Novel insights into vascular calcification M Ketteler 1 and C Giachelli 2 1 Department of Medicine II, Nephrology and Clinical Immunology, University Hospital Aachen, Aachen, Germany and 2 Department of Bioengineering, University of Washington, Seattle, Washington, USA Vascular calcification is not just a hallmark of uremic arterio- and atherosclerosis, but also a significant cardiovascular risk factor in patients with chronic kidney disease. In contrast to the previous assumption that vascular calcification predominantly occurs by passive precipitation of calcium and phosphate ions, recent research led to the insight that extraosseous calcification is a highly regulated process. High serum phosphate and calcium levels may induce a process of osteogenic ‘bone-like’ differentiation of vascular smooth muscle cells, while deficiencies of calcification inhibitors or a disturbed balance towards calcification inducers may have a relevant pathophysiological influence on the initiation and progression of calcified lesions. This overview summarizes some of the best explored novel risk factors for disturbances of calcium and phosphate homeostasis and points to the integral role of hyperphosphatemia as a modifiable key trigger in calcification processes. Kidney International (2006) 70, S5–S9. doi:10.1038/sj.ki.50001996 KEYWORDS: hyperphosphatemia; calcium; fetuin-A; MGP; vascualr calcifica- tion; cardiovascular mortality Chronic kidney disease (CKD) Stage 5 is associated with an increased risk of cardiovascular mortality. 1,2 Indeed, more than 50% of deaths in these patients are due to cardiovascular disease, 3 a risk that is 20- to 30-fold higher than in the general population. 3 The presence and extent of vascular calcification is highly correlated with cardiovascular disease and all-cause mortality and extensive arterial calcification is typical of patients on hemodialysis, even at a young age (o30 years). 2,4,5 Two types of vascular calcification have been observed: 6 intimal calcification of the atherosclerotic plaques and medial calcification of large elastic arteries and small arterioles. Intimal calcification may increase the risk of plaque erosion and rupture (especially ‘calcified nodules’), whereas medial calcification increases arterial stiffness, leading to high systolic and pulse pressures. 7–9 Both types of calcification are associated with an increased risk of myocardial infarction 10 and cardiovascular mortality. 11 Intimal calcification may occur independently of medial calcification, and vice versa, and a mixture of both intimal and medial calcifications has been observed in affected vessels of patients with CKD Stage 5. 12,13 This article examines the mechanisms of vascular calcification, highlighting the role of calcium and phosphate levels, in patients with CKD Stage 5. In addition, the potential for reducing vascular calcification risk by modifying calcium load is explored. MECHANISMS OF VASCULAR CALCIFICATION Overview One major pathomechanism in the process of vascular calcification is similar to that of bone formation: vascular smooth muscle cells (VSMCs) undergo osteogenic differ- entiation into phenotypically distinct osteoblast-like cells. 5 These differentiated cells start to lay down a collagenous extracellular matrix into which minerals are deposited, resulting in vascular calcification. In vitro studies have indicated that mineral deposition may be initiated by the release of mineralization-competent, membrane-bound matrix vesicles from VSMCs, a process that is increased at high extracellular calcium and/or phosphate concentrations. 14 However, the release of mem- brane bound matrix vesicles and mineralization in VSMC cultures is inhibited by the addition of serum, indicating that vascular calcification in vivo is normally modulated by endogenous calcification inhibitors. 15 http://www.kidney-international.org & 2006 International Society of Nephrology Correspondence: M Ketteler, Department of Medicine II, Nephrology and Clinical Immunology, University Hospital Aachen, Pauwelsstasse. 30, Aachen D-52057, Germany. E-mail: [email protected] Kidney International (2006) 70, S5–S9 S5
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