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Nutrients
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Vitamin K in Chronic Disease and Human Health
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Vitamin K in Chronic Disease and Human Health

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Micronutrients and Human Health".

Deadline for manuscript submissions: closed (10 September 2021) | Viewed by 22292

Special Issue Editors

Dr. Evangelia Dounousi

E-Mail Website
Guest Editor
Department of Nephrology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
Interests: kidney disease; biomarkers; oxidative stress
Special Issues, Collections and Topics in MDPI journals
Dr. Vassilios Liakopoulos

E-Mail Website
Guest Editor
2nd Department of Nephrology, AHEPA Hospital, Aristotle University of Thessaloniki, GR54636 Thessaloniki, Greece
Interests: chronic kidney disease; cardiovascular disease; vascular calcification; diabetes mellitus; hemodialysis; peritoneal dialysis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Vitamin K is a complex of fat-soluble vitamins that functions as a cofactor for the enzyme γ-glutamyl carboxylase, which is required for the activation of several essential vitamin K-dependent proteins containing carboxyglutamic acid residues. Vitamin K has a plethora of potential properties, including the prevention and treatment of arterial calcifications, coronary heart disease, and cancer, the improvement of bone strength, the reduction of fractures risk, as well as the improvement of insulin sensitivity. Additionally, vitamin K may play a vital role in the stabilization of INR control for patients on warfarin.

The adequate dietary requirement for vitamin K is 90 µg daily for women and 120 µg daily for men. Considering vitamin K wide availability, its deficiency is usually associated with malabsorption states or deregulation of the gut microbiota by antibiotics. The clinical consequences of vitamin K deficiency are ascribed to the impairment of the coagulation cascade. Unfortunately, there are inherent difficulties in determining vitamin K status or body stores.

Vitamin K-dependent carboxylase is an integral membrane protein, requiring the hydroquinone form of vitamin K to convert glutamic acid residues to gamma-carboxyglutamic acid. The enzyme epoxide reductase converts vitamin K epoxide, also produced during this process, to its active form. Gamma-carboxyglutamic acid bestows metal binding properties on vitamin K-dependent proteins, which, following the addition of calcium ions, undergo a structural transition that leads to the exposure of a phospholipid binding site. The clotting factors that require gamma-carboxyglutamic acid for their function include prothrombin (factor II) and factors VII, IX, and X, as well as protein C and protein S.

Additionally, vitamin K is required for osteocalcin carboxylation, thus regulating bone mineral formation and growth. Evidence suggests that it promotes the transition of osteoblasts to osteocytes and, on the other hand, hinders the process of osteoclastogenesis. With regard to blood vessels, vitamin K prevents the formation of hydroxyapatite, inhibits apoptosis in vascular smooth muscle cells by increasing growth arrest-specific gene 6, and reduces the differentiation of vascular smooth muscle cells to osteoblasts.

The impact of vitamin K on hemostasis, bone formation, and prevention of vascular calcification remains a subject of ongoing investigation. Although there are data which suggest that long-term vitamin K supplementation might beneficially affect cardiovascular disease, bone density, fracture risk, and insulin resistance, the current evidence remains controversial, and further robust data are needed to elucidate the efficacy, safety, and possible side effects of vitamin K supplementation.

This Special issue invites original research and review papers on the role of “Vitamin K in Chronic Disease and Human Health”.

Dr. Evangelia Dounousi
Dr. Vassilios Liakopoulos
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Nutrients is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Vitamin K-dependent protein 
  • Vitamin K supplementation 
  • Hemostasis 
  • Insulin resistance 
  • Bone formation 
  • Bone fracture 
  • Vascular calcification 
  • Cardiovascular disease 
  • Warfarin

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 184 KiB  
Editorial
Editorial for the Special Issue “Vitamin K in Chronic Disease and Human Health”
by Evangelia Dounousi and Vasillios Liakopoulos
Nutrients 2022, 14(13), 2595; https://doi.org/10.3390/nu14132595 - 23 Jun 2022
Cited by 1 | Viewed by 1852
Abstract
Vitamin K and its derivatives represent a complex of fat-soluble vitamins, playing a major role in the regulation of a large number of physiologic processes required for optimal homeostasis [...] Full article
(This article belongs to the Special Issue Vitamin K in Chronic Disease and Human Health)

Research

Jump to: Editorial, Review, Other

12 pages, 1062 KiB  
Article
Vitamin K Effects on Gas6 and Soluble Axl Receptors in Intensive Care Patients: An Observational Screening Study
by Ulf Schött, Cecilia Augustsson, Luukas Lilover, Caroline Ulfsdotter Nilsson, Louise Walther-Sturesson and Thomas Kander
Nutrients 2021, 13(11), 4101; https://doi.org/10.3390/nu13114101 - 16 Nov 2021
Cited by 5 | Viewed by 3236
Abstract
Growth arrest-specific gene 6 protein (Gas6) is avitamin K-dependent tissue bound protein. Gas6 has been shown to promote growth and therapy resistance among different types of cancer as well as thromboembolism. The aim of this prospective screening study: ClinicalTrials.gov; Identifier: NTC3782025, was to [...] Read more.
Growth arrest-specific gene 6 protein (Gas6) is avitamin K-dependent tissue bound protein. Gas6 has been shown to promote growth and therapy resistance among different types of cancer as well as thromboembolism. The aim of this prospective screening study: ClinicalTrials.gov; Identifier: NTC3782025, was to evaluate the effects of intravenously administered vitamin K1 on Gas6 and its soluble (s)Axl receptor plasma levels in intensive care patients. Vitamin K1 was intravenously injected in non-warfarin treated patients with prolonged Owren prothrombin time international normalized ratio (PT-INR) > 1.2 and blood samples were retrieved before and 20–28 h after injection. Citrate plasma samples from 52 intensive care patients were analysed for different vitamin K dependent proteins. There was a significant, but small increase in median Gas6. Only one patient had a large increase in sAxl, but overall, no significant changes in sAxl Gas6 did not correlate to PT-INR, thrombin generation assay, coagulation factors II, VII, IX and X, but to protein S and decarboxylated matrix Gla protein (dp-ucMGP). In conclusion, there was a small increase in Gas6 over 20–28 h. The pathophysiology and clinical importance of this remains to be investigated. To verify a true vitamin K effect, improvement of Gas6 carboxylation defects needs to be studied. Full article
(This article belongs to the Special Issue Vitamin K in Chronic Disease and Human Health)
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11 pages, 1058 KiB  
Article
Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk
by Nikolas Rapp, Vincent M. Brandenburg, Nadine Kaesler, Stephan J. L. Bakker, Robert Stöhr, Alexander Schuh, Pieter Evenepoel and Leon J. Schurgers
Nutrients 2021, 13(10), 3490; https://doi.org/10.3390/nu13103490 - 1 Oct 2021
Cited by 9 | Viewed by 3219
Abstract
Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk [...] Read more.
Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients. Full article
(This article belongs to the Special Issue Vitamin K in Chronic Disease and Human Health)
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13 pages, 1903 KiB  
Article
Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies
by Daan Kremer, Dion Groothof, Charlotte A. Keyzer, Coby Eelderink, Tim J. Knobbe, Adrian Post, Marco van Londen, Michele F. Eisenga, TransplantLines Investigators, Leon J. Schurgers, Stefan P. Berger, Martin H. de Borst and Stephan J. L. Bakker
Nutrients 2021, 13(9), 3069; https://doi.org/10.3390/nu13093069 - 31 Aug 2021
Cited by 7 | Viewed by 2818
Abstract
High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend [...] Read more.
High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 mL/min/1.73 m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman’s ρ 0.54, 0.60, and −0.54, respectively, p < 0.001 for all), and each 10 mL/min/1.73 m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research. Full article
(This article belongs to the Special Issue Vitamin K in Chronic Disease and Human Health)
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12 pages, 514 KiB  
Article
Intravenous Vitamin K1 for the Correction of Prolonged Prothrombin Times in Non-Bleeding Critically Ill Patients: A Prospective Observational Study
by Sofia Dahlberg, Ulf Schött, Emilia Ängeby Eriksson, Yllnor Tahirsylaj, Leon Schurgers and Thomas Kander
Nutrients 2021, 13(8), 2580; https://doi.org/10.3390/nu13082580 - 27 Jul 2021
Cited by 8 | Viewed by 2971
Abstract
The aim of this study was to evaluate the effects of vitamin K1 on various vitamin K-dependent proteins in critically ill patients with prolonged Owren PT. We included critically ill non-bleeding adult patients without liver failure or anticoagulation treatment, with Owren PT > [...] Read more.
The aim of this study was to evaluate the effects of vitamin K1 on various vitamin K-dependent proteins in critically ill patients with prolonged Owren PT. We included critically ill non-bleeding adult patients without liver failure or anticoagulation treatment, with Owren PT > 1.2, who were prescribed intravenous vitamin K1. Blood was drawn at baseline and at 20–28 h after vitamin K1 administration. At both time points, we measured various vitamin K-dependent proteins and coagulation assays. ClinicalTrials.gov; Identifier: NTC3782025. In total, 52 patients were included. Intravenous vitamin K1 reduced Owren PT, Quick PT, protein induced by vitamin K absence/antagonist-II and desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), but not to normal levels. Concomitantly, there were increases in thrombin generation and the activity of coagulation factors II, VII, IX and X that was only counteracted with a small increase in Protein C activity. In conclusion, the results suggest that vitamin K1 strengthens coagulation as measured by PT decrease and increases in the activity of vitamin K-dependent clotting factors and thrombin generation. The decreased dp-ucMGP, and its potential positive short- and long-term non-coagulative effects, merits further research. Full article
(This article belongs to the Special Issue Vitamin K in Chronic Disease and Human Health)
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Review

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14 pages, 329 KiB  
Review
Vitamin K Supplementation for Prevention of Vascular Calcification in Chronic Kidney Disease Patients: Are We There Yet?
by Stefanos Roumeliotis, Anila Duni, Vasilios Vaios, Athanasios Kitsos, Vassilios Liakopoulos and Evangelia Dounousi
Nutrients 2022, 14(5), 925; https://doi.org/10.3390/nu14050925 - 22 Feb 2022
Cited by 18 | Viewed by 4434
Abstract
Chronic Kidney Disease (CKD) patients are at high risk of presenting with arterial calcification or stiffness, which confers increased cardiovascular mortality and morbidity. In recent years, it has become evident that VC is an active process regulated by various molecules that may act [...] Read more.
Chronic Kidney Disease (CKD) patients are at high risk of presenting with arterial calcification or stiffness, which confers increased cardiovascular mortality and morbidity. In recent years, it has become evident that VC is an active process regulated by various molecules that may act as inhibitors of vessel mineralization. Matrix Gla Protein (MGP), one the most powerful naturally occurring inhibitors of arterial calcification, requires vitamin K as a co-factor in order to undergo post-translational γ-carboxylation and phosphrorylation and become biologically active. The inactive form of MGP (dephosphorylated, uncarboxylated dp-ucMGP) reflects vitamin K deficiency and has been repeatedly associated with surrogate markers of VC, stiffness, and cardiovascular outcomes in CKD populations. As CKD is a state of progressive vitamin K depletion and VC, research has focused on clinical trials aiming to investigate the possible beneficial effects of vitamin K in CKD and dialysis patients. In this study, we aim to review the current evidence regarding vitamin K supplementation in uremic patients. Full article
(This article belongs to the Special Issue Vitamin K in Chronic Disease and Human Health)

Other

3 pages, 210 KiB  
Reply
Reply to Janssen et al. Comment on “Kremer et al. Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies. Nutrients 2021, 13, 3069”
by Daan Kremer, Dion Groothof, Charlotte A. Keyzer, Coby Eelderink, Tim J. Knobbe, Adrian Post, Marco van Londen, Michele F. Eisenga, TransplantLines Investigators, Leon J. Schurgers, Stefan P. Berger, Martin H. de Borst and Stephan J. L. Bakker
Nutrients 2022, 14(12), 2440; https://doi.org/10.3390/nu14122440 - 13 Jun 2022
Cited by 1 | Viewed by 1417
Abstract
We read with interest the comment by Janssen et al. [...] Full article
(This article belongs to the Special Issue Vitamin K in Chronic Disease and Human Health)
2 pages, 184 KiB  
Comment
Comment on Kremer et al. Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies. Nutrients 2021, 13, 3069
by Rob Janssen, Jona Walk and Cees Vermeer
Nutrients 2022, 14(12), 2439; https://doi.org/10.3390/nu14122439 - 13 Jun 2022
Cited by 1 | Viewed by 1392
Abstract
In the article “Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies”, Kremer et al. [...] Full article
(This article belongs to the Special Issue Vitamin K in Chronic Disease and Human Health)
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