Chronic Progressive Nephropathy (CPN) in the Rat: Review of Pathology and Relationship to Renal Tumorigenesis

Abstract

Chronic progressive nephropathy (CPN) is a rodent-specific, age-related renal disease, particularly of male rats, characterized by a spectrum of distinct histological changes which may begin early in the animal's life and progress to end-stage renal disease in certain rat strains. Although CPN-related pathology is well known to most toxicological pathologists other features of CPN such as pathogenesis, modulating factors, proliferative nature, response to chemical exposure and relationship to tumorigenesis are less clearly acknowledged. CPN is generally regarded as a degenerative to atrophic disease with compensatory regenerative hyperplasia. The proliferative nature of CPN often becomes problematic in advanced to end-stage renal disease. At this stage, a number of tubule profiles may be mistaken for atypical tubule hyperplasia, the reported precursor lesion of tubule adenoma. CPN associated proliferative tubule profiles must be carefully separated from atypical tubule hyperplasia particularly in studies where chemical exposure has exacerbated CPN. Over the past several years increasing evidence has supported the hypothesis that CPN may be regarded as a type of mode of action during renal carcinogenesis in rodent bioassay studies. Retrospective studies of control and treated animals have consistently shown a relationship between the increased severity of CPN and the presence of atypical tubule hyperplasia and small, incipient renal adenomas. Understanding CPN-related tumorigenesis is important for human risk assessment interpretation. Since CPN is a rodent specific disease with no apparent similar human kidney disease condition, evidence that renal tumors may arise from an interaction with CPN could assist regulatory agencies in interpreting data from studies with exacerbated CPN.