Renal toxicity of antineoplastic agents

Abstract

Most of the drugs currently used in the treatment of cancer are highly cytotoxic and possess relatively low therapeutic selectivity. Given the major role of the kidney in the excretion of these drugs or their metabolites, it is perhaps surprising that clinically significant nephrotoxicity occurs with a limited number of drugs. Adriamycin induces a nephrotic syndrome in rats characterized by severe acute glomerular injury and sustained proteinuria. Tubular lesions subsequently develop, and the formation of tubular casts with resulting interstitial changes is accompanied by the appearance of glomerulosclerosis. Although the mechanism of adriamycin-induced nephrotoxicity is not known, it has been suggested that redox cycling may contribute to this toxicity by enhancing membrane lipid peroxidation, resulting in damage to kidney endoplasmic reticulum and mitochondrial membranes [l]. Mitocycin C is another redox-cycling drug with a cytotoxic mechanism of action that is very different from adriamycin. A hemolytic uremic syndrome of unknown pathogenesis has been reported in some patients treated with mitomycin C; this syndrome has been reproduced in’a unilateral perfusion study in the rat [2]. Nephrotoxicity has been reported for the nitrosoureas in both clinical and laboratory studies. Methyl-CCNU administered as a single, high dose produces acute proximal tubular necrosis in the rat; impaired tubular transport was evident 1 h after drug treatment. Proteinuria and decreased urine-concentrating ability accompanied necrosis of the papillary collecting ducts l-6 days later. Low-dose treatment resulted in a delayed-onset chronic progressive nephropathy involving polyuria, enzymuria, and decreased urine-concentrating ability [3,4]. Several lines of evidence point to the