Long-term morphological and biochemical observations in cisplatin-induced hypomagnesemia in rats

A model of cisplatin (cis-diamminedichloroplatinum II) induced hypomagnesemia with renal magnesium wasting was developed in rats. Following three weekly intraperitoneal injections of cisplatin (2.5 mg/kg body weight) hypomagnesemia was evident after the second injection of cisplatin and persisted for at least 24 weeks after the last injection. The plasma magnesium concentration was 0.69 +/- 0.01 mM in cisplatin-treated rats and 0.79 +/- 0.01 mM in control rats 24 h after the second injection (less than 0.01). Despite a lower plasma magnesium concentration in cisplatin-treated rats, the fractional urinary excretion of magnesium was similar in both groups, indicating inappropriate renal magnesium excretion in cisplatin-treated rats. Rat kidneys fixed in situ by arterial infusion were examined by light and electron microscopy at the following times: 24 h after the first and second injections and 48 h and 1, 4, 8, 16, and 24 weeks after the third injection. Focal necrosis of the proximal tubule cells in the outer stripe of the medulla (S3 segment) was noted 24 h after the second injection. Following this, there was dilatation of the S3 segment proximal tubules which were lined by variably flattened epithelial cells devoid of brush borders. Many of these cells had enlarged, hyperchromatic nuclei, and few mitoses were observed. These changes were most extensive at 4 weeks, diminished after this, but were still present focally at 24 weeks. In this model the cisplatin-induced hypomagnesemia persists long after discontinuation of therapy as in humans, and the S3 segment is the prime target of the cisplatin.(ABSTRACT TRUNCATED AT 250 WORDS)