Phenacetin-induced Renal Disease in Rats

Abstract

Pair-fed Sprague-Dawley rats were given USP acetophenetidin twice daily by gavage over a period of 4 weeks in three separate experiments. The dose of the compound was increased in 2 steps from 300 to 600 mg/rat/day. Control animals received an equal volume of water by gavage. At the termination of each experiment, blood was obtained from the aorta for chemical determinations, and the left kidney was removed for histological study. In one study, muscle, and in another, carcass (excluding kidneys) were examined for K content. In each experiment the drug-fed animals had significant azotemia, depression of the CO2 content of the serum, and hyperkalemia. The potassium content of muscle and carcass in these animals, however, in terms of fat-free dry solids, was modestly but significantly reduced. The gross appearance of the kidneys was dark in color, and on cut section, the papillae were pale. Histologically, there were consistent changes in the tubular epithelium in the proximal papillary region of the drug-fed animals. These changes included swelling of the cells and swelling and distortion of the nuclei; a striking increase in mitotic figures was noted. The cytoplasm of the tubular epithelium in the cortex contained a brown, granular pigment which stained with iron stains. Three of 39 animals exhibited necrosis and calcification of the papillary tip. The changes in the cortical epithelial cells, the papillary epithelial cells, and the papillary tip lesions were seen in none of the control animals. A consistent and reproducible renal lesion can be induced in rats by the administration of USP acetophenetidin in the manner described. Extrapolation to clinical disease in humans is not possible. A model for further study of the problem is therefore now available.