Valvular calcification in chronic kidney disease: new insights from recent clinical and preclinical studies

Abstract

Valvular calcification, developing either in the mitral or the aortic valve, is highly prevalent in patients suffering from chronic kidney disease (CKD), in whom their presence correlates with higher cardiovascular and all-cause mortality risk. To date, the exact mechanisms that promote heart valve calcification remain unclear, and none of the treatments tested so far have shown efficacy in preventing valvular fibrocalcific remodelling. It is therefore essential to improve our understanding of the mechanisms involved in the pathological process if we are to find new, effective therapies. The purpose of this review is to (i) summarize our current knowledge of the mechanisms by which CKD and related therapies affect valvular cell activity, (ii) present the latest therapeutic targets identified in preclinical studies, and (iii) discuss the most recent clinical trials evaluating the efficacy of therapies aimed at preventing valvular calcification in CKD.

Keywords: aortic valve calcification; chronic kidney disease; mitral valve calcification.

Figure 1:

Overview of the main mechanisms leading to valvular remodelling. Among the main mechanisms involved in AV remodelling, shear stress can induce endothelial damage and TGF-β accumulation within the valvular tissue. TGF-β promotes the EndMT of VECs as well as the transformation of qVICs into myofibroblast-activated VICs (aVICs), which can secrete collagen and promote valvular fibrosis and thickening. VECs dysfunction favours the infiltration of oxidized LDL and inflammatory cells, including macrophages, thereby promoting foam cell formation and initiating a process that resembles vascular atherosclerosis. Macrophage secretion of TNF-α and IL-1β promotes the deactivation of aVICs. Subsequent exposure to IL-6 promotes their osteogenic transition towards obVICs capable of promoting the mineralization process. αSMA, α-smooth muscle actin; MФ, macrophage; oxLDL, oxidized LDL; ALP: alkaline phosphatase.

Figure 2:

Main mechanisms by which CKD-related disorders promote VC. α-SMA, α-smooth muscle actin. GAA, guanidine acetic acid; HCY, homocysteine; IS, indoxyl-sulfate; PCS, paracresyl sulfate; Pi, inorganic phosphate; PPi, pyrophosphate; MG, methylguanidine; ALP: alkaline phosphatase.