Development of resistance to nephrotoxic insult: Changes in urine composition and kidney morphology on repeated exposures to mercuric chloride or biphenyl

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Abstract
Adult male Fischer 344 rats were treated singly or repeatedly with 1 of several oral doses of HgCl2 (5, 10 or 20 mg/kg) or biphenyl (250, 500 or 1000 mg/kg). Urinalyses were conducted at various times after a single treatment or during repeated treatments. Groups of animals treated in the same manner were killed and the kidneys examined for histopathologic alterations. HgCl2 produced dose-dependenet polyuria, proteinuria, glucosuria and enzymuria [increased alkaline phosphatase (AP), .gamma.-glutamyl transpeptidase (GGT), glutamicoxaloacetic transaminase (GOT), lactate dehydrogenase (LDH) and N-acetyl-.beta.-D-glucosaminidase (NAGA) excretions]. The effects were quantitatively greatest 1-3 days after the original treatment but returned to normal or below-normal ranges shortly thereafter whether HgCl2 was administered once or continuously. Biphenyl administration also increased urine volume and urinary protein, glucose and enzyme excretions in a dose-dependent manner, but the effects were quantitatively less severe than those of HgCl2. The 14th and final dose of biphenyl elicited increases in urine volume and urinary AP and GOT excretions of the same magnitudes as did the 1st, while other parameters of renal function (e.g., protein and glucose excretions) became refractory to continued biphenyl treatment. Single and repeated treatment with HgCl2 produced dose-dependent necrosis of the proximal tubular epithelium in the kidney. The lesion was rapidly repaired in the single-treatment studies, but it was still observed, along with extensive tissue regeneration, at the end of the repeated-treatment studies despite the lack of functional abnormalities. The highest dose of biphenyl (1000 mg/kg) produced a 25% incidence of renal papillary necrosis, a lesion that had not repaired within 15 days. Lower doses of biphenyl (single or repeated treatments) did not produce a consistent change in kidney morphology. Incubation of freshly collected urine with HgCl2 concentrations .gtoreq. 0.8 mg/ml produced inhibition of urinary AP and GGT activities. These effects were observed whether or not Hg2+ was removed by dialysis before the enzyme activity measurements. The results of this study demonstrated the refractoriness of many aspects of kidney function to repeated chemical insults and suggested that toxicological evaluations conducted only at the end of repeated-treatment studies may underestimate nephrotoxic potential. Histological examination of the kidney may reveal evidence of prior tissue injury even though organ function has returned to normal.