An evaluation of the nephrotoxicity of ethylenediaminetetraacetate and diethylenetriaminepentaacetate in the rat

Abstract Clinical reports and certain experimental studies have indicated that ethylenediaminetetraacetate and diethylenetriaminepentaacetate are nephrotoxic. Since these compounds have a very high order of physiologic and biochemical specificity, studies were performed in the expectation that insights of a mechanistic nature might be obtained. It was found that the tubular vacuolization produced in the rat by intraperitoneal injection of the chelates daily for 10 days was not accompanied by significant elevation of serum creatinine or urea nitrogen. In addition, there was no impairment in renal excretion of the 14 C-labeled chelates or in the ability of slices of the renal cortex to accumulate p -aminohippurate. The results with labeled compounds indicated that the vacuoles were not simple repositories of accumulated chelate, and metal analyses of the kidney indicated that vacuolization could occur independent of changes in the metal spectrum. Kidneys with preexisting or evolving damage due to vitamin D 2 or lead intoxication did not appear to be more vulnerable to the action of the chelates. Advice to the effect that renal function should be followed in patients receiving these chelates is consistent with good medical practice, but the label “nephrotoxin” is unjustified. There are similarities between the vacuoles produced by these chelates and those observed with sucrose and mannitol. The driving forces in these morphologic events appear to center on the moiety of these materials that gain entrance to the cell rather than on the number of osmotically active particles in the filtrate or urine volume. Observations and thoughts concerning the origin and fate of the vacuoles are discussed.