Urinary System

Kidney - Nephropathy, Chronic Progressive

Narrative
Comment:
Chronic progressive nephropathy, or CPN, is one of the most common spontaneous lesions and the single most important renal disease in rats and mice. The etiology of CPN is unknown, but factors such as strain, sex, age, diet, and hormones may modulate its occurrence and severity. The incidence and severity of CPN are generally greater in rats than in mice, and male rats are more severely affected than female rats. Nephropathy is both a degenerative and regenerative disease with characteristic morphology that is age dependent. It is a progressive disease and can lead to chronic renal failure and death. Early lesions can be seen in 2- to 3-month-old animals; by the end of 90-day studies, it is commonly observed in nearly all male rats.

Early lesions consist of focal to multifocal foci of tubule basophilia, nuclear crowding, peritubular basement membrane thickening, and variable infiltration by mononuclear inflammatory cells (Figure 1). As the disease progresses, the amount of affected renal parenchyma increases, individual components of CPN become more severe, and hyaline casts are prominent (Figure 2 and Figure 3). At the same time, glomerular changes, such as capillary tuft thickening, adhesions between the glomerular epithelium and Bowman’s capsule, and glomerulosclerosis, may be evident. CPN may progress to end-stage kidney disease, resulting in the death of the animal (Figure 4). CPN can often be exacerbated by chemical administration. The incidence and severity of CPN are generally less in the mouse than in the rat (Figure 5).

CPN is often accompanied by hyperplasia of the lining epithelium of the renal papilla. It is important to know that in advanced stages of CPN, there may be a small but significant increase in the incidence of proliferative lesions of the proximal tubule. Nephropathy is a bilateral lesion and differing severities of nephropathy between the two kidneys is rarely noted.
Recommendations:
CPN should be diagnosed and graded according to the extent and severity of the lesion. Currently, there are no universally accepted recommendations for assigning a severity grade to CPN. However, some published guidelines have been reported, and each pathologist may use his or her own criteria, based on training and experience, to achieve consistent grading. However, if CPN is reported as a potential treatment-related finding, then the pathologist should clearly define the severity and severity grading in the pathology narrative. It is not recommended to grade the separate components of nephropathy.
Related Links:
Kidney - Glomerulonephritis
Kidney - Glomerulosclerosis
References:

Barthold SW. 1998. Chronic progressive nephropathy, rat. In: Monographs on Pathology of Laboratory Animals: Urinary System, 2nd ed (Jones TC, Hard GC, Mohr U, eds). Springer, Berlin, 228-233.

Abstract: http://www.ilsi.org/publications/urinarysystem.pdf

Gray JE. 1977. Chronic progressive nephrosis in the albino rat. Crit Rev Toxicol 5:115-144.

Greaves P. 2012. Histopathology of Preclinical Toxicity Studies, 4th ed. Elsevier, Amsterdam, 552-555.

Abstract: http://www.sciencedirect.com/science/book/9780444538567

Hard GC, Khan KN. 2004. A contemporary overview of chronic progressive nephropathy in the laboratory rat, and its significance for human risk assessment. Toxicol Pathol 32:171-180.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/15200155

Hard GC, Seely JC. 2005. Recommendations for the interpretation of renal tubule proliferative lesions occurring in rat kidneys with advanced chronic progressive nephropathy (CPN). Toxicol Pathol 33:641-649.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/16207638

Hard GC, Seely JC. 2006. Histological investigation of diagnostically challenging tubule profiles in advanced chronic progressive nephropathy (CPN) in the Fischer 344 rat. Toxicol Pathol 34:941-948.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/17178694

Montgomery CA, Seely JC. 1990. Kidney. In: Pathology of the Fischer Rat: Reference and Atlas (Boorman GA, Eustis SL, Elwell MR, Montgomery CA, MacKenzie WF, eds). Academic Press, San Diego, 127-153.

Abstract: http://www.ncbi.nlm.nih.gov/nlmcatalog/9002563

Seely JC, Hard GC. 2008. Chronic progressive nephropathy (CPN) in the rat: Review of pathology and relationship to renal tumorigenesis. J Toxicol Pathol 21:199-205.

Full Text: https://www.jstage.jst.go.jp/article/tox/21/4/21_4_199/_pdf
  • Image of nephropathy, chronic progressive in the kidney from a male F344/N rat in a subchronic study

    Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a subchronic study. The early cases of chronic progressive nephropathy (CPN) occur as focal to multifocal areas of tubule basophilia with or without hyaline (protein) casts.

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<p>Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a subchronic study. The early cases of chronic progressive nephropathy (CPN) occur as focal to multifocal areas of tubule basophilia with or without hyaline (protein) casts.</p>

Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a subchronic study. The early cases of chronic progressive nephropathy (CPN) occur as focal to multifocal areas of tubule basophilia with or without hyaline (protein) casts.
<p>Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a chronic study. This is a more severe case of CPN with prominent hyaline casts.</p>

Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a chronic study. This is a more severe case of CPN with prominent hyaline casts.
<p>Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a chronic study. As the severity of CPN progresses, all components of CPN become more prominent, with nearly all of the renal parenchyma involved.</p>

Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a chronic study. As the severity of CPN progresses, all components of CPN become more prominent, with nearly all of the renal parenchyma involved.
<p>Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a subchronic study. CPN may become quite severe, leading to an "end-stage" kidney with little normal parenchyma remaining.</p>

Kidney - Nephropathy, Chronic progressive in a male F344/N rat from a subchronic study. CPN may become quite severe, leading to an "end-stage" kidney with little normal parenchyma remaining.
<p>Kidney - Nephropathy, Chronic progressive in a male B6C3F1 mouse from a subchronic study. Though usually less severe, CPN has a similar appearance in mice.</p>

Kidney - Nephropathy, Chronic progressive in a male B6C3F1 mouse from a subchronic study. Though usually less severe, CPN has a similar appearance in mice.

Authors 

John Curtis Seely, DVM, DACVP
Senior Pathologist
Experimental Pathology Laboratories, Inc.
Research Triangle Park, NC

Amy Brix, DVM, PhD, DACVP
Senior Pathologist
Experimental Pathology Laboratories, Inc.
Research Triangle Park, NC

Reviewers

Kendall S. Frazier, DVM, PhD, DACVP, DABT
Director, Cellular and Molecular Pathology, Safety Assessment
GlaxoSmithKline
King of Prussia, PA

Gordon C. Hard, BSc, BVSc, PhD, DSc, FRCPath, FRCVS, FAToxSci, DACVP
Expert Consultant
Tairua, New Zealand

Susan A. Elmore, MS, DVM, DACVP, DABT, FIATP
Staff Scientist, NTP Pathologist
NTP Pathology Group
National Toxicology Program
National Institute of Environmental Health Sciences
Research Triangle Park, NC