Novel mechanisms in accelerated vascular calcification in renal disease patients

Vascular calcification occurs more often and earlier in patients with end-stage renal disease than in normal controls. It is a regulated biological process following many of the cellular and molecular programs in osteogenesis. This review summarizes some of the regulatory mechanisms that may explain its severity in renal patients.

A subpopulation of cells from arteries and cardiac valves produce a mineralizing matrix and undergo osteoblastic differentiation. Osteogenic differentiation regulators are found in calcified but not normal arteries. Phosphate levels have dramatic effects on vascular calcification in vitro, through a sodium phosphate transporter signaling molecular changes. Atherogenic oxidized lipids promote osteoblastic differentiation of vascular cells and inhibit bone mineralization. In uremic patients, the severity of dyslipidemia corresponds with the progression of vascular calcification. Oxidative stress and inflammatory mediators may underlie the effects of oxidized lipids. In dialysis patients, the degree of cardiac valvular calcification corresponds with levels of C-reactive protein. Genetic factors may also contribute. Polymorphisms of the inflammatory adhesion molecule, E-selectin, associate with coronary calcification in young women. Mice deficient in matrix GLA protein, which inhibits bone morphogenetic protein activity, develop complete ossification of the aorta, presumably as a result of unopposed osteogenic activity on vascular mesenchyme. Since matrix GLA protein function requires gamma-carboxylation of its glutamate residues by a vitamin K dependent carboxylase, warfarin treatment may affect vascular calcification by blocking vitamin K and hence matrix GLA protein activity.

These findings indicate that vascular calcification is regulated both positively and negatively by a wide variety of mechanisms affecting patients with renal disease.