Chronic cyclosporin A (CsA) nephrotoxicity in the rat: the effect of calcium blockade with verapamil

Abstract

Renal structure and function were assessed in groups of male Sprague-Dawley rats, either surgically intact (SI) or nephrectomized (N), treated with either CsA alone (20 mg/kg, p.o.) or in combination with verapamil (VER; 10 mg/kg/day, i.p.) daily for up to 28 days. Compared to vehicle treated controls, reduced creatinine clearance rates (CCR, mean +/- s.e.m.) were noted following CsA treatment in Sl animals on days 21 and 28 (279 +/- 4 vs 196 +/- 20 and 296 +/- 13 vs 122 +/- 13 ml/h/kg, respectively, both P < 0.05). However, CCR was around 60% of pretreatment values in all N animals from day 7 onwards. A two to three-fold elevation in urinary N-acetyl-beta-D-glucosaminidase activity was noted from day 7 to 28 in all CsA treated animals. In addition, a similar severity of both renal tubular basophilia and corticomedullary microcalcification (but not proximal tubular vacuolation), was noted at all time points in animals receiving CsA alone. Co-treatment with VER reduced the severity of microcalcification in CsA groups, particularly N animals, increased CCR on day 14 in the Sl (196 +/- 23 vs 391 +/- 64) and days 21 and 28 in N (141 +/- 14 vs 357 +/- 32 and 152 +/- 28 vs 261 +/- 20) groups, respectively but had no effect on the magnitude of enzymuria, despite significantly increased trough whole blood CsA levels (20-30%) in both Sl and N groups. These results indicate that calcium blockade reduces both structural and functional features of chronic CsA nephrotoxicity.