Use of the isolated perfused kidney model to assess the acute pharmacologic effects of cyclosporine and its vehicle, cremophor EL.

ABSTRACT

"Nephrotoxicity" secondary to cyclosporine and its clinically used vehicle, Cremophor EL, was examined in the isolated perfused rat kidney model. This model allows the serial determination of renal hemodynamic and tubular functional studies over a 3-hr duration using a normothermic, low hematocrit (13-15%) perfusion system. Initial studies indicated that the addition of small quantities of Cremophor EL resulted in marked renal vasoconstriction with decreased renal blood flow and deterioration in renal tubular function. These effects were highly significant and were of the same magnitude whether or not cyclosporine was present in the system. Cyclosporine was therefore examined after being dissolved in another vehicle, methanol. A 10% (v/v) amount of plasma was necessary in the perfusate to prevent significant adsorption of cyclosporine to the perfusion apparatus. Cyclosporine at concentrations below 100 ng/ml resulted in minor changes in renal hemodynamics. Beginning at 100 ng/ml glomerular filtration rate dropped significantly and renal vascular resistance increased three-fold. Fractional excretion of sodium significantly increased and the urineplasma inulin ratio significantly decreased. We conclude that the clinically used drug vehicle, Cremophor EL, has significantly adverse effects on renal hemodynamics and tubular function. In addition, CsA causes similar renal toxicity in a dose-dependent fashion. Simultaneous administration of these two nephrotoxic agents could contribute to the high incidence of acute renal failure seen after transplantation. These observations suggest that an alternate vehicle with less renal toxicity might significantly decrease the incidence of this clinical problem.