Vascular calcification in end-stage renal disease

Abstract

Vascular calcification is highly prevalent in end-stage renal disease and independently predictive of future cardiovascular events and mortality. Calcification can occur in both the intimal and medial layers of vasculature, but medial calcification is the major form in end-stage renal disease. Medial calcification increases large elastic artery stiffness and pulse-pressure, promotes left ventricular hypertrophy, reduces perfusion of the coronary arteries, and ultimately promotes increased cardiovascular mortality via increased risk of myocardial infarction and heart failure. It results not from a passive deposition of calcium and phosphate due to increased circulating levels, but rather is an active cell-mediated process involving vascular smooth muscle cell apoptosis and vesicle release, a shift in the balance of inhibitors and promoters of vascular calcification, and vascular smooth muscle cell differentiation from a contractile to osteochondrogenic phenotype. This phenotypic shift requires phosphate, as well as the uptake of phosphate by the sodium-dependent phosphate cotransporter PiT-1, which is upregulated by proinflammatory cytokines and the uremic milieu. Further research is needed to determine if targeting these processes can ultimately reduce vascular calcification in this high cardiovascular risk population.

Keywords: Calcium; end-stage renal disease; phosphate; vascular calcification.

Figure 1

Cardiovascular implications of vascular calcification. Medial vascular calcification increased aortic stiffness (decreased arterial compliance), as reflected by increased aortic pulse-wave velocity. This reduction in arterial distensiblity increases systolic blood pressure (SBP) and also reduces (DBP). Such hemodynamic alterations increases cardiac afterload, while also compromising perfusion of the coronary arteries. Subsequent left ventricular remodeling and hypertrophy increases risk of myocardial infarction (MI) and heart failure, and ultimately favors increased cardiovascular mortality.

Figure 2

Simplified diagram of the passive and active processes involved in vascular calcification in end-stage renal disease. Vascular calcification is not just a passive process resulting from an increased in serum calcium and phosphorus concentration but active process involving key regulatory proteins typically involved in bone formation and structure that become expressed in arterial tissue and lead to ossification of the vasculature. In end-stage renal disease (ESRD), both serum calcium and phosphorous are elevated, and although they work synergistically to promote vascular calcification, it is thought that calcium primarily induces apoptosis, leading to the formation of a mineral nucleation nidus, and phosphorous promotes active osteochondrosis. Calcium promotes vascular smooth muscle cell (VSMC) apoptosis and release of membrane-bound matrix vesicles, leading to vesicle deposition and extracellular matrix mineralization. Subsequently, phenotypic changes in VSMCs occur, a process requiring a shift in the balance of cell-mediated processes regulated by active inhibitors and active inducers. Pro-inflammatory cytokines (increased inflammation) and the uremic milieu can increase expression of sodium-dependent phosphate cotransporters (in particular PiT-1) in VSMCs, leading to increased uptake of phosphorus even if levels are still normal. PiT-1 is required for the osteochondrogenic phenotypic changes that occur in VSMC as a result of active processes.