Cyclosporine-induced renal structural damage: influence of dosage, strain, age and sex with reference to the rat and guinea pig

Abstract

Cyclosporine (CsA)-induced renal structural damage was investigated in rats of different strains, age and sex, and in outbred guinea pigs, given the drug orally for periods of 1 to 7 weeks. In adult male Sprague-Dawley (SD) rats, proximal straight tubular (PST) cell vacuolation and nuclear pyknosis (affecting less than 5% of tubular profiles) can consistently be demonstrated by light microscopy within a few days of commencement of treatment with 25 mg/kg. The extent of damage observed with longer term, continuous drug administration is generally more pronounced, dose-related and subject to "spontaneous" remission. Comparison of SD with DA male rats undergoing similar treatment shows that at 4 weeks, structural damage is less pronounced in the latter strain. In juvenile (LEW X DA)F1 hybrids, male animals exhibit greater susceptibility to CsA-induced nephrotoxicity than do females. This is related to differences in circulating levels of CsA in males and females. However, in adult SD rats both male and female animals show almost the same degree of tubular nephrotoxicity when given the drug at 50 mg/kg. Use of the electron microscope improves detection of early and minimal tubular cell damage: for example, in guinea pigs receiving 75 mg/kg orally for 4 days, ultrastructural changes are evident although the renal tubules are apparently unaffected when examined by light microscopy.