CHRONIC CYCLOSPORINE-A (CSA) NEPHROTOXICITY IN THE RAT - THE EFFECT OF CALCIUM BLOCKADE WITH VERAPAMIL

Renal structure and function were assessed in groups of male Sprague-D awley rats, either surgically intact (SI) or nephrectomized (N), treat ed with either CsA alone (20 mg/kg, p.o.) or in combination with verap amil (VER; 10 mg/kg/day, i.p.) daily for up to 28 days. Compared to ve hicle treated controls, reduced creatinine clearance rates (CCR, mean +/-s.e.m.) were noted following CsA treatment in SI animals on days 21 and 28 (279+/-4 vs 196+/-20 and 296+/-13 vs 122+/-13 ml/h/kg, respect ively, both P<0.05). However, CCR was around 60% of pretreatment value s in all N animals from day 7 onwards. A two to three-fold elevation i n 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 seve rity of microcalcification in CsA groups, particularly N animals, incr eased CCR on day 14 in the SI (196+/-23 vs 391+/-64) and days 21 and 2 8 in N (141+/-14 vs 357+/-32 and 152+/-28 vs 261+/-20) groups, respect ively but had no effect on the magnitude of enzymuria, despite signifi cantly increased trough whole blood CsA levels (20-30%) in both SI and N groups. These results indicate that calcium blockade reduces both s tructural and functional features of chronic CsA nephrotoxicity.