Vitamin D and vascular calcification in chronic kidney disease

Abstract

Vascular calcification is frequently observed and is closely associated with cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular calcification is largely divided into two types. One is atherosclerotic intimal layer calcification and the other is medial layer calcification (Monckeberg's calcification). The latter is more common in patients with CKD than in general population. Evidence is growing that vascular calcification is a regulated active process as well as a passive process resulting from elevated serum phosphate (P) and an increase in the calcium phosphate (Ca × P) product leading to oversaturated plasma. Proving the active process, in vitro studies have demonstrated that the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells is a crucial mechanism in the progression of vascular calcification. Reduction of the activity of systemic and local inhibitors has also been recognized to be important. The link between vitamin D and vascular calcification is complex. Experimental and clinical researches have revealed that both vitamin D excess and vitamin D deficiency have been shown to be associated with vascular calcification in uremic milieu. On the other hand, although there are some biases, recent large observational studies have demonstrated that vitamin D has beneficial effects on the mortality of patients with CKD independent of serum Ca, P, and parathyroid hormone levels, likely due to its activation of the vitamin D receptor in vasculature and cardiac myocytes. Further prospective studies are necessary to evaluate the direct effect of vitamin D on vascular calcification in order to improve the cardiovascular health of patients with CKD.

Introduction

Vascular calcification is categorized into two types: atherosclerotic intimal layer calcification and medial layer calcification. Medial layer calcification (Monckeberg's calcification) is common in patients with chronic kidney disease (CKD) [1], [2]. Vascular smooth muscle cells (VSMCs) have been shown to possess 25-hydroxyvitamin D3-1α hydroxylase [3] and the vitamin D receptor (VDR) [4], [5], [6], [7] indicating that the vitamin D-VDR axis has an important role in VSMC function locally. Besides mineral metabolism, vitamin D possesses several properties also in physiological response including anti-inflammatory actions [8], [9]. In clinical settings, vitamin D excess and deficiency are associated with not only vascular calcification, but also cardiovascular disease, the most common cause of mortality in patients with CKD [10], [11], [12], [13], [14]. Recently, both low and high vitamin D levels have been shown to be associated with vascular calcification (a U-curve relationship) [14]. Several recent observational cohort studies have shown an association of treatment with calcitriol or its analogs and improved survival of patients with CKD [15], [16], [17], [18], [19], [20], [21]. Taking these factors into consideration, the appropriate VDR activation, especially in organs that relate to cardiovascular disease, would be essential in avoiding the increase in mortality of patients with CKD. In this manuscript, we focus on the relationship between vitamin D and vascular calcification especially in uremic milieu.