Studies on the pathogenesis of cisplatin-induced hypomagnesemia in rats

Studies on the pathogenesis of cisplatin-induced hypomagnesemia in rats. After three weekly intraperitoneal injections of cisplatin (2.5 mg/kg body wt), male Wistar rats developed chronic hypomagnesemia, which was evident from the second week and persisted throughout the 8-week experiments. Plasma magnesium concentration was 0.69 ± 0.01mM in cisplatin-treated rats compared to 0.80 ± 0.02mM in pair-fed control rats (P < 0.01) in the eighth week of experimentation. Despite a similar dietary magnesium intake, urinary excretion of magnesium in cisplatin-treated rats was inappropriately high, relative to the lower plasma magnesium concentration, indicating the presence of renal magnesium wasting induced by cisplatin. During the 3 weeks of cisplatin injections, metabolic balance studies indicated abnormal renal excretion and a reduction in the fractional intestinal absorption of magnesium. A compensatory period of significantly greater retention of magnesium then occurred in cisplatin-treated rats beginning in the fourth week. Clearance and recollection micropuncture studies in a separate group of rats revealed normal magnesium and calcium transport in the superficial proximal and distal nephron. Following acute MgCl2 infusion, the urinary excretion of magnesium and calcium were significantly higher in cisplatin-treated rats than in control rats; however, micropuncture studies of superficial nephrons failed to demonstrate abnormal transport of these divalent cations. It is possible, therefore, that 7 weeks of cisplatin treatment led to tubular adaptation that might have obscured the defect in magnesium reabsorption. Morphological examination indicated that pathological changes were confined to the S3 segment of proximal corticomedullary nephrons. Analysis of mineral content in the bone and muscle at the end of the eighth week indicated a significant reduction in bone magnesium and in bone and muscle phosphorus content in cisplatin-treated rats compared with control rats. These studies suggest that (1) abnormalities of magnesium metabolism were present during cisplatin administration and involved both kidney and intestine. (2) Abnormal renal magnesium transport persisted, along with residual lesions in the S3 segment of corticomedullary nephrons. (3) The chronic hypomagnesemia in this animal model is associated with a significant decrease in body magnesium and phosphorus stores