313
Views
10
CrossRef citations to date
0
Altmetric
Review Article

Critical review of renal tubule karyomegaly in non-clinical safety evaluation studies and its significance for human risk assessment

Pages 575-595 | Received 05 Mar 2018, Accepted 19 Jul 2018, Published online: 02 Oct 2018
 

Abstract

Scientific databases were searched for terms applicable to karyomegaly in renal tubules of laboratory animals used in preclinical safety evaluation studies, and in humans. Renal tubule karyomegaly was more frequently reported in the rat in response to chemical exposure compared to other laboratory animal species. Renal tubule karyomegaly also occurred in the mouse in response to chemical insult, but much less commonly than in the rat. This nuclear lesion was recorded infrequently for hamster, dog, guinea pig, rabbit, pig, and non-human primate. Most instances of renal karyomegaly reported in humans represented cases of the genetic syndrome, karyomegalic interstitial nephritis, known to be caused by a mutation in the FAN1 gene. Human reports of karyomegaly in the kidney associated with chemical exposure are rare, and linked mainly to chemotherapeutic or antiviral therapies. The rat appears to be highly predisposed to developing karyomegaly as a renal response on exposure to diverse chemical agents, but karyomegaly in the rat is not consistently associated with renal tubule tumor development. Because of this inconsistency, renal tubule karyomegaly is an inaccurate predictor of renal tubule neoplasia, and there is no evidence that karyomegalic cells are involved in tumor development as a form of preneoplasia. A chemically induced karyomegalic response in the rat does not necessarily predict a similar alteration in human kidneys. Because modest nuclear enlargement of kidney tubule cells can occur as physiological or functional responses, it is recommended that the threshold for diagnosing renal tubule karyomegaly in animal studies should be accepted as at least four times normal nuclear size or larger.Abbreviations: BEN: Balkan Endemic Nephropathy; DMN: dimethylnitrosamine; GLP: Good Laboratory Practice; KIN: karyomegalic interstitial nephritis; LAL: lysinoalanine; MeCCNU: 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea; NTP: National Toxicology Program; OSOM: outer stripe of outer medulla; OTA: ochratoxin A; RTT: renal tubule tumor

Acknowledgments

The author is deeply grateful to The Royal Society of Medicine (RSM), London, UK, for conducting the literature search, and to the following for their help in accessing copies of some of the references: the late Dr Gordon Flake, National Toxicology Program, Research Triangle Park, NC, USA; Professor Wolfgang Dekant and Hana Poppa-Henning, Institute for Toxicology, University of Wuerzburg, Würzburg, Germany; the author is also very grateful to Dr. Albert Bär, Basel, Switzerland, for assisting in some translation of German, and to Dr. Peter Mantle, Imperial College, London, England, for contributing a photographic illustration.

Declaration of interest

The author has no potential conflicts of interest to disclose. The author received no remuneration for producing this article.

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access

  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 65.00 Add to cart

Issue Purchase

  • 30 days online access to complete issue
  • Article PDFs can be downloaded
  • Article PDFs can be printed
USD 739.00 Add to cart

* Local tax will be added as applicable

Related Research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.