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Glomerular Calcification Induced by Bolus Injection with Dibasic Sodium Phosphate Solution in Sprague—Dawley Rats

Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., Japan, noriko.tsuchiya{at}shionogi.co.jp

Shuuichi Matsushima

Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., Japan

Nobuo Takasu

Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., Japan

Yoshimasa Kyokawa

Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., Japan

Mikinori Torii

Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., Japan

To elucidate the nephrotoxicity of phosphate, dibasic sodium phosphate solution was given to Sprague—Dawley rats by daily bolus intravenous administration at concentrations of 0, 1, 25, 250, or 360 mM (0, 1, 28, 284, or 408 mg/kg Na₂HPO₄)for 14 days, and the kidneys were pathologically examined. There were no remarkable changes in blood chemistry values; however, urinalysis revealed mild to moderate proteinuria in the 250 and 360 mM groups. The kidneys from the 360 mM group were macroscopically pale. Histopathology revealed panglomerular deposition of basophilic dense granules, which were positive for von Kossa's staining, accompanied by dose-dependent degeneration of the glomerular epithelium and parietal epithelium in the 250 and 360 mM groups. Electron microscopic examination showed fusion of podocytes and increased microvilli, with large amounts of debris in the Bowman's space. Low-density lamellar structures were present not only in the glomerular epithelium, basement membrane, mesangial matrix and parietal epithelium but also within the Bowman's space depending on the severity of the glomerular lesion. Phosphorus and calcium were detected by X-ray microanalysis as fine particles admixed with lamellar structures. These results suggest that high-dose phosphate used in this study transiently overloads the glomerular epithelium during filtration through glomerular capillaries and produces insoluble calcium salt and glomerular lesions, resulting in proteinuria.

Key Words: Rat kidney • Na2HPO4 • glomerulopathy • calcification • nephrotoxicity.

Toxicologic Pathology, Vol. 32, No. 4, 408-412 (2004)
DOI: 10.1080/01926230490452490


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