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Toxicologic Pathology
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Chronic Nephropathy in Ad Libitum Overfed Sprague-Dawley Rats and Its Early Attenuation by Increasing Degrees of Dietary (Caloric) Restriction to Control Growth

Kevin P. Keenan

Departments of Safety Assessment and Biometrics, Merck Research Laboratories, West Point, Pennsylvania, USA, kevin_keenan{at}merck.com

John B. Coleman

Departments of Safety Assessment and Biometrics, Merck Research Laboratories, West Point, Pennsylvania, USA

Carol L. Mccoy

Departments of Safety Assessment and Biometrics, Merck Research Laboratories, West Point, Pennsylvania, USA

Chao-Min Hoe

Departments of Safety Assessment and Biometrics, Merck Research Laboratories, West Point, Pennsylvania, USA

Keith A. Soper

Departments of Safety Assessment and Biometrics, Merck Research Laboratories, West Point, Pennsylvania, USA

Philippe Laroque

Departments of Safety Assessment and Biometrics, Merck Research Laboratories, West Point, Pennsylvania, USA

The early development and progression of chronic nephropathy and its amelioration by moderate and marked dietary restriction (DR) was determined in Sprague-Dawley (SD) rats at 20, 33, 60, and 113 weeks of age. Both sexes of SD rats were overfed ad libitum (AL) or DR-fed at 72-79%, 68-72%, or 47-48% of the adult AL intake. The AL-fed rats rapidly developed increased body and kidney size, increased glomerular area (GA) and urinary protein loss, followed by declining creatinine clearance. Early increased kidney growth and glomerular hypertrophy by 20 weeks preceded increases in glomerular sclerotic index (GSI), 7-day BrdU tubular labeling index (TLI), and the lesions associated with chronic nephropathy. The glomerular number (GN) or the number of nephrons did not differ between the groups over the course of the study. Moderate DR (68-79% of AL) prevented the increased kidney size and GA at 20 weeks and delayed increases in GSI and TLI until 60 weeks of age. Marked DR (47—48% of AL) prevented increases in kidney size, GA and TLI at 20 weeks, and GSI at 60 weeks of age. In AL-fed rats, the early increase in GA predicted the early onset of proteinuria and the later decrease in creatinine clearance, and increased GSI, TLI, and mortality from severe nephropathy. The temporal and dose-related effects of increasing degrees of DR demonstrated that while nephron numbers were unchanged with age, the early development of glomerular hypertrophy was the critical morphological biomarker predicting the progression and severity of chronic nephropathy. Caloric restriction by DR prevented or delayed the development of glomerulosclerosis, tubulointerstitial damage, functional changes, morbidity, and mortality associated with chronic nephropathy in AL-overfed SD rats by controlling initial body and kidney growth, glomerular size, and nephron hypertrophy. These results indicate that control of body and renal growth by DR may be essential to prevent the development and progression of glomerulosclerosis in spontaneous nephropathy of laboratory rats.

Key Words: Glomerular hypertrophy • glomerulosclerosis • chronic nephropathy • dietary restriction • caloric restriction • overnutrition

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Toxicologic Pathology, Vol. 28, No. 6, 788-798 (2000)
DOI: 10.1177/019262330002800604
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