Role of calcium-phosphate product and bone-associated proteins on vascular calcification in renal failure.

Cardiovascular events are the most frequent cause of death in patients with chronic renal failure (1–2). Heterotopic calcification of blood vessel walls occurs frequently with advanced age, atherosclerosis, and diabetes mellitus (3). In chronic renal failure, autopsy (4–5) and clinical investigations (6) have documented a higher prevalence of coronary plaques in dialyzed patients compared with the nonuremic population. The risk factors that contribute to the higher prevalence of atherosclerotic lesions in chronic renal failure include dyslipidemia, hyperhomocysteinemia, and hypertension (3). In addition, hyperphosphatemia and increased calcium-phosphate product are important contributors to vascular calcifications in patients with uremia (7). A new, noninvasive imaging technology, electron beam computed tomography, has demonstrated that both hyperphosphatemia and increased calcium-phosphate product cause a progressive increase in calcium deposition in the coronary arteries and mitral and aortic valves in patients with advanced renal failure (8). Hyperphosphatemia associates with ectopic calcifications, increased risk of calciphylaxis, and calcinosis (9–10). Figure 1 illustrates direct and indirect mechanisms for hyperphosphatemia to increase calcium-phosphate product. High levels of phosphate, due to phosphorus retention, worsen the secondary hyperparathyroidism commonly present in renal failure through direct and indirect mechanisms. High phosphate enhances parathyroid cell proliferation and parathyroid hormone (PTH) synthesis and secretion directly and indirectly through both a reduction in serum calcitriol and ionized calcium levels and a reduction of skeletal resistance to PTH. The resultant high PTH causes osteitis fibrosa and bone loss and therefore further increases in calcium-phosphate product (11– 12). In addition to its effects on bone, high PTH, by elevating cytosolic calcium, could cause microcalcifications, as has been demonstrated in lung (13) and skin (14). Also, PTH impairment of lipid metabolism and immune cell function (15) could directly contribute to enhance cardiovascular calcification. The relative contribution of hyperphosphatemia, high calciumphosphate product, and secondary hyperparathyroidism to enhance vascular calcification, as well as the mechanisms involved, are incompletely understood. In recent years, vascular calcification was shown to involve not a passive deposition of calcium-phosphate crystals on atherosclerotic vessels but an active process in which vascular cells elicit osteoblastic functions (16). Furthermore, there is a paradoxical coincidence of vascular mineralization with bone loss in human and animal models, which suggests that the same factors that induce high-turnover bone disease in renal failure could also mediate vascular calcification. This review presents the emerging understanding of the mechanisms by which hyperphosphatemia and elevated Ca P product affect vascular calcification. In addition, we present the biologic interactions and functional parallels between bone and vascular tissues in bone-associated proteins and PTH-related peptide (PTH-rP).