Understanding Vascular Calcification in Chronic Kidney Disease: Pathogenesis and Therapeutic Implications

Abstract

Vascular calcification (VC) is a biological phenomenon characterized by an accumulation of calcium and phosphate deposits within the walls of blood vessels causing the loss of elasticity of the arterial walls. VC plays a crucial role in the incidence and progression of chronic kidney disease (CKD), leading to a significant increase in cardiovascular mortality in these patients. Different conditions such as age, sex, dyslipidemia, diabetes, and hypertension are the main risk factors in patients affected by chronic kidney disease. However, VC may occur earlier and faster in these patients if it is associated with new or non-traditional risk factors such as oxidative stress, anemia, and inflammation. In chronic kidney disease, several pathophysiological processes contribute to vascular calcifications, including osteochondrogenic differentiation of vascular cells, hyperphosphatemia and hypercalcemia, and the loss of specific vascular calcification inhibitors including pyrophosphate, fetuin-A, osteoprotegerin, and matrix GLA protein. In this review we discuss the main traditional and non-traditional risk factors that can promote VC in patients with kidney disease. In addition, we provide an overview of the main pathogenetic mechanisms responsible for VC that may be crucial to identify new prevention strategies and possible new therapeutic approaches to reduce cardiovascular risk in patients with kidney disease.

Keywords: aortic stenosis; cardiovascular risk; chronic kidney disease; precision medicine; vascular calcification.

Figure 1

Pathogenic mechanisms of vascular calcification (VC) in chronic kidney disease (CKD). Hyperphosphatemia and hypercalcemia with loss of calcification inhibitors such as fetuin A, osteoprotegerin, and matrix GLA protein (MGP) promote osteochondrogenic differentiation of vascular cells. VC is, furthermore, influenced by traditional risk factors (e.g., aging, smoking) and non-traditional factors related to calcium-phosphorus metabolism dysfunction and increased FGF23. The accumulation of minerals in the arterial walls and the degradation of elastin lead to progressive vascular stiffness. Inflammation and the accumulation of oxidized lipids in plaques further promote calcification, negatively affecting vascular compliance and increasing the risk of cardiovascular complications (aortic and mitral valve calcifications, left ventricular hypertrophy).

Figure 2

Clinical management of vascular calcifications in CKD patients and intervention strategies to delay the progression.

Figure 3

Role of micro- and macro-calcifications in the large vessels, heart valves, and cardiac conduction system.