Vascular calcification in patients with end-stage renal disease

Vascular calcification is the most common type of extra-osseous calcification in end-stage renal disease (ESRD), manifesting as both medial and intimal calcification of large arteries. It is highly prevalent, often progressive and is associated with reduced arterial elasticity and increased mortality. Risk factors for calcification in ESRD include age, duration of dialysis, diabetes mellitus, most probably an elevated calcium-phosphorus product (Ca x P) level, the dose of calcium-containing phosphate binders and the induction of the systemic inflammatory response. Uraemic calcification was thought to be a largely physico-chemical process facilitated by elevated Ca x P (i.e. "metastatic" calcification). It is now well established, however, that vascular smooth muscle cells actively take up phosphate to form bioapatite. This process is associated with a phenotypic transformation of vascular smooth muscle cells during which they express osteoblast markers. In addition to phosphate, various other factors are likely to increase bioapatite formation, e.g. lipids and inflammatory cytokines. There have also been relatively new insights relating to the role of endogenous inhibitors of calcification i.e. matrix Gla protein and fetuin-A (alpha(2)-Heremans-Schmid glycoprotein), in particular the downregulation of fetuin-A in systemic inflammation. Decreased serum fetuin-A has been shown to be associated with a reduced capacity to inhibit calcium phosphate precipitation in vitro and is predictive of mortality in dialysis patients. These new insights into pathogenesis may lead to better prevention and treatment of calcification (e.g. with calcimimetics, anti-cytokines, etc.). However, the only preventive approach to have been established prospectively to date is the replacement of calcium-containing phosphate binders with sevelamer HCl, a non-calcaemic phosphate binder. Yet, it remains unclear whether sevelamer HCl reduces vascular calcification by preventing episodes of hypercalcaemia and/or by reducing low-density lipoprotein (LDL)-cholesterol levels.