Abstract
Both the extent and the severity of renal tubular cell toxicity associated with constant systemic loads of nitrilotriacetate (NTA) were shown to be dependent upon the availability of zinc in the circulation. NTA ingestion at doses that produced plasma ultrafiltrate (UF) NTA concentrations > 20 μ m caused an increase in UF zinc. The majority of the increased zinc but not the NTA was resorbed during renal clearance of NTA and the extent and severity of tubular cell lesions was proportional to the amount of zinc resorbed. Intravenous infusion studies demonstrated that both zinc salts and ZnNaNTA produced nephrotoxicity that is very similar to heavy metal toxicity. The toxicity of iv ZnNaNTA was accompanied by renal tissue accumulation of zinc but not of NTA and the increased tissue zinc was not removed by saline infusion. These studies have led to the development of a model for NTA-associated nephrotoxicity that demonstrates that the initiation, propagation and extent of renal tubular cell toxicity are all dependent upon NTA-induced changes in zinc metabolism. This model negates the use of any mathematical models that estimate low dose (UF nta < 20 μ m) effects from toxicity data obtained at doses that exceed the threshold (UF nta > 20 μ m).
Published Version
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