Pitting Phosphate Transport Inhibitors Against Vascular Calcification

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Abstract
Ascular calcification is widespread in patients with coronary artery disease, peripheral vascular disease, and diabetes, but by far the most severe and exten- sive vascular calcification is in those with end-stage renal disease, especially those with the longest exposure to hemo- dialysis. Their coronary calcification scores on electron beam CT scanning are often an order of magnitude greater than in ordinary CAD patients. The severity of their vascular calci- fication closely relates to the duration of hemodialysis; after a decade of dialysis, even pediatric patients are affected.1 Histopathologically, these calcium deposits are located pri- marily in the medial layer, unlike atherosclerotic calcifica- tion, which is located within the intimal lesions. This and other differences suggest that the two forms may have different underlying mechanisms. Although it remains con- troversial whether vascular calcification promotes plaque destabilization, it is clear that arterial rigidity contributes to hypertension, cardiac hypertrophy, and heart failure, in part because of increased aortic impedance, as seen in experimen- tal models that use aortic banding to produce heart failure. This is likely the reason that patients with chronic renal disease most often die of cardiovascular complications. This clinical phenomenon offers important mechanistic clues about vascular calcification, as recognized by Giachelli and colleagues at University of Washington. As a result of their interdisciplinary work, they were aware that bone biologists routinely treat their osteoblast cultures with phos- phate supplements, usually in the form of beta- glycerophosphate, and that phosphate supplements acceler- ated osteoblast mineralization. Together with the knowledge that end-stage renal disease patients almost uniformly have both elevated serum phosphate and extensive vascular calci- fication, this observation raised the possibility that hyper- phosphatemia may be a major contributing factor to the calcification in these patients. These investigators went on to show that phosphate supplements also accelerate mineraliza- tion in vascular cells and implicated sodium-dependent phos- phate transport.2 In this issue of Circulation Research, these investigators3 now provide compelling evidence that a spe-