Magnesium metabolism: basic aspects and implications of ciclosporine toxicity in rats

In rapidly growing male Sprague-Dawley rats with an initial body weight of 100 +/- 10 g, we investigated how alimentary magnesium (Mg) supply, Mg metabolism and ciclosporine (Ci)-associated nephrotoxicity are interrelated. Food with 100 ppm Mg (1Mg) or 1,000 ppm Mg (stMg) or 10,000 ppm Mg (rMg), Ci 20 mg/kg body weight daily or olive oil were applied for 3 months (n = 10/group). Mg concentrations in various compartments were measured by atomic absorption spectrophotometry. Creatinine clearance (Jaffe), urinary N-acetyl-beta-D-glucosaminidase (NAG) activity (fluorometrically), urinary sodium excretion (flame photometry) and osmolality were measured. Histomorphological examination was done and renal renin expression was studied by monoclonal antibodies. Ci reduced the Mg concentration of the femur under 1Mg (72.6 +/- 9.7 vs. 112.6 +/- 14.3 mmol/kg dry substance, p < 0.05) and under stMg (150.6 +/- 16.6 vs. 194.1 +/- 10.2 mmol/kg dry substance, p < 0.05), thus indicating Ci-related Mg deficiency. This was due to a significant increase in Mg excretion in Ci treatment compared to dietary controls. Under rMg, there was no difference between Ci-treated and control animals. Ci treatment lowered creatinine clearance in 1Mg (1.42 +/- 0.05 vs. 3.02 +/- 0.58 ml/min) and in stMg (1.04 +/- 0.45 vs. 2.18 +/- 0.51 ml/min), NAG/creatinine and urinary sodium excretion were negatively affected by Ci under 1Mg and stMg. Histomorphology showed macrocalcifications due to Mg deficiency and Ci-specific findings, which were markedly enhanced in 1Mg and stMg. Animals with plentiful Mg supply had no functional alterations due to Ci and no or weakly expressed histomorphological lesions. Renin-positive stained cells were higher in Ci-treated animals. This seems to be functionally relevant under 1Mg and stMg, since it was associated with sodium retention and elevated relative heart weight, indicating hypertension. Alimentary or drug-induced Mg deficiency plays a relevant role in the pathophysiology of chronic Ci nephrotoxicity. Our data suggest that Mg supplementation is helpful to reduce Ci toxicity, even if there is 'normal' alimentary Mg intake.