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• W2020125823 abstract "The purpose of this review is to summarize currently available evidence implicating vitamin K in the pathogenesis of vascular calcification (VC), in particular arterial medial calcification. In doing so, we try to provide a rationale for an interventional clinical study testing whether vitamin K supplementation can retard VC or even affect cardiovascular mortality in chronic kidney disease patients. Additionally, we wish to give an overview of the current literature indicating potential adverse effects of long-term vitamin K antagonists in this population. The purpose of this review is to summarize currently available evidence implicating vitamin K in the pathogenesis of vascular calcification (VC), in particular arterial medial calcification. In doing so, we try to provide a rationale for an interventional clinical study testing whether vitamin K supplementation can retard VC or even affect cardiovascular mortality in chronic kidney disease patients. Additionally, we wish to give an overview of the current literature indicating potential adverse effects of long-term vitamin K antagonists in this population. Cardiovascular disease underlies 50% of all deaths in chronic kidney disease (CKD) patients. Vascular calcifications (VCs), that is, atherosclerotic intima calcifications and calcification of media, are major contributors to mortality. Although atherosclerotic lesions are cholesterol- and lipid-associated, medial calcification is associated with diabetes, uremia, and disturbed mineral metabolism. Medial calcifications often underlie VC in CKD patients and non-invasive distinction between intimal and medial calcification is difficult and both may occur simultaneously.1.Amann K. Media calcification and intima calcification are distinct entities in chronic kidney disease.Clin J Am Soc Nephrol. 2008; 3: 1599-1605Crossref PubMed Scopus (260) Google Scholar It is assumed that medial calcification increases vascular stiffness resulting in left ventricular hypertrophy, a major contributor to mortality. Accordingly, any detection of VC has been associated with cardiovascular mortality.2.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1433) Google Scholar, 3.Block G.A. Raggi P. Bellasi A. et al.Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Abstract Full Text Full Text PDF PubMed Scopus (640) Google Scholar, 4.Lehto S. Niskanen L. Suhonen M. et al.Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus.Arterioscler Thromb Vasc Biol. 1996; 16: 978-983Crossref PubMed Scopus (466) Google Scholar Numerous factors influence VC development.5.Ketteler M. Schlieper G. Floege J. Calcification and cardiovascular health: new insights into an old phenomenon.Hypertension. 2006; 47: 1027-1034Crossref PubMed Scopus (93) Google Scholar This review focuses on the major local calcification inhibitor in the arterial media, the matrix-Gla protein (MGP), a vitamin K-dependent protein. Accumulating evidence suggests that diet-induced vitamin K deficiency or its antagonism may induce VC. Vitamin K supplementation is a safe approach but whether it can reduce CKD complications, will require an interventional trial. Moreover, these data imply that vitamin K antagonists in CKD patients should only be given after a thorough assessment of its benefits. Matrix-Gla protein, an approximately 10 kDa protein, is produced and secreted by osteoclasts, chondrocytes, and vascular smooth muscle cells (VSMCs) of the arterial media. MGP needs to undergo post-translational γ-glutamyl carboxylation of five glutamate residues to achieve full biological activity. This activation depends on the availability of vitamin K and thereby resembles the biology of the coagulation factors II, VII, IX, X and proteins C and S. During vitamin K deficiency MPG is not activated, under-carboxylated MGP (ucMGP) is formed. Vitamin K replenishment then leads to the bioactive fully carboxylated MGP (cMGP). Complete absence of MGP in MGP−/− mice led to disturbed bone mineralization and the animals all died at about 8 weeks after birth because of the rupture of a severely calcified aorta.6.Luo G. Ducy P. McKee M.D. et al.Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein.Nature. 1997; 386: 78-81Crossref PubMed Scopus (1647) Google Scholar In humans, a loss-of-function mutation within the MGP gene is responsible for the Keutel syndrome, which among others is characterized by abnormal cartilage calcification and accelerated calcification of the aorta as well as coronary and cerebral arteries.7.Meier M. Weng L.P. Alexandrakis E. et al.Tracheobronchial stenosis in Keutel syndrome.Eur Respir J. 2001; 17: 566-569Crossref PubMed Scopus (93) Google Scholar To exert its anti-calcification actions, MGP needs to be expressed locally in the vessel wall. Thus, the lethal phenotype of MGP−/− mice was rescued by re-expressing MGP in arterial VSMCs, but not by an increase in circulating MPG after hepatic overexpression.8.Murshed M. Schinke T. McKee M.D. et al.Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins.J Cell Biol. 2004; 165: 625-630Crossref PubMed Scopus (389) Google Scholar The mechanisms by which MGP prevents arterial calcification are unclear. One of the potential modes of action is a direct inhibition of calcium precipitation and crystallization. This is probably why MGP is enriched in so-called matrix vesicles, which are released by cells such as VSMC. These vesicles are thought to counterbalance potentially harmful high intracellular/intravesicular calcium concentrations.9.Shanahan C.M. Mechanisms of vascular calcification in renal disease.Clin Nephrol. 2005; 63: 146-157Crossref PubMed Scopus (76) Google Scholar Another anti-calcification mechanism is MGP's antagonism of the bone formation inducing bone morphogenetic protein-2.10.Zebboudj A.F. Imura M. Bostrom K. Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2.J Biol Chem. 2002; 277: 4388-4394Crossref PubMed Scopus (288) Google Scholar The development of conformation-specific antibodies against the two MGP subtypes led to studies in rodents and humans, showing that the inactive form, ucMGP, is detected in areas of VC, whereas bioactive cMGP is localized to intact vessel walls11.Schurgers L.J. Teunissen K.J. Knapen M.H. et al.Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification.Arterioscler Thromb Vasc Biol. 2005; 25: 1629-1633Crossref PubMed Scopus (238) Google Scholar (Figure 1). In rodent studies, vitamin K depletion by coumarin resulted in VC of the tunica media,12.Price P.A. Faus S.A. Williamson M.K. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves.Arterioscler Thromb Vasc Biol. 1998; 18: 1400-1407Crossref PubMed Scopus (445) Google Scholar that is, the major site of MGP expression, and this could be prevented by the co-administration of vitamin K2,13.Schurgers L.J. Teunissen K.J. Hamulyak K. et al.Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.Blood. 2007; 109: 3279-3283Crossref PubMed Scopus (212) Google Scholar but not vitamin K1.14.Spronk H.M. Soute B.A. Schurgers L.J. et al.Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats.J Vasc Res. 2003; 40: 531-537Crossref PubMed Scopus (127) Google Scholar Gas6, the product of the gene growth arrest-specific 6 (GAS6), like MGP, depends on carboxylation of glutamate residues to achieve bioactivity. In its active form, Gas6 prevents apoptosis of VSMC.15.Melaragno M.G. Cavet M.E. Yan C. et al.Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt.J Mol Cell Cardiol. 2004; 37: 881-887Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar This is relevant in the context of VC, as apoptotic VSMC can serve as a nidus for calcium phosphate precipitation. After warfarin administration, Gas6 could no longer phosphorylate its receptor Axl, thus blocking the signal cascade of Gas6,16.Konishi A. Aizawa T. Mohan A. et al.Hydrogen peroxide activates the Gas6-Axl pathway in vascular smooth muscle cells.J Biol Chem. 2004; 279: 28766-28770Crossref PubMed Scopus (72) Google Scholar upregulating apoptosis in VSMC, 17.Nakano T. Kawamoto K. Kishino J. et al.Requirement of gamma-carboxyglutamic acid residues for the biological activity of Gas6: contribution of endogenous Gas6 to the proliferation of vascular smooth muscle cells.Biochem J. 1997; 323: 387-392Crossref PubMed Scopus (137) Google Scholar and increasing calcification of VSMC in vitro.18.Collett G.D. Sage A.P. Kirton J.P. et al.Axl/phosphatidylinositol 3-kinase signaling inhibits mineral deposition by vascular smooth muscle cells.Circ Res. 2007; 100: 502-509Crossref PubMed Scopus (61) Google Scholar However, the extent to which reduced Gas6 bioactivity contributes to VC in vivo is currently unknown. Besides its effects on apoptosis, Gas6 also affects inflammation and thrombogenesis (reviewed in19.Fernandez-Fernandez L. Bellido-Martin L. Garcia dF Growth arrest-specific gene 6 (GAS6). An outline of its role in haemostasis and inflammation.Thromb Haemost. 2008; 100: 604-610PubMed Google Scholar). Vitamin K was discovered in the 1930s, when chicken on a fat-free diet developed hemorrhages. Administration of vitamin K was then shown to cure bleeding complications in patients with hepatic and biliary diseases. The group of K vitamins comprises phylloquinone (vitamin K1) and several menaquinones (vitamin K2). The synthetic forms, menadion (vitamin K3) and esterified menadion (vitamin K4), have no importance for normal human food. Vitamin K1 is bound to membranes of the chloroplasts of green leafy vegetables. In contrast, vitamin K2 is relatively rare in Western diets. The main source of dietary vitamin K2 is fermented food such as cheese and in particular the Japanese natto, a fermentation product from soy beans. The mammalian intestinal flora and/or intestinal enterocytes are also able to produce vitamin K2, but the extent to which this contributes to the daily intake is unknown.20.Suttie J.W. The importance of menaquinones in human nutrition.Annu Rev Nutr. 1995; 15: 399-417Crossref PubMed Scopus (179) Google Scholar,21.Thijssen H.H. Vervoort L.M. Schurgers L.J. et al.Menadione is a metabolite of oral vitamin K.Br J Nutr. 2006; 95: 260-266Crossref PubMed Scopus (115) Google Scholar The individual denomination of the several isoforms of menaquinones (MK) is dependent on the number of isoprenoid residues in the side chain. In human food those having 7, 8, or 9 isoprenoid groups are most common. On account of the increased hydrophobic properties of longer side chains, the various isoforms exhibit different half-lives. For example, MK-4 with four isoprenoid groups has a half-life time of 1 h and MK-7 of around 3 days. In mammals, vitamin K serves as a redox partner in cellular metabolism pathways of γ-glutamyl carboxylations, and a recycling mechanism helps to reduce the daily requirement of vitamin K. The vitamin K cycle can be effectively inhibited by coumarins such as warfarin, primarily known as potent coagulation inhibitors (Figure 2). Both vitamin K1 and vitamin K2 catalyze the γ-glutamyl carboxylation of all vitamin K-dependent proteins, including coagulation factors, osteocalcin, and MGP. Osteocalcin, also called bone Gla protein, is exclusively synthesized by osteoblasts and odontoblasts and is a regulator of bone formation. Differences in vitamin K1 and K2 bioactivities result from differences in enzyme affinity and tissue distribution: K2 vitamins have a higher affinity for the enzyme γ-glutamyl carboxylase, which implies that lower concentrations of vitamin K2 are needed to obtain a similar activity of the γ-glutamyl carboxylase compared with vitamin K1. In terms of tissue distribution, vitamin K1 predominantly accumulates in the liver, where it catalyzes the γ-glutamyl carboxylation of the coagulation factors. Vitamin K2 has a more widespread tissue distribution and is also involved in the carboxylation of MGP and osteocalcin. The recommended daily allowance of total vitamin K is 1 μg/kg per d; the estimated daily intake in a Western diet ranges from 60 to 200 μg, of which vitamin K1 constitutes the major part. However, only 10% of K1 is absorbed from food given its tight binding to the chloroplast membranes. There are no exact data on the amount of vitamin K2 intake, but it is assumed that around 10% of the total vitamin K intake is vitamin K2.13.Schurgers L.J. Teunissen K.J. Hamulyak K. et al.Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.Blood. 2007; 109: 3279-3283Crossref PubMed Scopus (212) Google Scholar The mean daily dose is sufficient to maintain a normal coagulation status, but is it unclear whether the dose is sufficient to enable extrahepatic protein carboxylation. Determination of the ratio of extrahepatic carboxylated versus under-carboxylated vitamin K-dependent proteins, such as osteocalcin or MGP, could serve as a biomarker to assess whether vitamin K intake is sufficient. Indeed, with a Western diet, the carboxylation grade of serum osteocalcin is only about 70%, indicating suboptimal vitamin K2 concentrations in extrahepatic organs.11.Schurgers L.J. Teunissen K.J. Knapen M.H. et al.Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification.Arterioscler Thromb Vasc Biol. 2005; 25: 1629-1633Crossref PubMed Scopus (238) Google Scholar,22.Luukinen H. Kakonen S.M. Pettersson K. et al.Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin.J Bone Miner Res. 2000; 15: 2473-2478Crossref PubMed Scopus (167) Google Scholar The percentage of circulating ucMGP in the healthy population is around 40%, again pointing to a relative vitamin K deficiency (Schurgers, unpublished data). In postmenopausal women with osteoporosis vitamin K levels were lower in affected patients than in healthy controls.23.Binkley N.C. Suttie J.W. Vitamin K nutrition and osteoporosis.J Nutr. 1995; 125: 1812-1821Crossref PubMed Scopus (156) Google Scholar Vice versa, in 72,000 women, the risk of hip fractures was significantly lower in patients consuming higher amounts of vitamin K.24.Feskanich D. Weber P. Willett W.C. et al.Vitamin K intake and hip fractures in women: a prospective study.Am J Clin Nutr. 1999; 69: 74-79Crossref PubMed Scopus (376) Google Scholar In double-blind, placebo-controlled clinical trials, bone loss was reduced by 35% with vitamin K1 over a 3-year period25.Braam L.A. Knapen M.H. Geusens P. et al.Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.Calcif Tissue Int. 2003; 73: 21-26Crossref PubMed Scopus (174) Google Scholar and by 100% with vitamin K2.26.Knapen M.H. Schurgers L.J. Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women.Osteoporos Int. 2007; 18: 963-972Crossref PubMed Scopus (157) Google Scholar These studies are of relevance for the present discussion given that increasing degrees of osteoporosis are associated with increasing VC.27.Naves M. Rodriguez-Garcia M. Diaz-Lopez J.B. et al.Progression of vascular calcifications is associated with greater bone loss and increased bone fractures.Osteoporos Int. 2008; 19: 1161-1166Crossref PubMed Scopus (141) Google Scholar However, this area is controversial, as recent data do not confirm such an association.28.Booth S.L. Dallal G. Shea M.K. et al.Effect of vitamin K supplementation on bone loss in elderly men and women.J Clin Endocrinol Metab. 2008; 93: 1217-1223Crossref PubMed Scopus (130) Google Scholar In the Rotterdam trial in 4800 elderly patients, low vitamin K2 intake was associated with a higher incidence of severe aortic calcification and increased mortality.29.Geleijnse J.M. Vermeer C. Grobbee D.E. et al.Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study.J Nutr. 2004; 134: 3100-3105PubMed Google Scholar In a clinical trial in 100 postmenopausal women, the supplementation of vitamin K1 for 3 years improved vascular compliance, distensibility, and intima media thickness compared with placebo.30.Braam L.A. Hoeks A.P. Brouns F. et al.Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study.Thromb Haemost. 2004; 91: 373-380Crossref PubMed Scopus (138) Google Scholar However, a specific link between low vitamin K2 intake leading to accelerated VC through an increase in ucMGP has not been proven so far. Blockade of the vitamin K metabolism with vitamin K antagonists affects skeletal and vascular health as well. In males receiving long-term warfarin, the odds ratio for fractures was 30% higher in comparison with patients without warfarin.31.Gage B.F. Birman-Deych E. Radford M.J. et al.Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2.Arch Intern Med. 2006; 166: 241-246Crossref PubMed Scopus (172) Google Scholar Furthermore, both the prevalence and extent of aortic valve and coronary calcifications increased significantly in patients on coumarin.32.Koos R. Mahnken A.H. Muhlenbruch G. et al.Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography.Am J Cardiol. 2005; 96: 747-749Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar In hemodialysis patients as well long-term use of warfarin was associated with more severe aortic valve calcification.33.Holden R.M. Sanfilippo A.S. Hopman W.M. et al.Warfarin and aortic valve calcification in hemodialysis patients.J Nephrol. 2007; 20: 417-422PubMed Google Scholar Finally, epidemiological studies have identified the treatment with warfarin as a risk factor for calciphylaxis, a severe complication in CKD patients, which is characterized by extensive VC.34.Mehta R.L. Scott G. Sloand J.A. et al.Skin necrosis associated with acquired protein C deficiency in patients with renal failure and calciphylaxis.Am J Med. 1990; 88: 252-257Abstract Full Text PDF PubMed Scopus (192) Google Scholar On account of its lipophilic properties and incorporation into lipoproteins, vitamin K is not supposed to be dialysed. Earlier reports of a vitamin K deficiency in dialysis patients35.Malyszko J. Wolczynski S. Skrzydlewska E. et al.Vitamin K status in relation to bone metabolism in patients with renal failure.Am J Nephrol. 2002; 22: 504-508Crossref PubMed Scopus (19) Google Scholar therefore point to a diminished dietary intake. Thus, as discussed above, a differential assessment of carboxylated versus under-carboxylated vitamin K-dependent proteins may yield better insight into the vitamin K status. Indeed, increased under-carboxylated osteocalcin levels were detected in dialysis patients compared with healthy controls,36.Pilkey R.M. Morton A.R. Boffa M.B. et al.Subclinical vitamin K deficiency in hemodialysis patients.Am J Kidney Dis. 2007; 49: 432-439Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar pointing to subclinical vitamin K deficiency. Data on ucMGP levels in the circulation of CKD patients are more difficult to interpret, which is in line with the experimental observations cited above,8.Murshed M. Schinke T. McKee M.D. et al.Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins.J Cell Biol. 2004; 165: 625-630Crossref PubMed Scopus (389) Google Scholar in which local vascular but not systemically overexpressed MGP is protected from VC. In patients, low rather than high circulating ucMGP was a powerful predictor of coronary artery calcification37.Cranenburg E.C. Vermeer C. Koos R. et al.The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification.J Vasc Res. 2008; 45: 427-436Crossref PubMed Scopus (139) Google Scholar and ucMGP was decreased rather than increased within the serum of CKD patients.38.Hermans M.M. Vermeer C. Kooman J.P. et al.Undercarboxylated matrix GLA protein levels are decreased in dialysis patients and related to parameters of calcium-phosphate metabolism and aortic augmentation index.Blood Purif. 2007; 25: 395-401Crossref PubMed Scopus (53) Google Scholar One explanation for these unexpected findings may be an accumulation of ucMGP within the calcified vessel wall resulting in low circulating levels.38.Hermans M.M. Vermeer C. Kooman J.P. et al.Undercarboxylated matrix GLA protein levels are decreased in dialysis patients and related to parameters of calcium-phosphate metabolism and aortic augmentation index.Blood Purif. 2007; 25: 395-401Crossref PubMed Scopus (53) Google Scholar Alternatively, uncarboxylated Gla proteins are secreted less from the cells, possibly to avoid inactive proteins to enter the tissues. Moreover, besides carboxylation, altered phosphorylation of MGP may, at least in part, influence MGP levels. Three serine residues of MGP are supposed to be phosphorylated, which seems to be important for the secretion of this protein. As a consequence, phosphorylated and dephosphorylated MGP are also detectable, probably resembling immature and mature forms of MGP. Recent findings from Schurgers and colleagues show that the serum levels of phosphorylated ucMGP are inversely associated with calcification scores in patients and thus may reflect the degree of existing VC.37.Cranenburg E.C. Vermeer C. Koos R. et al.The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification.J Vasc Res. 2008; 45: 427-436Crossref PubMed Scopus (139) Google Scholar,39.Cranenburg E.C. Brandenburg V.M. Vermeer C. et al.Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients.Thromb Haemost. 2009; 101: 359-366PubMed Google Scholar On the other hand, dephosphorylated ucMGP is set free more easily in the circulation even in the presence of extensive VC and thus may allow better assessment of the vitamin K status.37.Cranenburg E.C. Vermeer C. Koos R. et al.The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification.J Vasc Res. 2008; 45: 427-436Crossref PubMed Scopus (139) Google Scholar,40.Schurgers L.J. Cranenburg E.C. Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K.Thromb Haemost. 2008; 100: 593-603Crossref PubMed Scopus (220) Google Scholar Taken together, the assessment of MGP may be more complex because of its several modifications and needs further investigation to specify the relevance of each form. At present only scant data are available to answer the above question. The answer clearly awaits interventional outcome studies in CKD patients. The rationale for such studies, that is, to place CKD patients with their excessive cardiovascular risk on Vitamin K is given below. In a study in 190 women, the incidence of fractures was significantly reduced in those supplemented with 45 mg vitamin K2 per day.41.Shiraki M. Shiraki Y. Aoki C. et al.Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis.J Bone Miner Res. 2000; 15: 515-521Crossref PubMed Scopus (339) Google Scholar In another Japanese study, dialysis patients received 45 mg per day vitamin K2 over a 12-month period, which resulted in increased serum levels of carboxylated osteocalcin within 1 month.42.Nakashima A. Yorioka N. Doi S. et al.Effects of vitamin K2 in hemodialysis patients with low serum parathyroid hormone levels.Bone. 2004; 34: 579-583Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar In rodent studies, the therapeutic administration of vitamin K2 resulted in reduced VC (own observations and Schurgers et al.13.Schurgers L.J. Teunissen K.J. Hamulyak K. et al.Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.Blood. 2007; 109: 3279-3283Crossref PubMed Scopus (212) Google Scholar), but confirmation in humans is lacking. However, in a pilot study in 50 dialysis patients we have recently shown that the daily administration of 360 μg vitamin K2 resulted in a significant increase of cMGP as well as osteocalcin (Westenfeld R et al.: ASN Renal Week 2008, Abstract Book). With regard to the safety of vitamin K2 supplements, no relevant side effects have been described so far. In particular, no thromboembolic events or shunt dysfunctions were reported.41.Shiraki M. Shiraki Y. Aoki C. et al.Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis.J Bone Miner Res. 2000; 15: 515-521Crossref PubMed Scopus (339) Google Scholar,42.Nakashima A. Yorioka N. Doi S. et al.Effects of vitamin K2 in hemodialysis patients with low serum parathyroid hormone levels.Bone. 2004; 34: 579-583Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Moreover, vitamin K substitution has been carried out in neonates in Asia and Europe for years with no side effects being observed. On account of its availability for extrahepatic tissues, vitamin K2 should be regarded as the isoform being optimal for supplementation. The optimal dose of vitamin K2 remains to be tested. Isoforms with longer side chains, for example, MK-7, may be the best choice given their half-life. Schurgers et al.13.Schurgers L.J. Teunissen K.J. Hamulyak K. et al.Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.Blood. 2007; 109: 3279-3283Crossref PubMed Scopus (212) Google Scholar showed that 146 μg MK-7 daily significantly increased serum levels of vitamin K2 after 14 days. Vitamin K supplementation in the form of vitamin K2 isoforms may be an easy intervention to counteract the relative vitamin K deficiency observed in particular in dialysis patients. Although such an intervention has been shown to be safe, the optimal daily dosage and the clinical long-term benefits, in particular reduced VC and improved bone mineral density or fracture rates, need to be determined in clinical studies. Vice versa, the above findings indicate that warfarin may not be neutral in the context of VC and larger trials could elucidate the role of warfarin, especially in CKD patients with their high risk for VC. In addition, whether vitamin K2 supplementation is safe and efficacious in preventing VC progress in patients with an absolute indication for long-term vitamin K antagonist therapy remains to be tested." @default.
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• W2020125823 title "Vitamin K deficiency in CKD patients: a modifiable risk factor for vascular calcification?" @default.
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