Age-related nephropathy in laboratory rats.

Chronic progressive nephropathy is a spontaneous disease common among aging laboratory rats, often making it difficult to distinguish age-related from drug-related effects in chronic toxicity studies. Morphological changes of the kidney that occur with age include thickening of glomerular and proximal tubular basement membranes, mesangial proliferation, fusion of foot processes, and, ultimately, glomerular sclerosis. Proteinuria (specifically, albuminuria) is the most striking characteristic change in renal function of aging rats and, generally, correlates well with the severity of age-related glomerular pathology. Changes in tubular functions also may occur with aging but have not been investigated sufficiently. The pathogenesis of chronic progressive nephropathy is not known; however, hemodynamic adaptations after ad libitum consumption of protein-rich diets may be a contributing factor. High-protein diets increase glomerular pressures and flows, perhaps facilitating excretion of metabolic end products. These hemodynamic adaptations may impair the permselective properties of the glomerulus, leading to: enhanced accumulation of macromolecules in the mesangium, progressive mesangial expansion, and, ultimately, glomerular sclerosis. Indeed, decreasing total food or protein intake retards or prevents the progression of age-related nephropathy. Inasmuch as chronic toxicity studies are complicated by a high incidence of spontaneous nephropathy, implementation of a restricted dietary regimen may improve detection of drug-induced toxicity.