Vascular Calcification
Authors: Sharon M. Moe
Journal: Journal of the American Society of Nephrology (2009)

Vascular calcification, primarily arterial calcification, is one of multiple forms of extraskeletal calcification that is highly prevalent in patients with chronic kidney disease (CKD), especially those on dialysis. Arterial calcification is not a new or novel phenomenon: Mummified bodies from the ice age and many older adults and patients with diabetes and without CKD have at least some arterial calcification.1 The presence and magnitude of arterial calcification are associated with an increase in cardiovascular events or death in the general population2 and, in some studies, in dialysis patients.3,4 Cross-sectional and longitudinal studies in dialysis patients identify a plethora of risk factors, including advanced age, diabetes, duration of dialysis or magnitude of CKD, hyperphosphatemia, inflammation, and excess calcium-containing phosphate binders, but these associations are not consistently found in all studies.1 Importantly, some patients with CKD do not have arterial calcification despite significant exposure to various risk factors, and these same patients remain calcification-free over time on dialysis. This observation suggests some individuals are protected from the devastating effects of calcification and has led to a search for protective factors or inhibitors of calcification. This concept also holds true for other forms of mineralization, because human and animal studies have demonstrated that cartilage mineralization5 and kidney stone growth would proceed unabated if it were not for the effects of inhibitors. Thus, much evidence supports the notion that regulation of both desirable and undesirable calcification/mineralization is at least partly mediated through the function and availability of inhibitors.6 Multiple inhibitors of vascular calcification are known. Local tissue inhibitors include matrix gla protein, pyrophosphates, and osteopontin, which inhibit arterial mineralization in both animal models and in vitro cultures of vascular smooth muscle cells.1,6 Fetuin-A (α2 Heremans Schmidt glycoprotein [Ahsg]) is another inhibitor of calcification but acts as a circulating inhibitor. It is synthesized predominately in the liver and is abundant in serum at levels of 0.5 to 1.0 g/L. The transcription and synthesis of fetuin-A are downregulated during inflammation; therefore, fetuin-A represent a reverse acute-phase reactant.7 Low levels of fetuin-A in patients with CKD are associated with arterial calcification, calciphylaxis, and mortality.8–10 Fetuin-A binds to both calcium and phosphate in the serum, forming small "calciparticles" that are presumably removed through the reticuloendothelial system11; therefore, fetuin-A acts in host defense to clean the blood of unwanted calcium and phosphate. Targeted disruption of fetuin-A (Ahsg) in mice leads to diffuse and profound soft tissue calcification on a normal diet but only on a DBA/2 background, which is inherently prone to calcification. On the C57BL/6 background, the calcification requires very high dietary calcium, phosphorus, and vitamin D, leading to calcification in soft tissue and small arterioles of muscle, kidney, and lung.10 Additional studies demonstrated that the addition of CKD results in marked hyperphosphatemia in C57BL/6 Ahsg−/− null mice, leading to myocardial and pulmonary calcification but not arterial deposits.12 These studies suggested that fetuin-A protects against calcification in settings of genetic predisposition and CKD but that different combinations of factors lead to variable phenotype. In this issue of JASN, Westenfeld et al.13 add to our understanding of calcification in CKD and the importance of fetuin-A. They hypothesize that endothelial damage is required for development of large artery calcification. To test this hypothesis, they crossed Ahsg−/− null mice with ApoE−/− null mice, the latter known to have increased cholesterol and atherosclerosis. They then examined whether a high-phosphate diet alone or high-phosphate diet plus CKD induces arterial calcification. All mice developed hyperphosphatemia on the high-phosphate diet, but only animals with CKD developed hyperparathyroidism. The double-deficient Ahsg−/−/ApoE−/− null mice developed a similar degree of atherosclerosis as the ApoE−/− mice, which is unaffected by either high-phosphate diet or CKD. In the ApoE−/− null mice, high-phosphate diet and CKD led to an increase in aortic but not coronary artery calcification. In contrast, the double-deficient Ahsg−/−/ApoE−/− null mice developed both aortic and coronary artery calcification with high-phosphate diet alone, but this was aggravated further in the presence of CKD. Thus, extensive and multisite arterial calcification in this animal model requires genetic predisposition to atherosclerosis (apolipoprotein E deficiency), a genetic defect in an inhibitor of mineralization (Ahsg deficiency), and hyperphosphatemia that is further accelerated by CKD: A three-hit model. Unfortunately, it seems that patients on dialysis frequently have two hits: The first hit is diabetes or hypertension with arterial tissue damage, endothelial dysfunction, and atherosclerosis, and the second hit is a disorder of mineral metabolism in the form of hyperphosphatemia and/or hyperparathyroidism. The difference in patients who do and do not develop calcification despite these similar risk factors may be the third hit. Those who have inflammation with resulting decreases in fetuin-A (or deficiency in another inhibitor) develop calcification, and those with normal inhibitors do not. Furthermore, it may not be the absolute level of fetuin-A or other inhibitor but rather the relative amount for a given level of calcium and phosphate that is important. Ideally, one could imagine characterizing the required inhibitor/phosphate ratio to predict those who develop calcification. Perhaps the future holds such a personalized medicine approach: Individualized, anti-calcification profiling leading to an ability to target high-risk patients. DISCLOSURES S.M.M. has grant support and is a consultant/scientific advisor for Genzyme, Shire, Ineos, and Amgen. She has also consulted for Litholink and DiaSorin and received royalties from Amgen. S.M.M. is supported by a Veterans Administration Merit Award and National Institutes of Health grant DK002775.