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.
Abrass, C.K. (2000). The nature of chronic progressive nephropathy in aging rats. Adv Renal Replacement Ther7, 4—10.
2.
Andrews, L.K., Anderson, J.A., Kim, S.N., and Jayasekara, M.U. (1986). Chronic toxicity evaluation of the nonsulfhydryl angiotensin converting enzyme inhibitor quinapril. Toxicologist6, 181 (abstr. 729).
3.
Anver, M.R., Cohen, B.J., Lattuada, C.P., and Foster, C.J. (1982). Ageassoaciated lesions in barrier-reared male Sprague—Dawley rats: a comparison between Hap:(SD) and Crl:COBS[R]CD[R]SD stocks. Exp Aging Res8, 3—24.
Baylis, C. (1994). Age-dependent glomerular damage in the rat. Dissociation between glomerular injury and both glomerular hypertension and hypertrophy . Male gender as a primary risk factor. J Clin Invest94, 1823—9.
6.
Baylis, C., and Corman, B. (1998). The aging kidney: insights from experimental studies . J Am Soc Nephrol9, 699—709.
7.
Benigni, A., Zoja, C., and Remuzzi, G. (1995). The renal toxicity of sustained glomerular protein traffic. Lab Invest73, 461—8.
8.
Berg, B.N. (1965). Spontaneous nephrosis, with proteinuria, hyperglobulinemia, and hypercholesterolemia in the rat. Proc Soc Exp Biol Med119, 417—20.
9.
Bertani, T., Zoja, C., Abbate, M., Rossini, M., and Remuzzi, G. (1989). Age-related nephropathy and proteinuria in rats with intact kidneys exposed to diets with different protein content. Lab Invest60, 196—204.
10.
Birn, H., Fyfe, J.C., Jacobsen, C., Mounier, F., Verroust, P.J., rskov, H., Willnow, T.E., Moestrup, S.K., and Christensen, E.I. (2000). Cubulin is an albumin binding protein important for renal tubular albumin reabsorption. J Clin Invest105, 1353—61.
11.
Blatherwick, N.R., and Medlar, E.M. (1937). Chronic nephritis in rats fed high protein diets . Arch Intern Med59, 572—96.
12.
Bolton, W.K., Benton, F.R., Maclay, J.G., and Sturgill, B.C. (1976). Spontaneous glomerular sclerosis in aging Sprague—Dawley rats. I. Lesions associated with mesangial IgM deposits. Am J Pathol85, 277— 302.
13.
Brenner, B.M. (1985). Nephron adaptation to renal injury or ablation . Am J Physiol249, F324—37.
14.
Bucher, J.R., Huff, J., Haseman, J.K., Eustis, S.L., Davis, W.E., and Meierhenry, E.F. (1990a). Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 2. Furosemide. J Appl Toxicol10, 369—78.
15.
Bucher, J.R., Huff, J., Haseman, J.K., Eustis, S.L., Elwell, M.R., Davis, W.E., and Meierhenry, E.F. (1990b). Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 1. Hydrochlorothiazide. J Appl Toxicol10, 359—67.
16.
Cessac-Guillemet, A.L., Moumier, F., Borot, C., Bakala, H., Perichon, M., Schaeverbeke, M., and Schaeverbeke, J. (1996). Characterization and distribution of albumin binding protein in normal rat kidney. Am J Physiol271, F101—7.
Coleman, G.L., Barthold, S.W., Osbaldiston, G.W., Foster, S.J., and Jonas, A. (1977). Pathological changes during aging in barrier-reared Fischer 344 male rats. J Gerontol32, 258—78.
Couser, W.G., and Stillmant, M.M. (1975). Mesangial lesions and focal glomerular sclerosis in the aging rat. Lab Invest33, 491—501.
21.
Cowden, E.A., Dobbie, J.W., Mountjoy, K., Ratcliffe, J.G., Richardson, B., and Kennedy, A.C. (1981). Prolactin status in chronic nephropathy in the rat. Nephron27, 84—8.
22.
Cui, S., Verroust, P.J., Moestrup, S.K., and Christensen, E.I. (1996). Megalin/gp330 mediates uptake of albumin in renal proximal tubule. Am J Physiol271, F900—7.
23.
D'Amico, G. (1999). Tubulointerstitium as predictor of progression of glomerular diseases. Nephron83, 289—95.
24.
Dietrich, D.R., and Swenberg, J.A. (1991). Preneoplastic lesions in rodent kidney induced spontaneously or by non-genotoxic agents: predictive nature and comparison to lesions induced by genotoxic carcinogens. Mutation Res248, 239—60.
25.
Dodane, V., Chevalier, J., Bariety, J., Pratz, J., and Corman, B. (1991). Longitudinal study of solute excretion and glomerular ultrastructure in an experimental model of aging rats free of kidney disease . Lab Invest64, 377—91.
26.
Dominick, M.A., Robertson, D.G., Bleavins, M.R., Sigler, R.E., Bobrowski, W.F., and Gough, A.W. (1991). ∝2u-Globulin nephropathy without nephrocarcinogenesis in male Wistar rats administered 1-(aminomethyl)cyclohexaneacetic acid. Toxicol Appl Pharmacol111, 375—87.
27.
Emmanouel, D.S., Fang, V.S., and Katz, A.I. (1981). Prolactin metabolism in the rat: role of the kidney in degradation of the hormone. Am J Physiol240, F437—45.
28.
Eppel, G.A., Nagy, S., Jenkins, M.A., Tudball, R.N., Daskalakis, M., Balazs, N.H., and Comper, W.D. (2000). Variability of standard clinical protein assays in the analysis of a model urine solution of fragmented albumin. Clin Biochem33, 487—94.
29.
Eppel, G.A., Osicka, T.M., Pratt, L.M., Jablonski, P., Howden, B., Glasgow, E.F., and Comper, W.D. (2001). The return of glomerular filtered albumin to the rat renal vein—the albumin retrieval pathway. Renal Fail23, 347— 63.
30.
Eustis, S.L., Hailey, J.R., Boorman, G.A., and Haseman, J.K. (1994). The utility of multiple-section sampling in the histopathological evaluation of the kidney for carcinogenicity studies. Toxicol Pathol22, 457— 72.
31.
Everitt, A.V., and Duvall, L.K. (1965). Delayed onset of proteinuria in ageing hypophysectomized rats. Nature205, 1016.
32.
Everitt, A.V., Porter, B.D., and Wyndham, J.R. (1982). Effects of caloric intake and dietary composition on the development of proteinuria, ageassociated renal disease and longevity in the male rat. Gerontology28, 168— 75.
33.
Everitt, A.V., Wyndham, J.R., and Barnard, D.J. (1983). The anti-aging action of hypophysectomy in hypothalamic obese rats: effects on collagen aging, age-associated proteinuria development and renal histopathology. Mech Ageing Dev22, 233—51.
34.
Foley, W.A., Jones, D.C.L., Osborn, G.K., and Kimeldorf, D.J. (1964). A renal lesion associated with diuresis in the aging Sprague-Dawley rat. Lab Invest13, 439—49.
35.
Frocht, A., and Fillit, H. (1984). Renal disease in the geriatric patient. J Am Geriatrics Soc32, 28—43.
36.
Galla, J.H. (1995). IgA nephropathy. Kidney Int47, 377—87.
37.
Gilbert, R.E., and Cooper, M.E. (1999). The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int56, 1627—37.
38.
Goldstein, R.S., Tarloff, J.B., and Hook, J.B. (1988). Age-related nephropathy in laboratory rats. FASEB J2, 2241—51.
39.
Goya, R.G., Castelletto, L., and Sosa, Y.E. (1991). Plasma levels of growth hormone correlate with the severity of pathologic changes in the renal structure of aging rats. Lab Invest64, 29—34.
40.
Gray, J.E. (1977). Chronic progressive nephrosis in the albino rat . Crit Rev Toxicol5, 115—44.
41.
Gray, J.E., van Zwieten, M.J., and Hollander, C.F. (1982). Early light microscopic changes of chronic progressive nephrosis in several strains of aging laboratory rats. J Gerontol37, 142—50.
42.
Gray, J.E., Weaver, R.N., and Purmalis, A. (1974). Ultrastructural observations of chronic progressive nephrosis in the Sprague—Dawley rat. Vet Pathol11, 153—64.
43.
Greive, K.A., Balazs, N.D.H., and Comper, W.D. (2001a). Protein fragments in urine have been considerably underestimated by various protein assays. Clin Chem47, 1717—9.
44.
Greive, K.A., Nicolic-Paterson, D.J., Guim, L.M., Mu, W., Atkins, R.C., and Comper, W.D. (2001b). Glomerular permselectivity factors are not responsible for the increase in fractional clearance of albumin in rat glomerulonephritis . Am J Pathol159, 1159—70.
45.
Hard, G.C. (1990). Tumours of the kidney, renal pelvis and ureter . In Pathology of Tumours in Laboratory Animals. Vol. 1—Tumours of the Rat, second edition (V. S. Turusov and U. Mohr, eds.), No. 99, pp. 301—44. International Agency for Research on Cancer. IARC Scientific Publications, Lyon.
46.
Hard, G.C. (1998). Mechanisms of chemically induced renal carcinogenesis in the laboratory rodent. Toxicol Pathol26, 104—12.
47.
Hard, G.C. (2002). Significance of the renal effects of ethyl benzene in rodents for assessing human carcinogenic risk. Toxicol Sci69, 30—41.
48.
Hard, G.C., Alden, C.L., Bruner, R.H., Frith, C.H., Lewis, R.M., Owen, R.A., Krieg, K., and Durchfeld-Meyer, B. (1999). Non-proliferative lesions of the kidney and lower urinary tract in rats. In Guides for Toxicologic Pathology, pp. 1—32. STP/ARP /AFIP, Washington, D.C.
49.
Hard, G.C., Alden, C.L., Stula, E.F., and Trump, B.F. (1995). Proliferative lesions of the kidney in rats. In Guides for Toxicologic Pathology, pp. 1—19. STP/ ARP/AFIP, Washington, D.C.
50.
Hard, G.C., Rodgers, I.S., Baetcke, K.P., Richards, W.L., McGaughy, R.E., and Valcovic, L.R. (1993). Hazard evaluation of chemicals that cause accumulation of α2u-globulin, hyaline droplet nephropathy, and tubule neoplasia in the kidneys of male rats. Environ Health Perspect99, 313—49.
51.
Hard, G.C., Whysner, J., English, J.C., Zang, E., and Williams, G.M. (1997). Relationship of hydroquinone-associated rat renal tumors with spontaneous chronic progressive nephropathy. Toxicol Pathol25, 132—43.
52.
Hayashida, M., Yu, B.P., Masoro, E.J., Iwasaki, K., and Ikeda, T. (1986). An electron microscopic examination of age-related changes in the rat kidney: the influence of diet. Exp Gerontol21, 535—53.
53.
Hirokawa, K. (1975). Characterization of age-associated kidney disease in Wistar rats. Mech Ageing Dev4, 301—16.
54.
Iwasaki, K., Gleiser, C.A., Masoro, E.J., McMahan, C.A., Seo, E.J., and Yu, B.P. (1988a). The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J Gerontol43, B5—12.
55.
Iwasaki, K., Gleiser, C.A., Masoro, E.J., McMahan, C.A., Seo, E., and Yu, B.P. (1988b). Influence of the restriction of individual dietary components on longevity and age-related disease of Fischer rats: the fat component and the mineral component. J Gerontol43, B13—21.
56.
Kaplan, C., Pasternack, B., Shah, H., and Gallo, G. (1975). Age-related incidence of sclerotic glomeruli in human kidneys. Am J Pathol80, 227—34.
57.
Keenan, K.P., Coleman, J.B., McCoy, C.L., Hoe, C.-M., Soper, K.A., and Laroque, P. (2000). Chronic nephropathy in ad libitum overfed Sprague-Dawley rats and its early attenuation by increasing degrees of dietary (caloric) restriction to control growth. Toxicol Pathol28, 788—98.
58.
Khan, K.N.M., and Alden, C.L. (2002). Kidney. In Handbook of Toxicologic Pathology, Vol 2, 2nd ed. (W. M. Haschek, C. G. Rousseaux, and M. A. Wallig, eds.), pp. 255—336. Academic Press, San Diego.
59.
Klahr, S., Buerkert, J., and Purkeson, M.L. (1983). Role of dietary factors in the progression of chronic renal disease. Kidney Int24, 579—87.
60.
Kleinknecht, C., Laouari, D., Hinglais, N., Habib, R., Dodu, C., Lacour, B., and Broyer, M. (1986). Role of amount and nature of carbohydrates in the course of experimental renal failure. Kidney Int30, 687—93.
61.
Konishi, N., and Ward, J.M. (1989). Increased levels of DNA synthesis in hyperplastic renal tubules of aging nephropathy in female F344/NCr rats. Vet Pathol26, 6—10.
62.
Kreisberg, J.I., and Karnovsky, M.J. (1978). Focal glomerular sclerosis in the fawn-hooded rat. Am J Pathol92, 637—52.
63.
Lipsky, M.M., and Trump, B.F. (1988). Chemically induced renal epithelial neoplasia in experimental animals. Int Rev Exp Pathol30, 357—83.
64.
Lock, E.A., and Hard, G.C. (2004). Chemically-induced renal tubule tumors in the laboratory rat and mouse: review of the NCI/NTP database and categorization of renal carcinogens based on mechanistic information. Crit Rev Toxicol34, in press.
65.
Lu, J.K.H., Hooper, B.R., Vargo, T.M., and Yen, S.S.C. (1979). Chronological changes in sex-steroid, gonadotropin and prolactin secretion in aging female rats displaying different reproductive states. Biol Reprod21, 193—203.
66.
Lynch, B.S., Bryant, D.W., Hook, G.J., Nestmann, E.R., and Munro, I.C. (1998). Carcinogenicity of monochloro-1,2-propanediol (α-chlorohydrin, 3-MCPD). Int J Toxicol17, 47—76.
67.
Maisonneuve, P., Agodoa, L., Gellert, R., Srewart, J.H., Buccianti, G., Lowenfels, A.B., Wolfe, R.A., Jones, E., Disney, A.P., Briggs, D., McCredie, M., and Boyle, P. (2000). Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study. Am J Kidney Dis35, 157—65.
68.
Masoro, E.J., and Yu, B.P. (1989). Diet and nephropathy. Lab Invest60, 165—7.
69.
Masoro, E.J., Iwasaki, K., Gleiser, C.A., McMahan, C.A., Seo, E.J., and Yu, B.P. (1989). Dietary modulation of the progression of nephropathy in aging rats: an evaluation of the importance of protein. Am J Clin Nutr49, 1217—27.
70.
Montgomery, C.A., and Seely, J.C. (1990). Kidney. In: Pathology of the Fischer Rat. Reference and Atlas (G. A. Boorman, S. L. Eustis, M. R. Elwell, C. A. Montgomery, and W. F. MacKenzie, eds.), pp. 127—153. Academic Press, San Diego, CA.
71.
National Toxicology Program (1989a). Toxicology and Carcinogenesis Studies of Furosemide (CAS No. 54-31-9) in F344/N Rats and B6C3F1 Mice (Feed Studies). NTP TR 356, NIH Publication No. 89-2811, NIEHS, Research Triangle Park, NC.
72.
National Toxicology Program (1989b). Toxicology and Carcinogenesis Studies of Hydrochlorothiazide (CAS No. 58-93-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). NTP TR 357, NIH Publication No. 89-2812, NIEHS, Research Triangle Park, NC.
73.
National Toxicology Program (1993). Toxicology and Carcinogenesis Studies of Acetaminophen (CAS No. 103-90-2) in F344/N and B6C3F1 Mice (Feed Studies). NTP TR 394, NIH Publication No. 93-2849, NIEHS, Research Triangle Park, NC.
74.
Nogueira, E., Cardesa, A., and Mohr, U. (1993). Experimental models of renal carcinogenesis. Cancer Res Clin Oncol119, 190—8.
75.
Osicka, T.M., Pratt, L.M., and Comper, W.D. (1996). Glomerular capillary wall permeability to albumin and horseradish peroxidase. Nephrology2, 199—212.
76.
Peter, C.P., Burek, J.D., and van Zwieten, M.J. (1986). Spontaneous nephropathies in rats. Toxicol Pathol14, 91—100.
77.
Peterson, R.O. (1994). The urinary tract and male reproductive system . In Pathology, 2nd ed. (E. Rubin and J. L. Farber eds.), pp. 866—907. JB Lippincott, Philadelphia.
78.
Rao, G.N. (1996). New diet (NTP-2000) for rats in the National Toxicology Program toxicity and carcinogenicity studies. Fundam Appl Toxicol32, 102—8.
79.
Rao, G.N. (2002). Diet and kidney disease in rats. Toxicol Pathol30, 651—6.
80.
Rao, G.N., Edmondson, J., and Elwell, M.R. (1993). Influence of dietary protein concentration on severity of nephropathy in Fischer-344 (F-344/N) rats. Toxicol Pathol21, 353—61.
81.
Rao, G.N., Morris, R.W., and Seely, J.C. (2001). Beneficial effects of NTP-2000 diet on growth, survival, and kidney and heart diseases of Fischer F344 rats in chronic studies . Toxicol Sci63, 245—55.
82.
Richardson, B., and Luginbuhl, H. (1976). The role of prolactin in the development of chronic progressive nephropathy in the rat. Virchow Arch A Pathol Anat Histol370, 13—9.
83.
Rodriguez-Puyol, D. (1998). The aging kidney. Kidney Int54, 2247—65.
84.
Ruggenenti, P., Schieppati, A., and Remuzzi, G. (2001). Progression, remission, regression of chronic renal diseases. Lancet357, 1601—8.
85.
Russo, L.M., Bakris, G.L., and Comper, W.D. (2002). Renal handling of albumin: a critical review of basic concepts and perspective. Am J Kid Dis39, 899—919.
86.
Rutkowski, B., Tylicki, L., Manitius, J., and Lysiak-Szydlowska, W. (1999). Hypertensive nephropathy—an increasing problem. Mineral Electrolyte Metab25, 65—8.
87.
Salatka, K., Kresge, D., Harris, L., Edelstein, D., and Ove, P. (1971). Rat serum protein changes with age. Exp Gerontol6, 25—36.
88.
Saxton, J.A., and Kimball, G.C. (1941). Relation of nephrosis and other diseases of albino rats to age and to modifications of diet. Arch Pathol32, 951—65.
89.
Seely, J.C., Haseman, J.K., Nyska, A., Wolf, D.C., Everitt, J.I., and Hailey, J.R. (2002). The effect of chronic progressive nephropathy on the incidence of renal tubule cell neoplasms in control male F344 rats . Toxicol Pathol30, 681—6.
90.
Short, B.G., Burnett, V.L., and Swenberg, J.A. (1989). Elevated proliferation of proximal tubule cells and localization of accumulated α2u-globulin in F344 rats during chronic exposure to unleaded gasoline or 2,2,4-trimethylpentane. Toxicol Appl Pharmacol101, 414—31.
91.
Sworn, M.J., and Fox, M. (1974). Renal age changes in the rat compared with human renal senescence. An autoradiographic study. Investig Urol12, 140—5.
92.
Tanaka, A., Kyokuwa, M., Mori, T., and Kawashima, S. (1995). Acceleration of renal dysfunction with ageing by the use of androgen in Wistar/Tw rats. In Vivo9, 495—502.
U.S. Renal Data System. (1995). Incidence and causes of treated ESRD. Am J Kidney Dis26, S39—S50.
95.
Yu, B.P., Masoro, E.J., Murata, I., Bertrand, H.A., and Lynd, F.T. (1982). Life span study of SPF Fischer 344 male rats fed ad libitum or restricted diets: longevity, growth, lean body mass and disease . J Gerontol37, 130— 41.
96.
Zawada, E.T., Alavi, F.K., Santella, R.N., and Maddox, D.A. (1997). Influence of dietary macronutrients on glomerular senescence. Curr Nephrol20, 1—47.
97.
Zeisberg, M., Strutz, F., and Muller, G.A. (2001). Renal fibrosis: an update. Curr Opin Nephrol Hypertens10, 315—20.
