The Role of Vitamin K in CKD-MBD

Abstract

Purpose of review: We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD).

Recent findings: Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.

Keywords: Bone fractures; Cardiovascular disease; Chronic kidney disease; Inflammation; Vitamin K.

Fig. 1

The sources of vitamin K are different depending on the vitamers. PK can be found mainly in green leafy vegetables (e.g., kale), vegetables in the Brassica genus (e.g., Brussels sprouts, broccoli), fruits (e.g., avocado, kiwi, and green grapes), herbs (e.g., cilantro, parsley), and green and herbal teas. Other dietary sources are plant oils such as soybean, canola, and olive oils. Fermented foods such as fermented butter or cheese, curdled cheese, egg yolk, and beef liver are sources of MKn. Natto, a traditional Japanese soybean-based food produced by fermentation using Bacillus subtilis, is a source of menaquinone-7 (MK-7)

Fig. 2

CKD is characterized by low vitamin K levels, which in turn lead to reduced MGP and c-OC levels. C-MGP determines a reduction in intracellular calcium flux, causing a decreased NFATc1 activity. Low c-MGP leads to a reduced NFATc1 inhibition with increased osteoclast activity. OC, secreted by osteoblasts, plays an essential role in the synthesis and regulation of the bone matrix. The active carboxylated (c-OC) form is mainly involved in bone mineralization allowing the interaction between its calcium-binding Gla residues with hydroxyapatite. OC also acts as an inhibitor of bone mineralization, thus regulating the rate of mineral maturation. Lower vitamin K levels determine a decrease in SXR/PXR activation and a weaker inhibition of NK-kB, leading to reduced osteoblast differentiation and increased osteoclast activity, respectively. Elevated PTH levels contribute to bone loss both by activation of RANKL/RANK axis and by the release of ucOC from the bone matrix. In addition, in CKD-MBD, lower vitamin D levels lead to a reduced OC synthesis in osteoblasts through low VDR activation

Fig. 3

The role of NRF2 signaling and vitamin K in mediating oxidative stress, DNA damage, senescence, and vascular calcification (see the text for the details)