[Basic studies on the prevention of cyclosporin A induced nephrotoxicity]

Some studies were evaluated to examine how to prevent cyclosporin A (CsA) induced nephrotoxicity, using Wistar strain rats. First, three doses of CsA (10, 25 and 50 mg/kg) were orally administered and blood CsA levels were measured. In results, they were dose-dependent. Next CsA (25 mg/kg) and diltiazem (DIL), (1, 2, 10, 30 and 50 mg/kg), theophylline (TH), (10, 20 and 30 mg/kg) or ethylephrine (ET), (0.5 mg/kg) were administered and then blood CsA levels were measured. DIL (1 and 2 mg/kg) and TH (20 and 30 mg/kg) raised blood CsA levels, but ET failed to do. Second, CsA (10 and 25 mg/kg) was administered for 6 weeks and biochemical examination of the blood and urine and histopathology of the kidney were examined regularly. The ratio of Na and K (Na/K) in the urine was significantly decreased as compared with the control group and its decrease paralleled to the histopathological changes of the renal tubulus. Next, using urine Na/K as the indicator, the influence of DIL (2 mg/kg), TH (20 mg/kg) and ET (0.5 mg/kg) were examined. DIL and TH significantly raised the blood CsA levels, but ET had no effect on them, while DIL but TH and ET showed a tendency to prevent the decrease in urine Na/K. Finally, immunosuppressive effects of CsA and DIL were examined to make sure whether DIL could enhance the effects of CsA, using human lymphocytes in vitro. Proliferation assay showed both CsA and DIL were able to inhibit the proliferation of lymphocytes. 51Cr-release assay showed they inhibited the cytotoxic activity. DIL significantly enhanced this inhibition of CsA. These results suggested that CsA dosage could be reduced and the renal tubular damages could be lowered when DIL was used. It also seemed that DIL was able to enhance the immunosuppressive effect of CsA, therefore CsA dosage could be reduced when DIL was coadministered.