Evolving concepts of pathogenesis of cardiovascular disease in chronic uremia: Role of hyperparathyroidism, calcium-phosphate metabolism, and their therapy

W hemodialysis was introduced for the treatment of end-stage renal disease (ESRD), nephrologists were faced with the development of several new complications. Bone alterations and secondary hyperparathyroidism were between those complications and gave rise to major interest in experimental and clinical research. Although disturbances of calcium and phosphate metabolism were considered principally as factors controlling secretion of parathyroid hormone, PTH was considered as a major uremic toxin associated with bone disease and many nonskeletal disorders including cardiovascular complications. In in vitro studies, PTH was shown to have chronotropic and inotropic effects on isolated cardiomyocytes. These changes were associated with increased intracellular calcium content; disturbed lipoprotein metabolism; and altered mitochondrial energy production, storage, and utilization. These experimental studies were certainly interesting, but the clinical relevance was uncertain. Indeed, in ESRD patients, the secondary hyperparathyroidism was not associated with uniform cardiovascular abnormalities, the cardiovascular effects of parathyroidectomy or nonsurgical control of PTH levels were minimal or absent, and skeletal complications were rarely the cause of death. The role of PTH and associated calciumphosphate disorders on pathogenesis of cardiovascular disorders were recently reanalyzed. Several reports in the literature have suggested that hyperphosphatemia, in association with hyperparathyroidism or hypoparathyroidism and vitamin D3 or calcium overload, was an independent predictor of death and the possible culprit associated with cardiovascular complications in dialysis patients. Cardiovascular disease is the major cause of mortality and morbidity in patients suffering from ESRD. Atherosclerosis and aortic stiffening are the major vascular compliactions observed. Atheromatous plaques of ESRD patients are more frequently and more intensively calcified than those of nonuremic subjects, and several recent studies have shown the presence of extensive and almost generalized vascular calcifications in patients undergoing hemodialysis. Moreover, the extent of calcifications as such is an independent factor to cardiovascular mortality. These calcifications concern not only plaques (intimal calcifications) but also diffuse medial calcifications. Although the arterial calcifications are associated with nonspecific classical factors such as age, diabetes, or smoking habits, there is a growing body of evidence that alterations of phosphate and calcium metabolism play a predominant role. For many years, calcifications were considered to be caused by passive mineral precipitation associated with elevated calcium x phosphate product. Recent studies have shown that this process may be active involving mechanisms normally found in bone. Phosphate seems to be of primary importance in the initiation of cardiovascular calcification through the change of the vascular smooth muscle phenotype and induction of the expression by vascular smooth muscle cells of osteocalcin abd Cbfa-1, which are markers of osteoblastic differention. The pathogenic role of PTH as such is less clear than previously suspected, and extensive calcifications are frequently observed in patients with low bone activity and adynamic bone disease. Of note, in the general population, the cardiovascular calcifications are inversely correlated with bone density in osteoporotic