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Background and aim – Cardiovascular diseases with vascular calcification represent a common clinical problem for human patients with chronic kidney disease (CKD) and those having undergone renal transplantation. Preliminary studies verified that mycophenolic acid (MPA) has an inhibitive effect on the calcification of smooth muscle cells in vitro. The aim of this study is to verify the anti-calcifying impact of MPA in the animal model. MPA is a noncompetitive and reversible inhibitor of the inosinmonophosphate-dehydrogenase, which prevents proliferation of T- and B lymphocytes. In addition to the immunosuppressive characteristics of MPA, an anti-calcifying effect on the cardiovascular system could be suspected.
Methods – In order to induce CKD in the animal model, nephrectomies were conducted in two steps. During the first operation 75 % of the right kidney was nephrectomised by ligature. During the second operation the left kidney was completely removed and the osmotic pump with MPA was subcutaneously implanted into the back. Three days later a high phosphate diet was induced to all animals, because a high level of phosphate in the diet is necessary to develop a calcification. Female DBA/2 mice were split into four groups. The animals of the control group had no nephrectomies, only two sham operations without any medication were done. In the solvent group two operations were carried out, without MPA. In the low dose and a high dose MPA group nephrectomies were carried out. To the low dose MPA group 3 mg/kg body weight/per day of MPA was given. The high dose MPA group received 30 mg/kg body weight/per day of MPA. In both cases MPA was administered in a solvent. Blood samples were taken at the beginning and at the end of the trial. The level of parathyroid hormone was measured with ELISA. A parathyroid hormone dysbalance may point to a disturbance of the calcium and phosphate metabolism. In addition alkaline phosphatase, urea, total cholesterol, calcium and inorganic phosphate were analyzed with dry chemistry. The right kidney and the heart were examined histologically with hematoxylin, von Kossa and alizarin red S staining. In addition the heart wet weights and the calcium content of the hearts were measured biochemically and histomorphometricly.
Results – A renal failure was successfully induced by nephrectomy and high phosphate diet. In the solvent group an increase of parathyroid hormone and urea was detected. All four groups showed the development of secondary hyperparathyroidism, while the calcium and inorganic phosphate metabolism was disturbed. Urea and inorganic phosphate in blood plasma were decreased in both MPA groups compared to the solvent group. Furthermore, the heart was significantly calcified in the solvent group than in the control group (alizarin red S staining, heart wet weight, histomorphometry, biochemical calcium content). In the low dose MPA group, the biochemical calcium content of the heart was lower compared to the solvent group. In the high dose MPA group all measurements showed a decrease in cardiac calcification compared with the solvent and with the low dose MPA group. Conclusion – MPA has anti-calcifying properties, since it decreases the calcium content in the myocardium, as shown in the animal model. This finding could have a beneficial impact on the therapy of cardiovascular diseases.