Morphogenesis of epithelial neoplasms induced in the rat kidney by dimethylnitrosamine.

The sequential changes in tubular epithelium following single i.p. injections of dimethylnitrosamine in carcinogenic doses were followed from 24 hr up to the development of renal adenocarcinomas. The acute changes involved, in particular, the first segment of the proximal tubules, although at higher doses the distal tubules next to glomeruli were also invariably affected. The acute alterations consisted of the formation of lipid droplets and cytosegresomes, the accumulation of granular and membranous debris beneath injured epithelial cells, and sporadic cell necrosis. These changes were associated with a diffuse increase of cells throughout the cortical intertubular space, of which macrophages were the predominant cell type. As the epithelial damage resolved, so did the diffuse mononuclear reaction. Following the acute stage, grossly enlarged nuclei within the convoluted tubules increased in numbers, but their frequency and random distribution suggested that they were unrelated to neoplastic development. From 6 weeks onwards, occasional proliferative lesions were found within tubules located next to glomeruli. Electron microscopic examination revealed that such lesions possessed abnormal brush border formation and nucleoli, which were characteristic features of well-developed adenocarcinomas. Other slower growing proliferative lesions, consisting of hydrated cells, were also described. It was concluded that at least some dimethylnitrosamine-induced renal adenocarcinomas take their origin from the first segment of proximal convoluted tubules.