Pathology of Preneoplastic and Neoplastic Renal Tubular Lesions Induced in F-344 Rats by Sodium Barbital, a Nongenotoxic Renal Carcinogen and Nephrotoxin

Abstract

Sodium barbital (NaBB), a long-duration sedative/hypnotic barbiturate, is a nongenotoxic nephrotoxin and induces chronic persistent increases in rates of cell proliferation in renal cortical tubules of male F-344/NCr rats. In 5 of our 2-stage carcinogenesis experiments with NaBB at doses of 500, 1,000, or 4,000 ppm for periods of up to 106 wk of age, renal tubular cell tumors were found in incidences of up to 25% in rats receiving only NaBB while fewer than 1% of controls had renal epithelial tumors. We reviewed renal tubular proliferative lesions found in these studies and classified the lesions based on morphology, histogenesis, and immunohistochemical findings. Renal dysplastic tubules (DTs; atypical hyperplasia), putative preneoplastic lesions rarely seen in controls, were found in the renal cortex of more than 50% of the NaBB-exposed rats. DTs were classified into grades 1–3, based on lesion size and growth patterns. All renal adenomas were usually of the basophilic phenotype, and 70% of basophilic adenomas displayed solid patterns, while tumors with papillary, cystic, or tubular patterns were seen less commonly. By serial or step sectioning of the DTs and tumors, evidence was found indicating that the high grades (grade 2 or 3) of DTs, some of which arose in the P1 or P2 segment of the proximal tubules, were sometimes connected to the adenomas. Vimentin expression was demonstrated immunohistochemically in NaBB-induced renal tubular adenomas but not in normal tubules. Tumors were usually not immunoreactive for glutathione S-transferase, placental form, but heterogeneous immunoreactivity was also seen in some tumors. Lysozyme was absent in preneoplastic and neoplastic lesions induced by NaBB, while some intact normal proximal convoluted tubules were immunoreactive. The common tumor phenotype induced by NaBB, the basophilic solid adenoma, was similar to the most common type of spontaneous renal tumor found in untreated aging F-344 rats. NaBB may promote naturally occurring renal preneoplastic or neoplastic tubular lesions of this unique phenotype, but it is also possible that it may induce these lesions de novo.