Age-Related Variations in Renal Structure and Function in Sprague-Dawley Rats

Abstract

ABSTRAC~Data from 500 male and 500 female Sprague-Dawley rats used as controls in studies performed at Huntingdon Research Centre to assess the safety of drugs were sampled at 17, 30, 56, 82, or 108 weeks of age. Plasma urea nitrogen levels remained constant, except in aged males. Aging caused increased proteinuria and decreased urinary concentrating ability, in addition to increased size, weight, and degree of cortical scarring of kidneys. Chronic progressive nephropathy, first seen histopathologically at 30 weeks of age, accounted for these changes and ultimately affected 81% of male and 44% of female rats. One-fifth of twoyear-old male rats had diffuse parenchymal damage and a small number also had secondary hyperparathyroidism. Other notable changes included basophilic (often colloid-filled) cortical tubules, mononuclear cell infiltrations, parenchymal and pelvic mineralization, urothelial hyperplasia, and pyelonephritis. Miscellaneous low incidence findings included one lipomatous tumour and generalized lymphosarcoma. INTRODUC~IONDrug safety assessment depends on distinguishing spontaneous changes and pharmacological responses from toxic reactions. Base-line data are useful for putting anomalies into perspective and interpreting results (22). Age-related renal functional changes and lesions of rats have been reviewed several times (3, 8, 10, 14,28). Chronic progressive nephropathy (3) is of major importance in some strains of laboratory rats, and Sprague-Dawley rats are apparently more prone to develop this condition than are Wistars (30). This paper reports a retrospective survey of data obtained from a large number of laboratory-maintained Sprague-Dawley rats. METHODSData for this survey originated from records of chronic toxicity studies undertaken with SpragueDawley rats (CD strain from Charles River, Manston, UK, Wilmington, USA or St. Aubin-Les-Elbeuf, France) at the Huntingdon Research Centre between 1968 and 1979. Details of the rats used as untreated controls were examined. The rats were barrier maintained and housed in groups of five in suspended metal cages that had wire mesh floors. Room temperature and relative humidity were maintained at 21°C f 2°C and 50% 4 5% respectively. Lighting was controlled to allow 12 hours light (0800 to 2000 hours) and 12 hours dark per day. Except when blood or urine samples were taken, rats received Spillers' Laboratory Small Animal Diet or Spratts' Laboratory Rodent Diet Nos. 1 or 2 and tap water adlibition. Food was withheld overnight prior to obtaining blood from the orbital sinus of rats anesthetised with ether. Water was withdrawn when individual 16-1 8-hour overnight urine samples were obtained from rats placed in metabolism cages fitted with faecal separators. Blood samples were analyzed for plasma urea by routine methods. The volume of overnight urine voided was measured and the pH, specific gravity, and protein concentration were determined. At the end of the experimental periods, the rats were killed by carbon dioxide asphyxiation. A full macroscopic pos...

Quantitative analysis of the renal aging in rats. Stereological study

“…Another point to be considered is the fact that endogenous creatinine is produced in the organism to be directly proportional to the muscular mass. In Wistar rats, the decline in the muscular mass is very small (approximately 5%), whereas in men these values are around 25% reduction 15 With strong statistical significance, the gradual reduction of the glomerular volume density and the glomerular numerical density found in the stereological analysis of the renal tissue of the rats in the groups of animals gradually older, clearly demonstrates the process of renal aging as already well-established in literature [17][18][19][20][21] .…”

Diet, Overfeeding, and Moderate Dietary Restriction in Control Sprague-Dawley Rats: II. Effects on Age-Related Proliferative and Degenerative Lesions

“…This is probably due to the chronic compensatory nature of the spontaneous CRD that allows unaffected glomeruli to hypertrophy in compensation for those glomeruli that have sclerosed and decreased in area. Thus, the results obtained in studies of spontaneous CRD (6,17,50) describe a chronic compensatory disease that is slowly progressive as compared to the rapidly progressive changes observed in acute ablation models (13,71,76).…”

Regulatory Forum Opinion Piece*

“…Tubule basophilia is a morphological feature of several changes of the renal tubules in all species (Figures 1 and 2). Although tubule basophilia is one of the hallmark features of spontaneous chronic progressive nephropathy (CPN) in rodents (Gray, Zwieten, and Hollander 1982;Owen and Heywood 1986;Peter, Burek, and van Zwieten 1986), it may also represent persistent low-grade toxicologic insult to tubule cells or may reflect reparative processes when the cell is in the recovery phase (Frazier and Seely 2013).…”