Nephrotoxicity screening in rats: a validation study.

Abstract

A validation of our non-invasive screening test for the detection of renal damage (Zbinden et al. 1988) is presented. The test is based on repetitive, quantitative urine analysis in groups of six female Sprague-Dawley rats treated on 5 consecutive days with low doses of test substances. Higher doses were administered in the following weeks until nephrotoxic effects or signs of general toxicity were observed. Thirteen reference substances (hexachloro-1:3-butadiene [HCBD], cisplatin, carboplatin, suramin, chloroform, neomycin, rifampicin, phenacetin, phenylbutazone, methicilline, sodium oxalate, ethylene glycol and furosemide) were used. The percentage of rats reaching the test criteria, i.e., pathologic values defined on the basis of measured control values, was determined. In the controls, the overall percentage of rats reaching or exceeding the test criteria was 4.48%, a value that is close to the expected 5%. Evidence of nephrotoxicity was found with all reference compounds. Elevated excretion of cells and occurrence of cylinders were the most sensitive indicators of renal damage. Hematuria was the most frequent finding. Of the other urine constituents measured the enzyme malate dehydrogenase (MDH) was frequently increased. Water consumption, urine volume, pH and specific gravity were occasionally, and protein, glucose, electrolytes, amino acids and gamma-glutamyl-transpeptidase (GGT) were only rarely changed. It is concluded that the screening which is based on quantitative and repeated urine analysis is a useful procedure to detect nephrotoxic chemicals acting by a variety of mechanisms. The histopathological examination of the kidneys contributed useful information of the nature of the toxic effects, but as a screening tool it is less sensitive than quantitative urine analysis.