Aluminum exacerbates cyclosporin induced nephrotoxicity in rats

Cyclosporin (CSA) has been universally used as an immunosuppressant for the management of allotransplantation and autoimmune diseases. However, nephro toxicity of CSA limits ifs use to optimum level. Aluminum (AI) is an extens ively distributed element in the environment and human exposure to this met al is unavoidable. Recent studies suggest that even a slight impairment of renal function may increase the Al body burden significantly, which may lea d to neurotoxicity, nephrotoxicity, osteodystrophy or hypochromic anemia. I n the present study, an attempt was made to study the effect of concomitant use of Al and CSA. on structure and function of kidney in rats. This study was undertaken in two steps. In the first set of experiments, the effect o f single dose of Al (1% Al-2 (SO4)(3). 18H(2)O) on the nephrotoxicity of mu ltiple doses of CSA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) was studied, wherea s in the second set of experiments the effect of multiple doses of Al (0.25 %, 0.5% and 1%) on single dose of CSA (50 mg/kg) was undertaken. Male Sprag ue-Dawley rats (weighing 230 +/- 20 g) were used in this study CSA was give n once a day by gavage for seven days, where as Al was given in drinking wa ter for the same period Twenty four hours after the last dose of CSA, anima ls were sacrificed and blood and kidney were collected for biochemical and histopathological studies. The bio-chemical parameters included blood urea nitrogen (BUN), serum creatinine (SCr), CSA and Al levels. The kidney homog enates were assayed for malondialdehyde (MDA) and lipid hydroperoxides (LPH ). Treatment of rats with CSA alone produced dose-dependent structural and functional changes in kidney. Although Al alone failed to produce any delet erious effect on renal function, it significantly increased the bioavailabi lity and nephrotoxicity of CSA. Al also exacerbated CSA induced increase in oxidative stress (as evident by increased MDA and LPH). Thus, the exacerba tion of CSA nephrotoxicity by Al may be attributed to increased bioavailabi lity of CSA and excessive generation of free radicals following concomitant use of these drugs.