THE ROLE OF APOPTOSIS IN THE DEVELOPMENT OF RENAL CORTICAL TUBULAR ATROPHY ASSOCIATED WITH HEALED EXPERIMENTAL RENAL PAPILLARY NECROSIS

An animal model of chronic analgesic nephropathy, in which renal papillary necrosis was induced by the administration of a single injection of bromoethylamine 2-hydrobromide in male Sprague-Dawley rats, was used to investigate the pathogenesis of the atrophy of tubules that leads to cortical atrophy or 'scarring' in analgesic nephropathy. One of the major objectives was documentation of the participation of apoptosis, a distinctive mode of cell death, in the process of cortical tubular atrophy. Control and treated groups of animals were studied at 2 wks, and at subsequent monthly intervals up to 4 mths. At each time, light microscopy and ultrastructure were used to relate changes in cellular pathology to alterations in renal mass. Apoptosis was quantitated in paraffin sections, and autoradiographic identification of cells showing tritiated thymidine uptake was used as an indication of cell proliferation. In animals with total renal papillary necrosis (RPN), focal or diffuse cortical atrophy developed, the extent of which appeared to be proportional to the extent of the RPN. Renal mass was reduced only in those kidneys that developed extensive, diffuse lesions. Compensatory renal growth occurred in the areas of healthy tissue adjacent to the foci of atrophy, with both cellular hyperplasia and hypertrophy playing roles in its development. One of the prominent cellular events was the appearance of apoptotic cells and bodies, with invading intraepithelial macrophages involved in their phagocytosis and degradation. We propose that this form of cell death plays an important role in the pathogenesis of cortical atrophy. Current descriptions of the cortical lesions that occur in analgesic nephropathy refer to the changes as 'scars'. Although the focal lesions have a macroscopic appearance that resembles scars, the results of the present study indicate that usage of this terminology may be misleading, since scarring is often described after severe tissue injury or necrosis, which was not identified in the present study.