MAGNESIUM-METABOLISM - BASIC ASPECTS AND IMPLICATIONS OF CICLOSPORINETOXICITY IN RATS

In rapidly growing male Sprague-Dawley rats with an initial body weigh t of 100 +/- 10 g, we investigated how alimentary magnesium (Mg) suppl y, Mg metabolism and ciclosporine (Ci)-associated nephrotoxicity are i nterrelated. Food with 100 ppm Mg (1Mg) or 1,000 ppm Mg (stMg) or 10,0 00 ppm Mg (rMg), Ci 20 mg/kg body weight daily or olive oil were appli ed for 3 months (n = 10/group). Mg concentrations in various compartme nts were measured by atomic absorption spectrophotometry. Creatinine c learance (Jaffe), urinary N-acetyl-beta-D-glucosaminidase (NAG) activi ty (fluorometrically), urinary sodium excretion (flame photometry) and osmolality were measured. Histomorphological examination was done and renal renin expression was studied by monoclonal antibodies. Ci reduc ed 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 +/- 1 6.6 vs, 194.1 +/- 10.2 mmol/kg dry substance, p < 0.05), thus indicati ng 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 tr eatment 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), N AG/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 enhanc ed in 1Mg and stMg. Animals with plentiful Mg supply had no functional alterations due to Ci and no or weakly expressed histomorphological l esions. 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 weigh t, indicating hypertension. Alimentary or drug-induced Mg deficiency p lays a relevant role in the pathophysiology of chronic Ci nephrotoxici ty. Our data suggest that Mg supplementation is helpful to reduce Ci t oxicity, even if there is 'normal' alimentary Mg intake.