*4.2. Vitamin K*

Vitamin K is a cofactor for post-translational γ-carboxylation of calcification inhibitors and activators that plays a role in mineralization and osteogenic differentiation of vascular smooth muscle cells. More importantly, in CKD, vitamin K serves for the carboxylation of the calcification inhibitor MGP and the vitamin K-dependent calcium binder osteocalcin [69,70]. Vitamin K deficiency causes reduced carboxylation of uncarboxylated MGP (ucMGP) to carboxylated MGP (cMGP). Therefore, the inhibiting effect of cMGP is attenuated. The inactive form of ucMGP, which is dephosphorylated (dp-ucMGP), can be measured as a representative for the vitamin K status. In medial calcification (Mönckeberg's sclerosis), which is associated with renal disease, MGP is expressed in all calcified areas in human tissue samples [71]. There are two naturally occurring vitamers of vitamin K, that differ in bioavailability and distribution in the human body: vitamin K1 (phylloquinone) and vitamin K2 (menaquinone, MK). While the former is mainly retained in the liver to serve as a cofactor for the carboxylation of clotting factors, circulating vitamin K2 is available for the extrahepatic tissue and the vascular system [72] and thereby is more capable of acting in the vascular calcification process [70]. Due to its bioavailability, the vitamer MK-7 is mainly used in clinical trials [72]. A single-MK-7 treatment, as well as the combination of MK-7 and eicosapentaenoic, reduced the development of vascular calcification in an experimental model of adenine-induced CKD rats (Table 2) [66].

HD patients show low vitamin K intake, accompanied by increased levels of serum dp-ucMGP [73]. One explanation for this result could be the recommendation for CKD patients to avoid phosphate- and potassium-rich food, which often contains vitamin K [74]. Consequently, vitamin K deficiency increases the risk for vascular calcification in already calcification-prone CKD patients. A prospective cohort study of patients in CKD stages 4 to 5D revealed a positive correlation between serum dp-ucMGP levels and aortic calcification (Table 3) [75]. All-cause mortality was higher in patients with dp-ucMGP levels above the median [75]. HD patients did not reveal a positive correlation of the dp-ucMGP levels with the extent of vascular calcification [75]. After adjustment, low dp-cMGP levels were associated with a higher all-cause and CV mortality risk [75]. In a cohort with stable KTR, all-cause mortality was increased in patients in the highest dp-ucMGP quartile compared to the lowest quartile, after adjustment and exclusion of vitamin K antagonists [76].


**Table 3.** Observational studies investigating the role of vitamin K in CKD.

HD: hemodialysis; KTR: kidney transplant recipients; dp-ucMGP: dephosphorylated-uncarboxylated matrix Gla protein; dp-cMGP: dephosphorylated-carboxylated matrix Gla protein.

In vitro studies showed the binding of vitamin K by PB [77]. Therefore, PB inhibit the gastrointestinal uptake of vitamin K2, thus aggravating vitamin K deficiency in CKD patients [78]. In a study, calcium acetate and magnesium carbonate bound to vitamin K2, independent of the presence of phosphate, while sevelamer carbonate did not bind to vitamin K2 in vitro [64]. This could be one additional explanation as to why non-calcium-based PB are favored in the studies mentioned above. Interestingly, the non-calcium-based PB lanthanum bound to vitamin K2 only in the absence of phosphate [78]. In order to investigate the effect of PB on vitamin K deficiency in vivo, a cross-sectional study with HD patients, patients with peritoneal dialysis, and KTR was performed. Dp-ucMGP levels were significantly lower in KTR compared to dialysis patients. No association between the use of any PB and dp-ucMGP was observed, while sevelamer monotherapy was associated with elevated dp-ucMGP levels [79]. This evidence does not fit the in vitro observation that sevelamer did not bind to vitamin K2 [64]. The clinical relevance of the influence of PB on vitamin K deficiency remains unclear.

Clinical interventional trials investigated the effect of vitamin K2 supplementation in CKD patients with vitamin K deficiency (Table 4). In HD patients, MK-7 treatment reduced dp-ucMGP levels, while dp-cMGP did not alter them [75,80,81]. In CKD patients stage 3–5, a combined treatment of MK-7 and vitamin D reduced dp-ucMGP levels and carotid–intima–media thickness, compared to vitamin D therapy only [82]. The CAC score was increased in both groups. Due to the growing interest in vitamin K biology and the role in preventing CV calcification, ongoing randomized controlled trials on vitamin K supplementation in CKD patients are taking place [82]; according to the status update on clinicaltrials.gov, results have ye<sup>t</sup> to be published.


**Table 4.** Interventional studies investigating the effect of vitamin K in CKD.

MK-7: menaquinone-7 (vitamin K2); CAC: coronary artery calcification; Vit.K: vitamin K2; CCA–IMT: common carotid artery–intima media thickness.
