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Nutrients
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Physiology and Pathology of Vitamin K Intake
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Physiology and Pathology of Vitamin K Intake

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

Deadline for manuscript submissions: closed (30 July 2020) | Viewed by 49970

Special Issue Editors

Dr. Maria Fusaro

E-Mail Website
Guest Editor
1. National Research Council (CNR)—Institute of Clinical Physiology (IFC), Pisa Via G. Moruzzi 1, 56124 Pisa, PI, Italy
2. Department of Medicine, University of Padova Italy, Via Giustiniani 2, 35128 Padova, PD, Italy
Interests: vitamin K; vitamin D; mineral bone disorders, CKD; bone fractures; vascular calcifications; nutrition
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maurizio Gallieni

E-Mail Website
Co-Guest Editor
1. Department of Biomedical and Clinical Sciences, Università di Milano, 20157 Milano, Italy
2. Nephrology Unit, ASST Fatebenefratelli Sacco, 20157 Milano, Italy
Interests: vitamin K; vitamin D; phosphate; chronic kidney disease; nephrolithiasis; electrolyte disorders; peritoneal dialysis; hemodialysis; onconephrology

Special Issue Information

Dear Colleagues,

Vitamin K is characterized by a group of lipophilic vitamers determining post-translational modification of proteins. Vitamin K is mainly known as an agent involved in blood coagulation, maintaining the activity of coagulation factors in the liver, but several additional important functions have been discovered. There are two main forms of vitamin K: vitamin K1 (phylloquinone, found in vegetables) and vitamin K2 (menaquinone, produced by bacteria in the intestine and in fermented foods), both of which act as co-enzymes of g-glutamyl-carboxylase (GGCX), transforming vitamin K-dependent proteins (VKDPs) from the undercarboxylated into the carboxylated form. Vitamin K stores are limited in humans, but the vitamers can be recycled. Vitamin K1 is principally transported to the liver, regulating the production of coagulation factors. Vitamin K2, instead, also reaches extrahepatic tissues, such as bone and arteries, regulating the activity of Osteocalcin (Bone Gla-protein: BGP) and Matrix Gla-protein (MGP), respectively. Furthermore, vitamin K has been also identified as a ligand of the nuclear steroid and xenobiotic receptor (SXR) (in murine species, Pregnane X Receptor: PXR), expressed in osteoblasts. Several studies have highlighted a potential role of an adequate vitamin K intake in the prevention of bone and vascular diseases, both in the general population and in patients with chronic kidney disease (CKD): vitamin K repletion may potentially decrease morbidity and mortality and randomized studies should be planned to verify this hypothesis. Another possible role of vitamin K could be protective activity against some cancer types (e.g., hepatocellular carcinoma, prostate). These topics will be addressed in this Special Issue highlighting the biological functions associated to an adequate intake of vitamin K, as well as their abnormalities in case of vitamin K deficiency, in the general population and in CKD patients.

Dr. Maria Fusaro
Prof. Maurizio Gallieni
Guest Editors

Manuscript Submission Information

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Keywords

  • Xenobiotic Receptor (SXR), Pregnane X Receptor (PXR)
  • Vitamin K-Dependent Proteins (VKDPs)
  • Osteoporosis
  • Mineral bone disorders
  • Bone fractures
  • Cardiovascular disease
  • Chronic Kidney Disease (CKD)
  • Dialysis
  • Phosphate binders
  • Cancer

Published Papers (7 papers)

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Research

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10 pages, 554 KiB  
Article
Vitamin K Intake in Chronic Stroke: Implications for Dietary Recommendations
by Chad Wessinger, Charlene Hafer-Macko and Alice S. Ryan
Nutrients 2020, 12(10), 3059; https://doi.org/10.3390/nu12103059 - 06 Oct 2020
Cited by 3 | Viewed by 3606
Abstract
Previous research has identified a possible association between vitamin K intake and cardiometabolic disease. This could mean that the assessment of vitamin K intake is a meaningful tool when monitoring individuals with preexisting cardiovascular disease. Sixty chronic stroke survivors (men and women, body [...] Read more.
Previous research has identified a possible association between vitamin K intake and cardiometabolic disease. This could mean that the assessment of vitamin K intake is a meaningful tool when monitoring individuals with preexisting cardiovascular disease. Sixty chronic stroke survivors (men and women, body mass index (BMI) 30.36 ± 6.61 kg/m2, age 61.7 ± 7.2 years) completed food records which were analyzed for energy, macronutrient, micronutrient, and food group servings. Participants were divided into two groups: below vitamin K recommendation (BEL, n = 49) and met vitamin K recommendation (MET, n = 11). Energy and macronutrient intake did not differ between groups (all p > 0.127). Vegetable intake was higher in the MET group (p = 0.0001). Vitamin K intake was higher in the MET group (p = 0.0001). Calcium (p = 0.003), vitamin A (p = 0.007), and vitamin E (p = 0.005) intakes were higher in the MET group. There were no differences in sodium, potassium, vitamin D, vitamin C, and iron intakes between groups (all p > 0.212). In this sample of chronic stroke survivors, 82% reported consuming below the Dietary Reference Intake (DRI) for vitamin K. Given that the majority of this study population did not reach the DRI for vitamin K, it is advisable to promote the adequate intake of food rich in vitamin K. Further work is needed to determine the significance of low vitamin K intake in this population. Full article
(This article belongs to the Special Issue Physiology and Pathology of Vitamin K Intake)
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8 pages, 603 KiB  
Article
Causes of Vitamin K Deficiency in Patients on Haemodialysis
by Signe Wikstrøm, Katrine Aagaard Lentz, Ditte Hansen, Lars Melholt Rasmussen, Jette Jakobsen, Henrik Post Hansen and Jens Rikardt Andersen
Nutrients 2020, 12(9), 2513; https://doi.org/10.3390/nu12092513 - 20 Aug 2020
Cited by 8 | Viewed by 3579
Abstract
Background: A low vitamin K status is common in patients on haemodialysis, and this is considered one of the reasons for the accelerated atherosclerosis in these patients. The vitamin is essential in activation of the protein Matrix Gla Protein (MGP), and the inactive [...] Read more.
Background: A low vitamin K status is common in patients on haemodialysis, and this is considered one of the reasons for the accelerated atherosclerosis in these patients. The vitamin is essential in activation of the protein Matrix Gla Protein (MGP), and the inactive form, dp-ucMGP, is used to measure vitamin K status. The purpose of this study was to investigate possible underlying causes of low vitamin K status, which could potentially be low intake, washout during dialysis or inhibited absorption capacity. Moreover, the aim was to investigate whether the biomarker dp-ucMGP is affected in these patients. Method: Vitamin K intake was assessed by a Food Frequency Questionnaire (FFQ) and absorption capacity by means of D-xylose testing. dp-ucMGP was measured in plasma before and after dialysis, and phylloquinine (vitamin K1) and dp-ucMGP were measured in the dialysate. Changes in dp-ucMGP were measured after 14 days of protein supplementation. Results: All patients had plasma dp-ucMGP above 750 pmol/L, and a low intake of vitamin K. The absorption capacity was normal. The difference in dp-ucMGP before and after dialysis was −1022 pmol/L (p < 0.001). Vitamin K1 was not present in the dialysate but dp-ucMGP was at a high concentration. The change in dp-ucMGP before and after protein supplementation was −165 pmol/L (p = 0.06). Conclusion: All patients had vitamin K deficiency. The reason for the low vitamin K status is not due to removal of vitamin K during dialysis or decreased absorption but is plausibly due to a low intake of vitamin K in food. dp-ucMGP is washed out during dialysis, but not affected by protein intake to a clinically relevant degree. Full article
(This article belongs to the Special Issue Physiology and Pathology of Vitamin K Intake)
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Review

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13 pages, 623 KiB  
Review
Vitamin K and Osteoporosis
by Maria Fusaro, Giuseppe Cianciolo, Maria Luisa Brandi, Serge Ferrari, Thomas L. Nickolas, Giovanni Tripepi, Mario Plebani, Martina Zaninotto, Giorgio Iervasi, Gaetano La Manna, Maurizio Gallieni, Roberto Vettor, Andrea Aghi, Lorenzo Gasperoni, Sandro Giannini, Stefania Sella and Angela M. Cheung
Nutrients 2020, 12(12), 3625; https://doi.org/10.3390/nu12123625 - 25 Nov 2020
Cited by 61 | Viewed by 12087
Abstract
Vitamin K acts as a coenzyme of carboxylase, catalyzing the carboxylation of several vitamin K dependent proteins. Beyond its well-known effects on blood coagulation, it also exerts relevant effects on bone and the vascular system. In this review, we point out the relevance [...] Read more.
Vitamin K acts as a coenzyme of carboxylase, catalyzing the carboxylation of several vitamin K dependent proteins. Beyond its well-known effects on blood coagulation, it also exerts relevant effects on bone and the vascular system. In this review, we point out the relevance of an adequate vitamin K intake to obtain sufficient levels of carboxylated (active form) vitamin K dependent proteins (such as Osteocalcin and matrix Gla protein) to prevent bone health. Another bone-related action of Vitamin K is being a ligand of the nuclear steroid and xenobiotic receptor (SXR). We also discuss the recommended intake, deficiency, and assessment of vitamin K. Furthermore, we review the few available studies that have as pre-specified outcome bone fractures, indicating that we need more clinical studies to confirm that vitamin K is a potential therapeutic agent for bone fractures. Full article
(This article belongs to the Special Issue Physiology and Pathology of Vitamin K Intake)
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25 pages, 681 KiB  
Review
Vitamin K Supplementation for the Prevention of Cardiovascular Disease: Where Is the Evidence? A Systematic Review of Controlled Trials
by Caitlyn Vlasschaert, Chloe J. Goss, Nathan G. Pilkey, Sandra McKeown and Rachel M. Holden
Nutrients 2020, 12(10), 2909; https://doi.org/10.3390/nu12102909 - 23 Sep 2020
Cited by 23 | Viewed by 8423
Abstract
Matrix gla protein (MGP) is an important vitamin K-dependent inhibitor of vascular calcification. High levels of uncarboxylated, dephosphorylated MGP have been associated with vascular calcification and are responsive to vitamin K treatment. In this systematic review, we summarize the available evidence examining whether [...] Read more.
Matrix gla protein (MGP) is an important vitamin K-dependent inhibitor of vascular calcification. High levels of uncarboxylated, dephosphorylated MGP have been associated with vascular calcification and are responsive to vitamin K treatment. In this systematic review, we summarize the available evidence examining whether vitamin K supplementation improves surrogate measures of cardiovascular disease including artery and valve calcification, atherosclerosis and artery stiffening. Data from controlled trials of adults were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science Core Collection. We identified nine randomized controlled trials for review, including trials of vitamin K1 or vitamin K2 supplementation, that assessed a surrogate measure of cardiovascular disease including arterial calcification, atherosclerosis or arterial stiffening. For each trial, the risk of bias was assessed applying Cochrane Collaboration methodology. The findings indicate that vitamin K does not consistently prevent progression of calcification, atherosclerosis or arterial stiffness. There may be some benefit in people with calcification at study entry. Studies were heterogenous, with relatively short follow-up and outcome measures were varied. While vitamin K supplementation clearly improves the carboxylation of dephosphoylated MGP, its role in mitigating vascular calcification is uncertain, based on current evidence. Full article
(This article belongs to the Special Issue Physiology and Pathology of Vitamin K Intake)
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13 pages, 568 KiB  
Review
Vitamin K and Kidney Transplantation
by Maria Fusaro, Laura Cosmai, Pieter Evenepoel, Thomas L. Nickolas, Angela M. Cheung, Andrea Aghi, Giovanni Tripepi, Mario Plebani, Giorgio Iervasi, Roberto Vettor, Martina Zaninotto, Maura Ravera, Marina Foramitti, Sandro Giannini, Stefania Sella and Maurizio Gallieni
Nutrients 2020, 12(9), 2717; https://doi.org/10.3390/nu12092717 - 05 Sep 2020
Cited by 8 | Viewed by 3243
Abstract
The assessment of the vitamin K status and its effects on clinical outcomes in kidney transplantation (KT) patients has sparked interest, but it is still largely unfulfilled. In part, this is due to difficulties in laboratory measurements of vitamin K, especially K2 vitamers. [...] Read more.
The assessment of the vitamin K status and its effects on clinical outcomes in kidney transplantation (KT) patients has sparked interest, but it is still largely unfulfilled. In part, this is due to difficulties in laboratory measurements of vitamin K, especially K2 vitamers. Vitamin K status is currently best assessed by measuring undercarboxylated vitamin-K-dependent proteins. The relative contribution of vitamin K1 and K2 to the health status of the general population and CKD (chronic kidney disease) patients, including KT patients, is also poorly studied. Through a complete and first review of the existing literature, we summarize the current knowledge of vitamin K pathophysiology and its potential role in preventing KT complications and improving organ survival. A specific focus is placed on cardiovascular complications, bone fractures, and the relationship between vitamin K and cancer. Vitamin K deficiency could determine adverse outcomes, and KT patients should be better studied for vitamin K assessment and modalities of effective therapeutic approaches. Full article
(This article belongs to the Special Issue Physiology and Pathology of Vitamin K Intake)
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13 pages, 781 KiB  
Review
Vitamin K2 Needs an RDI Separate from Vitamin K1
by Asim Cengiz Akbulut, Angelina Pavlic, Ploingarm Petsophonsakul, Maurice Halder, Katarzyna Maresz, Rafael Kramann and Leon Schurgers
Nutrients 2020, 12(6), 1852; https://doi.org/10.3390/nu12061852 - 21 Jun 2020
Cited by 46 | Viewed by 13451
Abstract
Vitamin K and its essential role in coagulation (vitamin K [Koagulation]) have been well established and accepted the world over. Many countries have a Recommended Daily Intake (RDI) for vitamin K based on early research, and its necessary role in the activation of [...] Read more.
Vitamin K and its essential role in coagulation (vitamin K [Koagulation]) have been well established and accepted the world over. Many countries have a Recommended Daily Intake (RDI) for vitamin K based on early research, and its necessary role in the activation of vitamin K-dependent coagulation proteins is known. In the past few decades, the role of vitamin K-dependent proteins in processes beyond coagulation has been discovered. Various isoforms of vitamin K have been identified, and vitamin K2 specifically has been highlighted for its long half-life and extrahepatic activity, whereas the dietary form vitamin K1 has a shorter half-life. In this review, we highlight the specific activity of vitamin K2 based upon proposed frameworks necessary for a bioactive substance to be recommended for an RDI. Vitamin K2 meets all these criteria and should be considered for a specific dietary recommendation intake. Full article
(This article belongs to the Special Issue Physiology and Pathology of Vitamin K Intake)
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15 pages, 696 KiB  
Review
Current Therapy in CKD Patients Can Affect Vitamin K Status
by Mario Cozzolino, Giuseppe Cianciolo, Manuel Alfredo Podestà, Paola Ciceri, Andrea Galassi, Lorenzo Gasperoni and Gaetano La Manna
Nutrients 2020, 12(6), 1609; https://doi.org/10.3390/nu12061609 - 30 May 2020
Cited by 15 | Viewed by 4701
Abstract
Chronic kidney disease (CKD) patients have a higher risk of cardiovascular (CVD) morbidity and mortality compared to the general population. The links between CKD and CVD are not fully elucidated but encompass both traditional and uremic-related risk factors. The term CKD-mineral and bone [...] Read more.
Chronic kidney disease (CKD) patients have a higher risk of cardiovascular (CVD) morbidity and mortality compared to the general population. The links between CKD and CVD are not fully elucidated but encompass both traditional and uremic-related risk factors. The term CKD-mineral and bone disorder (CKD-MBD) indicates a systemic disorder characterized by abnormal levels of calcium, phosphate, PTH and FGF-23, along with vitamin D deficiency, decreased bone mineral density or altered bone turnover and vascular calcification. A growing body of evidence shows that CKD patients can be affected by subclinical vitamin K deficiency; this has led to identifying such a condition as a potential therapeutic target given the specific role of Vitamin K in metabolism of several proteins involved in bone and vascular health. In other words, we can hypothesize that vitamin K deficiency is the common pathogenetic link between impaired bone mineralization and vascular calcification. However, some of the most common approaches to CKD, such as (1) low vitamin K intake due to nutritional restrictions, (2) warfarin treatment, (3) VDRA and calcimimetics, and (4) phosphate binders, may instead have the opposite effects on vitamin K metabolism and storage in CKD patients. Full article
(This article belongs to the Special Issue Physiology and Pathology of Vitamin K Intake)
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