Chronic amphotericin B nephrotoxicity in the rat: Protective effect of calcium channel blockade

Amphotericin B is used despite predictable nephrotoxicity because it remains the most efficacious agent currently available for systemic fungal infections. It has been previously shown that calcium channel blockade prevents renal vasoconstriction and blunts the fall in glomerular filtration rate during acute amphotericin B infusion in the rat. Therefore, the effect of cotreatment with diltiazem on nephrotoxicity during chronic daily amphotericin therapy in rats was studied. Rats were given diltiazem (45 mg/ kg, 1 h before and 1 h after amphotericin) or vehicle by gastric tube; and amphotericin B (5 mg/kg/day i.p.)for 10 days. Control rats received corresponding vehicles by gastric tube and daily i.p. infection. Renal function was determined 24 h after the last dose of amphotericin or vehicle. Serum creatinine rose significantly in rats receiving amphotericin alone (initial versus final, 0.50 ± 0.07 versus 1.09 ± 0.20 mg/dL; P < 0.05) but not with amphotericin plus diltiazem (0.54 ± 0.11 versus 0.84 ± 0.23 mg/dL; P was not significant). Amphotericin rats had a marked decrease in glomerular filtration rate (amphotericin versus control, 0.28 ± 0.04 versus 1.23 ± 0.08 mL/ min/g kidney wt; P < 0.05) and renal plasma flow (1.63 ± 0.19 versus 3.50 ± 0.40 mL/min/g kidney wt; P < 0.05). These adverse renal hemodynamic effects were prevented by cotreatment with diltiazem (amphotericin plus diltiazem; glomerular filtration rate, 0.82 ± 0.18 mL/min/g kidney wt; P < 0.05 versus amphotericin; P was not significant versus control; renal plasma flow, 3.24 ± 0.63 mL/min/g kidney wt; P < 0.05 versus amphotericin; P was not significant versus control). In summary, cotreatment with diltiazem ameliorated amphotericin B-induced rise in creatinine, fall in glomerular filtration rate and fall in renal plasma flow. It was concluded that calcium channel blockade preserves renal function during chronic daily amphotericin B therapy in the rat.