Critical review of renal tubule karyomegaly in non-clinical safety evaluation studies and its significance for human risk assessment. (9th August 2018)

• Record Type: Journal Article
• Authors: Hard, Gordon C.
• Is Part Of: Critical reviews in toxicology. Volume 48:Number 7(2018)
• Page Start: 575
• Page End: 595
• Publication Date: 2018-08-09
• Subjects: Kidney -- renal tubule -- karyomegaly -- nuclear enlargement -- preclinical studies -- relevance to humans -- risk assessment; Toxicology -- Periodicals; Poisons -- Physiological effect -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1080/10408444.2018.1503641
• Languages: English
• ISSNs: 1040-8444

Abstract

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