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Chronic Progressive Nephropathy (CPN) and Renal Tubule Adenomas: The Controversy Continues

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In 2012, the association of chronic progressive nephropathy (CPN) in the rat and its relationship to renal tubule (RT) proliferative lesions (ie: hyperplasia and adenomas) became an important issue for debate among pathologists and toxicologists.  An association between CPN and RT proliferative lesions has been postulated for some time.  Recently, based on a comprehensive retrospective investigation involving a review of kidney slides from nearly 2,500 F344 rats from 24 long term NTP studies and defining the severity of CPN in more detail by Hard et al (Toxicol Pathol 40: 473-481, 2012), the results and interpretation of the data supported the premise that advanced CPN represented a risk factor for the development of RT proliferative lesions, most notably adenomas and those chemicals which enhance CPN are not directly tumorigenic.  A differing opinion by Melnick et al (Tox Sci 128:346-356, 2012) based on their data review of 60 NTP carcinogenic studies suggested that there was no biological plausibility to the CPN-RT tumor hypothesis, a mode of action (MOA) could not be supported, and that it would be wrong to dismiss the human relevance of kidney tumors induced by chemicals that also exacerbate CPN.  Hard et al (Tox Sci Advance Access Publication October 26, 2012) further addressed this debate by providing a more detailed review of CPN as a MOA for renal tumorigenesis and for the statistical analysis of the relationship of CPN and RT tumors.  For the time being, it appears that the debate will continue.  Hopefully, this issue will result in more laboratories re-examining their data base to see if this association holds up under further review and if the regulatory bodies begin to specifically address this issue.

Dr. John Curtis Seely

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