We have investigated the impact of the frequency of acute rejection episodes on the generation of chronic rejection in long-surviving rat renal allografts. A total of 33 renal transplantations was performed from DA to WF rats, receiving different cyclosporine-based immunosuppressive regimens. As a consequence, different numbers of acute rejection episodes were recorded in the recipients, all of which were successfully treated with cyclosporine. Upon sacrifice at 12 weeks posttransplantation, the frequency of acute rejection episodes was correlated with the major histological parameters of chronic rejection and with graft function. The intensity of the major histological parameters of chronic rejection, exemplified by vascular intimal proliferation and glomerular mesangial matrix increase, and the decline in graft function between the no-rejection vs. rejection groups, were directly proportional to the number of acute rejection episodes. Vascular intimal proliferation increased from 0.5 +/- 0.4 (arbitrary units) in the no-rejection group to 1.7 +/- 0.9 (P = 0.0093) after one rejection episode, to 2.2 +/- 0.3 (P = 0.0001) after two, and to 2.2 +/- 0.5 (P = 0.0014) after three or four rejection episodes. Glomerular mesangial matrix increased from 1.2 +/- 0.3 (arbitrary units) in the no-rejection group to 1.9 +/- 0.6 (P = 0.017) after one, to 2.2 +/- 0.5 (P = 0.0005) after two, and to 2.1 +/- 0.4 (P = 0.003) after three or four rejection episodes. Serum creatinine increased from 93 +/- 24 mumol/L in the no-rejection group to 196 +/- 92 mumol/L (P = 0.016) after one, to 238 +/- 38 mumol/L (P = 0.0001) after two, and to 308 +/- 85 mumol/L (P = 0.0016) after three or four rejection episodes. Prolongation of the preoperative ischemia time from 30-60 min correlated with an increase in the number of acute rejection episodes as well as an increase in chronic changes. To conclude, in the rat renal allograft model, acute allograft rejection carries a highly significant correlation with the development of chronic rejection.