Calcium entry blockers have a protective effect on experimental postischemic acute renal failure (ARF). Since delayed graft function (DGF) in cadaver kidney transplants is in part due to an ischemic damage to the kidney, we initiated two prospective, randomized clinical trials of human kidney transplants. Study I (control: n= 22; diltiazem: n= 20): Diltiazem (D) was added to Eurocollin's solution at a dose of 20 mg/1. If the donor had been treated with D, the graft recipient got a bolus injection of 0.28 mg/kg D and a continuous infusion of 0.002 mg/min/kg D for the first two days. A dose of 60 mg D was then given orally twice daily. Study II (control: n= 11; diltiazem: n= 10): We used the same regimen without donor pretreatment. All patients had immunosuppression with cyclosporine A (CsA) and low-dose steroids. Primary graft function (PGF) was defined as vital kidney function without hemodialysis (HD) during the first week. In both studies the incidence of PGF was higher in the D groups (I: 90% vs. 59%, p< 0.05; II: 70% vs. 55%). In the control groups, 3.6+/-0.4 (I) and 4.9+/-0.7 (II) HD per patient was necessary, compared to 0.6+/-0.2 (I), p< 0.05) and 1.9+/-0.4 (II) HD in the treatment groups. Although CsA blood trough levels were significantly higher in both D groups during the first week (I: 1150+/-24 vs. 729+/-18 ng/ml, p< 0.01; II: 1735+/-208 vs. 1,078+/-44 ng/ml, p< 0.05), glomerular filtration rate (GFR) was significantly improved on day 4 and day 7 in study I (day 4: 29+/-0.6 vs. 20+/-0.8 ml/min; day 7: 39.6+/-1.4 vs. 25+/-0.8 ml/min, p< 0.05). GFR was also improved in study II although not significantly. In addition, in both groups, fewer rejection episodes/patient occurred during the first month (I: 0.15 vs. 0.5, p< 0.05; II: 0.2 vs. 0.7). Our data indicate that combined treatment of donor and recipient with D lowers the incidence of DGF in CsA-treated recipients, despite significantly higher CsA levels in the D groups. Posttreatment of the recipient alone was less effective. Due to the interference of D and CsA, probably during degradation in the liver, therapeutic CsA blood trough levels were achieved with a substantial dose reduction of CsA by one third (p< 0.001). Thus, due to its vascular and cytoprotective effects, D may ameliorate not only ischemic but also toxic renal failure.