Differential toxicity expression of gentamicin in five-sixths nephrectomized rats assigned to three progressive stages of renal dysfunction - establishment of a new screening approach

Progressive renal dysfunction in 5/6 nephrectomized (NX) rats can be physio logically divided into three stages, coinciding with morphological stages, after definition of physiological parameters for identification of stage. N ow, for the establishment of a toxicity screening approach using 5/6 NX rat s, our concept, "Differential toxicity synchronized with renal dysfunction process could be identified using 5/6 NX rats" was examined by dosing genta micin, Firstly, electrophoretic fractional changes of urinary proteins duri ng gentamicin treatment were clarified with determination of amino acid seq uences and the three differential features were proven, revealing the unpre dictable depression of urinary albumin with progression of the stages in NX rats. Secondly, marked elevation of urinary lactate dehydrogenase (LDH) an d glucose (GLU) was evident, indicating the intensified hypoxic conditions and glycolysis in tubular cells synchronized with increased tubular damage. Thirdly, these transit metabolic changes were proven as intensive cause fo r the advancement of renal dysfunction by the reduction of FRelectrolytes a nd water at the end of each dosing period. These results indicate that toxi city studies of newly developed drugs using 5/6 NX rats have potentiality p rior to clinical dosing to the patients.