Cyclosporine nephrotoxicity in the Fischer rat.

Male Fischer rats received daily intraperitoneal injections of cyclosporine (IV preparation containing CsA + cremophor) diluted in NaCl or in NaCl + cremophor. At the dose of 100 mg and 50 mg/kg/day the animals developed seizures, motor weakness and died at 4-7 days. Light microscopy at 7 days in these rats showed diffuse vacuolization of all segments of the proximal tubules which was very extensive in the outer stripe. At the dose of 25 mg and 15 mg/kg/day animals were free of symptoms and were sacrificed at day 15 for functional and histological studies. Light and electron microscopy showed cytoplasmic vacuolization in all segments of the proximal tubules. Crystal structures were observed in the experimental animals as well as in the control group that received cremophor + NaCl. The CsA blood levels were at the range of 134-236 ng/ml. Reduction of the glomerular filtration rate was observed in experimental animals as compared with the controls. We concluded that CsA is not the cause of an interstitial nephritis in the Fischer rats and that CsA is nephrotoxic to all segments of the proximal tubules. The cremophor is the cause of the crystal structures seen in the proximal tubules.