We retrospectively studied 133 consecutive cardiac transplant patients who had lived more than 5 months post-transplantation. All patients had received a cyclosporine (CyA) based triple immunosuppressive protocol. Mean (+/- SE) duration of follow-up was 32 +/- 1.8 months (range 5-60 months). Serial mean serum creatinine significantly increased from 1.26 +/- 0.025 mg/dl at 1-2 months post-transplant to 1.4 +/- 0.05 at 3 months, 1.48 +/- 0.03 at 6 months, and 1.55 +/- 0.04 at 9 months with a subsequent plateau in serum creatinine levels up to 60 months of follow-up, at which point it had reached 1.66 +/- 0.1 mg/dl. The reciprocal creatinine (1/Cr) curve also showed a biphasic decline in renal function, with a rapid decline in the first 6 months followed by no further decline up to 60 months of follow-up. Approximately 4% of the patients at 1-2 months, 8% at 3 months, and 12-17% at 6-60 months had serum creatinine > and = 2.0 mg/dl. None of the patients developed end-stage renal disease requiring dialysis. At all time points, patients with serum creatinines > and = 2.0 mg/dl received a lower CyA dose than those with serum creatinines < 2.0 mg/dl (3.1 +/- 0.1 vs. 4.0 +/- 0.1 mg/kg/d, respectively, p < 0.0001), suggesting that the CyA dose had been appropriately reduced in response to a rise in serum creatinine. There was no significant rise in serum potassium (4.4 +/- 0.04 vs. 4.5 +/- 0.1 meq/l, 1-2 vs. 60 months, respectively, p = NS) or serum cholesterol (205.5 +/- 4.1 vs. 211 +/- 6.5 mg/dl, 1-2 vs. 60 months, respectively, p = NS). However, there was a significant rise in systolic (134 +/- 1.5 vs. 140.5 +/- 2.7 mmHg, p < 0.05), diastolic (84 +/- 1.0 vs. 90 +/- 2.1 mmHg, p < 0.05), and mean arterial (101 +/- 1.0 vs. 107 +/- 2.1 mmHg, p<0.05) pressures at 1-2 vs. 60 months. Serum trough CyA levels and CyA doses were significantly reduced over the follow-up period (174 +/- 6.7 vs 110.5 +/- 12.5 ng/ml, and 4.4 +/- 0.1 vs. 2.5 +/- 0.2 mg/kg/d, at 1-2 vs. 60 months, respectively, p < 0.05). At 1 yr, 56% of the patients were treated with antihypertensive medications (predominately calcium channel blockers) and 14% received lipid lowering medications (predominately an HMG-CoA reductase). We conclude, after an initial rise in serum creatinine and decline in 1/Cr curve, during the first 6-9 months post-cardiac transplant, renal function remains stable up to 5 yr of follow-up, if serum CyA levels and CyA doses are monitored and adjusted closely. However, we cannot rule out the possibility of subclinical progressive histopathologic changes, due to chronic CyA nephrotoxicity, which could become clinically apparent after a longer duration of follow-up.