Invited Review: A Contemporary Overview of Chronic Progressive Nephropathy in the Laboratory Rat, and Its Significance for Human Risk Assessment

Abstract

CPN (chronic progressive nephropathy) is a spontaneous age-related disease that occurs in high incidence in the strains of rat commonly used in preclinical toxicology studies, exhibiting a male predisposition. Although increasing in incidence and severity with age, evidence indicates that CPN should be regarded as a specific disease entity and not just a manifestation of the aging process. A number of factors, mainly dietary manipulations, have been shown to modify the expression of CPN. Amongst these, restriction of caloric intake is the most effective for inhibiting the disease process. The precise etiology of CPN and the mechanism(s) underlying its pathogenesis remain unknown, but the long-standing assumption that glomerular dysfunction is the primary basis is challenged in the light of contemporary developments in understanding filtration and postglomerular cellular processing of albumin. CPN is not only a degenerative disease, but also has regenerative aspects with a high cell proliferative rate in affected tubules. Accordingly, evidence is emerging that advanced, particularly end-stage CPN, is a risk factor for a marginal increase in the background incidence of renal tubule tumors. Many chemicals are known to exacerbate the severity of CPN to an advanced stage, and this interaction between chemical and CPN can result in a small increase in the incidence of renal adenomas in 2-year carcinogenicity bioassays. Review of the pathological entities associated with chronic renal failure in man emphasizes that this rodent condition has no strict human counterpart. Because CPN is a rodent-specific entity, the finding of a small, statistically significant increase in renal tubule tumors, linked to exacerbation of CPN by a test chemical in a preclinical study for carcinogenicity, can be regarded as having no relevance for extrapolation in human risk assessment.

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

“…Rather, the different tumor responses are most likely influenced by other differences reported in these two bioassays, such as severity of chronic progressive nephropathy. Because the male rat‐specific renal tumors induced by TBA operate through modes of action (α2u–globulin nephropathy and chronic progressive nephropathy) that are not relevant in humans (Hard & Khan, 2004; Hard & Seely, 2005; Hard et al ., 2009), the lesions associated with either of these syndromes should not be used to develop a point of departure in a risk assessment for either ETBE or TBA.…”

Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague–Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction

“…These observations indicate that this outbred SD rat model would make an excellent representative species for the analysis of the multi-factorial polygenic, nutritional and environmental factors known to influence renal and cardiovascular disease and as a testing system to evaluate the nephrotoxic and cardiotoxic potential of compounds. A current review of rat nephropathy questions the relevance of using rats with compromised kidneys as models for human risk assessment, and points out the need to control these diet-induced diseases in the animal model (Hard et al, 2004).…”

Health risk of ammonium released from water filters

“…per day, respectively) (Ota et al, 2006). Chronic nephropathy is a common finding in aging rats, particularly in males, and its incidence and severity are exacerbated by many chemicals, therefore this effect is thus considered of low relevance for humans (Hard and Khan, 2004).…”