Development of an Acute Model for the Study of Chloromethanediphosphonate Nephrotoxicity

Abstract

Chloromethanediphosphonate (Cl2MDP), a cation chelator, is used as a therapeutic for hypercalcemia of malignancy. Cl2MDP exhibits nephrotoxic potential. Thus, a useful model has been developed to study the mechanism of injury. Intraperitoneal administration of highly exaggerated dosages, specifically 200 mg/kg b.i.d., resulted in a consistent mild to moderate extent of kidney damage after the third day of treatment in rats. Proteinuria and lowered serum phosphorus levels occur prior to onset of histopathologic changes. Injury was characterized as necrosis of proximal tubular epithelium with predilection for pars recta. Unlike many renal toxicity models, the necrosis occurs as cell lysis only after 24 to 48 hours of treatment. However, this model significantly reduces the time required to induce renal toxicity observed in routine toxicity studies from months of treatment to less than 1 week and will, thus, serve as a baseline for subsequent pathogenetic studies.