Vascular Disease Prevention, 2006, 3, 123-128 123 1567-2700/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd. Role of Hyperphosphatemia on Cardiovascular Disease in Dialysis Patients Mario Cozzolino*, Maurizio Gallieni and Diego Brancaccio Renal Unit, S. Paolo Hospital, Milan, Italy Abstract: The first cause of mortality in the dialysis population is cardiovascular disease. Accelerated atherosclerosis and vascular calcifications play a key role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD) pa- tients. Mineral metabolism disorders and increased serum calcium-phosphate product have recently been investigated as factors inducing vascular calcification. Cardiovascular disease in renal failure appears to be associated with bone metabo- lism alterations. Hyperphosphatemia has been investigated as an inducing factor for cardiovascular morbidity in this population. Recent in vitro studies showed how vascular smooth muscle cells calcify when incubated in a medium con- taining elevated concentration of inorganic phosphate. Together with classical passive precipitation of calcium-phosphate in soft tissues, inorganic phosphate may cause extraskeletal calcification through “ossification” of the tunica media in the vasculature of CKD patients. In addition, the treatment of hyperphosphatemia and secondary hyperparathyroidism with calcium-based phosphate binders and calcitriol has increased the risk of vascular calcification in dialysis patients. “Second generation” therapy of hyperphosphatemia with free-calcium and aluminum phosphate binders, new vitamin D metabo- lites, and calcimimetics may prevent extraskeletal mineralization in uremic subjects, reducing both cardiovascular mor- bidity and mortality. Keywords: Phosphate, calcium, vascular calcification, chronic kidney disease, cardiovascular disease. INTRODUCTION Vascular calcification is common in patients affected by diabetes and chronic kidney disease (CKD) [1-2]. These pa- tients develop extensive medial calcification, which causes increased arterial stiffness and high morbidity and mortality due to cardiovascular events [3]. Calcification of soft tissues and blood vessel walls occurs frequently in dialyzed patients compared to the non-uremic population [4-6]. A growing number of risk factors are associated with vascular minerali- zation in dialysis patients (e.g. inflammation, age and time on dialysis), but abnormalities in bone mineral metabolism represents a major determinant (Table 1). Clearly, hyper- phosphatemia, elevated serum calcium-phosphate product levels, and secondary hyperparathyroidism are associated with vascular calcification, although their roles are incom- pletely investigated [7-8]. In addition to these classic alterations in bone and min- eral metabolism, an active process has been documented [9]. Enhanced serum phosphate levels have been recently inves- tigated as inducing factors on extra-skeletal calcification in uremic population. In particular, elevated blood levels of phosphate associate with ectopic calcification and increased risk of calciphylaxis, a dramatic calcification of subcutane- ous artery system [10-12]. In vitro studies demonstrated that human aortic smooth muscle cells calcify when incubated in a high phosphate medium, where calcium and calcitriol are not changed [13]. In the last decade, several studies defined calcification of atherosclerotic lesions as an active process similar to bone *Address correspondence to this author at the Renal Unit, Ospedale San Paolo, Azienda Ospedale San Paolo, Via A. di Rudinì, 8 – 20142 – Milano, Italy; E-mail: mariocozzolino@hotmail.com Table 1. Risk Factors for Cardiovascular Disease in Chronic Kidney Disease (CKD) Patients ‘Classic’ CKD-Associated Obesity Secondary Hyperparathyroidism Family History Hyperphosphatemia Smoking Inflammation Hypertension Hyperhomocysteinemia Diabetes Anaemia Dyslipidemia Increased Oxidative Stress Gender Increased ADMA Levels formation. Furthermore, vascular calcification was shown to involve not only a passive calcium-phosphate deposition on atherosclerotic vessels but also an active “ossification” of vascular structures [9]. Since vascular calcifications are predictive of higher morbidity and mortality, the control of serum phosphorus in CKD patients becomes crucial in preventing increases in calcium-phosphate product, secondary hyperparathyroidism, and vascular mineralization [14]. Recent studies have shown that new pharmacological tools may be useful to prevent vascular calcifications in animal models and humans [15- 17]. This review considers the role of phosphate in the patho- genesis of secondary hyperparathyroidism and vascular min- eralization in CKD patients (Fig. 1).