Chapter 4 84 Vascular calcification Abnormalities in mineral metabolism, particularly hyperphosphatemia and hypercalcemia, have been associated with increased vascular calcification (VC) in endstage renal disease patients 31,32. Preclinical studies showed that magnesium may be able to reduce or even prevent VC 33–37. Montezano and others showed that the effect of magnesium on VC was accompanied by an increased expression of osteopontin, matrix Gla protein and BMP-7 36. This and several other studies demonstrated that the magnesium transporter TRPM7 plays an important role in the process of VC, and that magnesium through TRPM7 might at least partly inhibit VC. Another study suggested that magnesiummight inhibit the transformation of VSMCs into osteoblast-like cells and hydroxyapatite crystals formation 33. CKD patients with higher magnesium levels had improved intima-media thickness and vascular stiffness, considered surrogate markers for VC, suggesting that high serum magnesium concentrations might be protective against VC. In line, serum magnesium was identified as an independent determinant of calcification propensity 38. Zelt and colleagues found a reduction of VC upon high magnesium intake and, moreover, that calcitriol-induced VC was inhibited by high magnesium intake 34. Another study observed a magnesium-induced down-regulation of the Wnt/b-catenin signaling pathway 39, which has been shown to be activated during the development of VC 35. Taken together, these molecular pathways might concertedly position magnesium as a major strategy to reduce VC, particularly in high-risk patients such as CKD patients. Vascular stiffness Previously, magnesium has shown beneficial effects on vascular stiffness 40,41, which in turn might affect total peripheral resistance.Many studies demonstrated vascular stiffness to be an independent predictor of cardiovascular disease in patients with hypertension 42. Van Laecke and colleagues studied the association between serum magnesium levels and vascular stiffness in 512 renal transplant recipients 40. Low magnesium levels were independently associated with increased vascular stiffness. Importantly, a recently published RCT reported a significant improvement of vascular stiffness after long-term magnesium supplementation 41. The clinical relevance of this finding is supported by longitudinal epidemiological studies, that estimated a decreased risk of cardiovascular disease of 14% when vascular stiffness,measured with pulse wave velocity, was improved by 1.0 m/s 43. Mechanisms by which magnesium reduces vascular stiffness have not been identified yet, although it seems likely that this is at least through an effect on VC (see below). No effect on BP was found in the study of Joris and others, suggesting
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