Mechanism of cisplatin nephrotoxicity

cis-Diamminedichloroplatinum II (cisplatin) is widely used in cancer treatments. Renal dysfunction is the major toxic effect of this drug. Micropuncture studies suggest that cisplatin reduces single-nephron glomerular filtration rate (GFR) and causes a significant backleak of inulin across the renal tubule. Pathological alterations are localized to the S3 segment of the proximal tubule situated in the outer stripe of the outer medulla. Renal clearance studies in humans demonstrate that the free platinum clearance exceeds the GFR, which suggests that cisplatin or a platinum metabolite is actively secreted by the kidney. Studies with renal cortex slices indicate that platinum is accumulated by renal tissue against a concentration gradient. This uptake is blocked by metabolic inhibitors and the organic base triethanolamine. Heavy metals are thought to produce renal damage because of interaction with renal sulfhydryl (SH) groups. After cisplatin administration to rats, total renal SH groups decreased by 14% owing to a decrease of protein-bound SH groups. The greatest decline of SH groups occurred in the mitochondrial and cytosolic fractions. These fractions also had the highest platinum concentrations. These results suggest that the nephrotoxic effects of cisplatin may be related to depletion of SH groups, but a cause and effect relationship has not been definitively established.