Deleterious effect of cyclosporines on the ischemic kidney in the rat and the protection by the calcium antagonist verapamil

Cyclosporine A (CsA) nephrotoxicity has been suggested to be aggravated in the presence of ischemia, as occurs after renal transplantation. Cyclosporine G (CsG) may be less nephrotoxic than CsA. This study evaluated in the rat (1) the effect of CsA and CsG on blood flow and the function of the kidney subjected to 60 min of warm ischemia and (2) the protective effect of the calcium antagonist verapamil (VP). After left nephrectomy, ischemia was induced in the right kidney by the clamping of the kidney pedicle for 60 min, which resulted in a significant increase in serum creatinine (SCr) to 2.30 ± 0.25 mg/dL by Day 1 with 25% mortality by Day 7. The administration of CsA or CsG (20 mg/kg iv daily for 7 days) after 60 min of renal ischemia significantly increased SCr and mortality compared with ischemia alone. In another set of experiments, 60 min of warm ischemia was applied to the right kidney and RBF was measured in both kidneys with a laser Doppler flowmeter. Blood flow in the ischemic kidney returned to the preischemic level by 15 min after the removal of the vascular clamp in the control animals. In contrast, in animals treated with CsA, a significant decrease in RBF was seen in both kidneys; however, blood flow in the ischemic kidney was significantly lower than that in the nonischemic kidney. CsG also decreased RBF in both kidneys, although in the left (nonischemic) kidney, RBF remained significantly higher with CsG than with CsA. VP treatment (0.35 mg/kg iv daily for 7 days) to animals subjected to 60 min of renal ischemia and CsA administration prevented the decrease in RBF and the increase in SCr and mortality. It is concluded that the ischemic kidney is more susceptible to CsA nephrotoxicity than the nonischemic kidney. Although CsG is less detrimental to the nonischemic kidney, it has a nephrotoxic effect on the ischemic kidney similar to that of CsA. Finally, the calcium antagonist VP prevents CsA-induced renal dysfunction in the ischemic kidney, most likely as a result of its renal hemodynamic effect.