PRESENTED BY
JÜRGEN FLOEGE

Presentation Summary

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).

Figure 1. Vitamin K cycle activity in uremia (12, 15)

Further studies on human subjects confirmed the beneficial effect of phylloquinone supplementation on slowing the progression of pre-existing coronary artery calcification in healthy older adults, and this effect was independent of changes in serum MGP (16). One of the first studies on the effects of vitamin K supplementation in HD patients confirmed that most of them had a functional vitamin K deficiency, but also showed that inactive MGP levels can be decreased markedly by daily vitamin K2 supplementation (17). However, in non-dialysis CKD patients, even though K2 supplementation significantly decreased the levels of calcification promoters, it did not significantly affect the progression of calcification (18). Nevertheless, it should be taken into consideration that this trial included only 42 patients and had only 9 months follow-up. One larger, 12-month prospective, single-center study, which included 99 patients, randomized to receive placebo or vitamin K1, showed a significant reduction of inactive MGP and calcification volume in patients on vitamin K supplementation (19).

The currently ongoing VitaVasK Study is set to analyze whether vitamin K1 supplementation has the same beneficial effect on the progression of coronary and aortic calcification in HD patients as vitamin K2 (20). The study randomized patients to continue on standard care or to receive additional supplementation with 5 mg vitamin K1 orally thrice weekly for 18 months. All participants received a multi-slice computed tomography of the heart and thoracic aorta at baseline and after 12 and 18 months to assess the progression of calcification as the primary endpoint. Secondary endpoints comprise changes in Agatston score, mitral and aortic valve calcification, and major adverse cardiovascular events 3 and 5 years from treatment initiation (20). The trial is expected to finish in July 2020 (Figure 2).

 

Figure 2. The VitaVasK study design (15)

A very recently published Valkyrie study investigated the effect of vitamin K status on vascular calcification progression in 132 patients on HD with atrial fibrillation treated with either vitamin K antagonist, rivaroxaban and vitamin K2, or rivaroxaban alone for 18 months (21). The results showed expected favorable changes in the inactive MGP levels with administration of vitamin K2, but failed to demonstrate clinical effects of these biochemical results. Severe bleeding complications, however, were lower with rivaroxaban than with vitamin K antagonists.

Several studies have failed to demonstrate the positive effect of warfarin on the risk of stroke in dialysis patients with atrial fibrillation, but confirmed its association with a higher risk of bleeding in this population (22). The most recently published meta-analysis on the association between the use of warfarin for atrial fibrillation and outcomes among ESRD patients concluded that warfarin use is associated with no benefit for ischemic stroke incidence or mortality and with a higher risk of hemorrhagic stroke (23). Based on all these data, the proposed clinical reasoning when considering the introduction of warfarin in dialysis patients with atrial fibrillation is presented in Figure 3.

Figure 3. Indications and contraindications for warfarin use in dialysis patients (8, 15, 24, 25)

Non-vitamin K antagonist oral anticoagulants (NOAC) are now widely used in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism. However, their safety and efficacy in dialysis patients are still controversial. The recently terminated RENAL-AF trial, which aimed to assess the effect of apixaban on stroke prophylaxis among HD patients with atrial fibrillation, failed to demonstrate its superiority over warfarin on preventing stroke. However, it did observe a higher rate of nonmajor bleed and cardiovascular death in the study group (26). Similar results were obtained in the yet unpublished study by Mavrakana et al, thus calling for further investigation to shed more light on this matter.

References

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