A comparison of rat chronic progressive nephropathy with human renal disease—implications for human risk assessment

Abstract

Chronic progressive nephropathy (CPN) is a single renal disease of unknown etiology, occurring in high incidence in laboratory rats, that can confound subchronic and carcinogenicity bioassay interpretation. It has effects on longevity and, in its early stages, it has a histological similarity to tubular degeneration from other causes. In its advanced stages it is associated with marginally increased renal tubule tumor incidences. Several natural or physiological factors influence its incidence and severity, most prominently protein and caloric intake and male sex hormones. By contrast, there is no entity in humans that presents with the combination or pattern of histological features found in rat CPN. Humans are affected by several different nephropathies of known etiology but generally these are found much less frequently than CPN is found in the rat. There are major differences in pathology between CPN and human nephropathies. Histological characteristics in CPN include prominently dilated tubules filled with proteinaceous casts with consequent kidney enlargement, which contrasts with the shrunken kidneys found in end-stage human nephropathy. Unlike human nephropathy, CPN is devoid of vascular changes, it has no immunological or autoimmune basis, and inflammation is not a prominent feature. Various chemicals exacerbate CPN; no equivalent chemical interactions are seen with human nephropathies. Because some chemicals exacerbate CPN, and advanced CPN is a small risk factor for renal tubule tumor development, an increase in renal tumors can be wrongly attributed to a direct chemical effect on the kidney. On the basis of differences in biology and pathology, this analysis concludes that there is no clear human counterpart of CPN. We recommend that chemically induced exacerbation of CPN not be acknowledged as an indicator of human toxic hazard. Increases in the incidence of CPN-related renal tumor is not considered relevant to humans.

Keywords::

• Chronic renal disease
• hazard assessment
• mode of action
• renal failure
• renal carcinogenesis
• species extrapolation

Acknowledgements

The preparation of this manuscript was financially supported in part by LyondellBasell Industries, in Rotterdam, The Netherlands. However, this sponsor was not involved in the preparation of the manuscript or in the selection of any of the material presented. The authors thank Dr Kirk Foster of the University of Nebraska Medical Center for providing Figures 9 and 10.

Declaration of interest: Two of the authors (G.C.H. and S.M.C.) have consulted for LyondellBasell Industries.