal allografts with a good and stable graft function demonstrate histopathological changes, though mostly mild, which are in accordance with those seen in chronic rejection.