Written by Jasna Trbojevic-Stankovic
Reviewed by Jürgen Floege
Vitamin K refers to a group of liposoluble vitamins that play an important role in blood clotting, bone metabolism and regulation of calcium levels. Its role in the coagulation process (germ. Koagulation – hence the K) was first observed by the Danish scientist, Henrik Dam, in 1929, while its chemical structure was discovered by Edward Adelbert Doisy in 1943. Still, it was not until 1974 that the exact function of vitamin K in the body was recognized. Although there are several different types of vitamin K, the two most often found in the human diet are vitamin K1 and vitamin K2. Vitamin K1, also called phylloquinone, is mostly found in plant foods, such as leafy green vegetables. Vitamin K2 is found in fermented foods and animal products, and is also produced by gut bacteria. It has several subtypes, called menaquinones (MKs), that are named by the length of their side chain. Unlike phylloquinone, menaquinone exhibits actions outside of the liver.
Recently accumulated evidence that vitamin K deficiency is associated with vascular calcification has sparked interest in possible implications of its supplementation in chronic renal disease (CKD) patients (1). It started over a decade ago when a relationship has been confirmed between the dietary intake of menaquinone and a reduced risk of coronary artery disease (2). Later on, high dietary menaquinone intake was associated with reduced coronary calcification and the incidence of coronary artery disease in women (3, 4). Newer studies have shown that vitamin K is essential for activating several proteins involved in the calcification process. These include the Matrix-Gla protein (MGP) and the Gas-6 protein, which are both expressed in vascular smooth muscle cells end exhibit a high affinity binding to calcium ions (1, 5, 6). Although on a molecular level its mechanism of action is not completely understood, MGP is generally accepted to be a potent inhibitor of arterial calcification and its activity depends on vitamin K (5, 7). Thus, when vitamin K antagonist, warfarin, is administered, it induces significant calcification with resulting functional cardiovascular damage in mice models (8).
All these observations may have significant implications for end-stage renal disease (ESRD) patients since vitamin K intake is commonly deficient in patients on hemodialysis (HD) due to dietary restrictions (9). This deficiency impairs MGP activation by vitamin K-dependent carboxylation, thus contributing to increased vascular calcification and mortality rate (10, 11). Another possible cause of functional vitamin K deficiency in dialyzed patients may be reduced activity of the vitamin K cycle enzyme γ-carboxylase as observed in uremic mice (Figure 1), (12, 13). Auspiciously, pharmacological vitamin K supplementation restores the vitamin K cycle and slows the progression of soft tissue calcification in experimental uremia (12, 14). Further investigation of the possible effect of warfarin treatment on vitamin-K dependent calcification processes showed that warfarin induced significant calcification with resulting functional cardiovascular damage in a mouse model. This effect was reversed with vitamin K2 supplementation (8).