A study of the protective effect of chloride salts on cisplatin nephrotoxicity

In rats NaCl and NH4Cl (25 mmoles/kg, p.o.) were found to be equally effective at preventing nephrotoxicity when administered to rats 90 min before cisplatin (5 mg/kg i.p.) but (NH4)2SO4 did not protect. The severity of nephrotoxicity, taken as the maximum elevation in blood urea concentration, showed a high degree of correlation with urinary chloride concentration, but not with urinary pH or volume. Sodium chloride did not protect against nephrotoxicity when administered 3 or 24 hr after cisplatin. Sodium chloride showed protection against nephrotoxicity caused by cisplatin metabolites only at low doses of platinum. For animals pretreated with NaCl (25 mmoles/kg) or water p.o. the urinary excretion of total platinum, cisplatin and six of the seven metabolites separated by hplc was not significantly different between the two treatments during the 0-5-hr period post dosing. However, one metabolite, possibly a nephrotoxic hydrolysis product, was excreted in significantly smaller amounts in the urine of animals pretreated with NaCl (P less than 0.05). Furthermore, in all cisplatin treated animals the amount of this species excreted correlated with the severity of nephrotoxicity. Whilst this suggests that chloride ions may protect against the nephrotoxicity of cisplatin by inhibiting its rate of metabolism this metabolite accounts for only 2.5% of the platinum excreted. Furthermore, the data do not exclude the possibility that NaCl prevents cisplatin-induced nephrotoxicity by preventing renal ischaemia, which may normally follow cisplatin treatment, or that the renal uptake or transport of platinum may be inhibited by NaCl.