The nephrotoxicity of intravenously administered cadmium-metallothionein: effect of dose, mode of administration, and preexisting renal cadmium burden.

Exogenously administered cadmium-metallothionein (Cd-MT) is highly nephrotoxic, producing renal damage similar to that seen following chronic Cd exposure. However, nephrotoxicity following Cd-MT administration occurs at a much lower renal Cd concentration than that following chronic Cd exposure. In the present study, the sensitivity of female rats to bolus and infused doses of Cd-MT was evaluated. The Cd-MT was administered via the jugular vein either as a bolus or infused over a 24-hr period via osmotic minipumps in naive rats and in rats which had been pretreated with 5 microM CdCl2/kg, sc, five times/week, for 9 weeks. Renal toxicity was evaluated by urinary lactate dehydrogenase, protein, and MT excretion. In naive rats, a bolus dose of 0.15 mg Cd/kg as Cd-MT was nephrotoxic. In comparison, a two-fold higher infused dose was required to cause nephrotoxicity. In Cd-pretreated rats, a bolus dose of 0.45 mg Cd/kg as Cd-MT was necessary to produce nephrotoxicity, presumably because Cd pretreatment yielded renal MT levels that were about 15 times higher than the levels in naive animals. Although a bolus dose of 3 mg Cd/kg as CdCl2 resulted in a renal Cd concentration about 1.5 times that found after administration of 0.15 mg Cd/kg as Cd-MT, it did not produce any nephro-toxicity. The results of this study suggest that a renal Cd concentration, which is nephrotoxic if the Cd-MT is administered as a bolus dose, is well tolerated if the Cd-MT is delivered at a sustained level over a 24-hr period. Furthermore, the preexisting renal Cd burden reduces the sensitivity to nephrotoxicity of Cd-MT, presumably due to elevated MT levels available for sequestration of incoming Cd. We conclude that mere accumulation of Cd in the kidney does not necessarily result in nephrotoxicity; instead, the circulating Cd-MT level, as well as the intracellular MT concentration, appear to be the more important determinants of nephrotoxicity.