The induction of renal papillary necrosis in Gunn rats by analgesics and analgesic mixtures.

Homozygous members of the mutant Gunn strain of Wistar rats genetically lack the enzyme uridine diphosphate glucuronyl transferase. "High" and "low" dose gavage feeding for 18-34 days of an analgesic mixture containing aspirin, phenacetin and caffeine (APC) confirmed the previously reported susceptibility of these animals to analgesic induced renal papillary necrosis. Heterozygotes do not share the gross enzyme deficiency of homozygotes and, when treated with APC under identical conditions, failed to develop renal papillary necrosis. Groups of homozygotes were dosed by gavage with aspirin, phenacetin and paracetamol for 4 weeks. Renal papillary necrosis was produced by all 3 drugs, the lowest frequency of lesions occurring with phenacetin. It is postulated that the enzyme deficiency of homozygous Gunn rats influences the metabolism of analgesics to favour the excretion of nephrotoxic metabolites. The renal papillary necrosis appearing in these experiments is essentially an acute lesion, differing both in natural history and morphology from the renal papillary necrosis of analgesic nephropathy, suggesting that the pathogeneses of the experimental and human lesions differ.