Vitamin K Abstracts 10

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The possible role of vitamin K deficiency in the pathogenesis of Alzheimer's disease and in augmenting brain damage associated with cardiovascular disease.
            (Allison, 2001)  Download
The incidence of Alzheimer's disease (AD) increases with age and in carriers of the apolipoprotein E4 genotype. A relative deficiency of vitamin K, affecting the extrahepatic functions of the vitamin, is common in ageing men and women. The concentration of vitamin K is lower in the circulating blood of APOE4 carriers than in that of persons with other APOE genotypes. Evidence is accumulating that vitamin K has important functions in the brain, including the regulation of sulfotransferase activity and the activity of a growth factor/tyrosine kinase receptor (Gas 6/Axl). The hypothesis is now proposed that vitamin K deficiency contributes to the pathogenesis of AD and that vitamin K supplementation may have a beneficial effect in preventing or treating the disease. Vitamin K may also reduce neuronal damage associated with cardiovascular disease.

High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: risk factors and response to vitamin K
            (Aoun et al., 2017)  Download
BACKGROUND:  Vascular calcifications are highly prevalent in hemodialysis patients. Dephosphorylated-uncarboxylated MGP (dp-ucMGP) was found to increase in vitamin K-deficient patients and may be associated with vascular calcifications. Supplementation of hemodialysis patients with vitamin K METHODS:  This is a prospective, pre-post intervention clinical trial involving 50 hemodialysis patients who received daily 360 μg of menaquinone-7 for 4 weeks. At baseline they were assessed for plasma dp-ucMGP levels and vascular calcification scores (AC-24) as well as for other demographic, clinical and biological variables. Dp-ucMGP levels were measured a second time at 4 weeks. RESULTS:  At baseline, dp-ucMGP levels were extremely elevated with a median of 3179.15 (1825.25; 4339.50) pM and correlated significantly with AC-24 (Spearman's rho = 0.43, P = 0.002). Using a bivariate regression analysis, the association between dp-ucMGP levels and AC-24 was most significant when comparing dp-ucMGP levels less than 1000 to those more than 1000 pM (P = 0.02). Dp-ucMGP levels higher than 5000 pM were significantly associated with females, patients with recent fracture and patients with lower serum albumin (respectively P = 0.02, 0.004 and 0.046). The average drop of dp-ucMGP at 4 weeks of treatment was found to be 86% with diabetics having the lowest drop rate (P = 0.01). CONCLUSION:  Vitamin K deficiency, as assessed by high dp-ucMGP levels, is profound in hemodialysis patients from the Eastern Mediterranean region and it is significantly correlated with vascular calcifications. Daily 360 μg of menaquinone-7, given for 4 weeks, effectively reduces dp-ucMGP in this population. Future studies are needed to assess the changes in vascular calcifications in hemodialysis patients treated with vitamin K TRIAL REGISTRATION:  The clinical trial was registered on clinicaltrials.gov (Identification number NCT02876354 , on August 11, 2016).

Vitamin K and cancer.
            (Dahlberg et al., 2017)  Download
Subclinical vitamin K deficits refer to carboxylation defects of different types of vitamin K-dependent hepatic and extrahepatic so-called Gla proteins without prolongation of the prothrombin time. This condition has been reported in different clinical situations due to insufficient supply or malabsorption of vitamin K as well as drug interactions. This review discusses the effects of different vitamin K subspecies on tumour growth and the possible anti-tumour effects of increased vitamin K intake. Blocking carboxylation of vitamin K-dependent proteins with warfarin anticoagulation - what are the risks/benefits for carcinogenesis? Previous studies on both heparin and low molecular weight heparin blocking of the vitamin K-dependent factors X and II have shown tumour suppressive effects. Vitamin K has anti-inflammatory effects that could also impact carcinogenesis, but little data exists on this subject.

Prophylactic role of vitamin K supplementation on vascular inflammation in type 2 diabetes by regulating the NF-κB/Nrf2 pathway via activating Gla proteins.
            (Dihingia et al., 2018)  Download
There is no previous study that has examined the relationship between circulating vitamin K1 (VK1) and vascular inflammation in type 2 diabetes (T2D). This study aims to examine the hypothesis that circulating VK1 deficiency may be associated with higher inflammation and insulin resistance in T2D patients and that VK1 supplementation regulates the NF-κB/Nrf2 pathway via activating VK-dependent Gla proteins and reduces vascular inflammation. The results showed that plasma VK1 levels were significantly lower and MCP-1, fasting glucose, HbA1c, and insulin resistance (HOMA-IR) were significantly higher in T2D patients compared to those in the controls. The lower levels of VK1 in T2D patients were significantly and inversely correlated with MCP-1 and HOMA-IR, which suggests that VK1 supplementation may reduce the vascular inflammation and insulin resistance in T2D. Using a high fat diet-fed T2D mice model this study further demonstrated that VK1 supplementation (1, 3, 5 μg per kg BW, 8 weeks) dose-dependently decreased the body weight gain, glucose intolerance, fasting glucose, glycated hemoglobin, HOMA-IR, and cytokine secretion (MCP-1 and IL-6) in T2D mice. Further cell culture studies showed that VK1 supplementation (1, 5, or 10 nM) decreased NF-κB phosphorylation and MCP-1 secretion and increased Nrf2 protein expression in high glucose (HG, 25 mM)-treated monocytes. Signal silencing studies with GGCX siRNA again depicted the role of VK-dependent Gla proteins in mediating the effect of VK1 on vascular inflammation in HG-treated cells. In conclusion, this study suggests that circulating VK1 has a positive effect in lowering vascular inflammation in T2D by regulating NF-κB/Nrf2 transcription factors via activating VK-dependent Gla proteins.

The Effects of Calcium, Vitamins D and K co-Supplementation on Markers of Insulin Metabolism and Lipid Profiles in Vitamin D-Deficient Women with Polycystic Ovary Syndrome.
            (Karamali et al., 2017)  Download
Data on the effects of calcium, vitamins D and K co-supplementation on markers of insulin metabolism and lipid profiles among vitamin D-deficient women with polycystic ovary syndrome (PCOS) are scarce. This study was done to determine the effects of calcium, vitamins D and K co-supplementation on markers of insulin metabolism and lipid profiles in vitamin D-deficient women with PCOS. This randomized double-blind, placebo-controlled trial was conducted among 55 vitamin D-deficient women diagnosed with PCOS aged 18-40 years old. Subjects were randomly assigned into 2 groups to intake either 500 mg calcium, 200 IU vitamin D and 90 µg vitamin K supplements (n=28) or placebo (n=27) twice a day for 8 weeks. After the 8-week intervention, compared with the placebo, joint calcium, vitamins D and K supplementation resulted in significant decreases in serum insulin concentrations (-1.9±3.5 vs. +1.8±6.6 µIU/mL, P=0.01), homeostasis model of assessment-estimated insulin resistance (-0.4±0.7 vs. +0.4±1.4, P=0.01), homeostasis model of assessment-estimated b cell function (-7.9±14.7 vs. +7.0±30.3, P=0.02) and a significant increase in quantitative insulin sensitivity check index (+0.01±0.01 vs. -0.008±0.03, P=0.01). In addition, significant decreases in serum triglycerides (-23.4±71.3 vs. +9.9±39.5 mg/dL, P=0.03) and VLDL-cholesterol levels (-4.7±14.3 vs. +2.0±7.9 mg/dL, P=0.03) was observed following supplementation with combined calcium, vitamins D and K compared with the placebo. Overall, calcium, vitamins D and K co-supplementation for 8 weeks among vitamin D-deficient women with PCOS had beneficial effects on markers of insulin metabolism, serum triglycerides and VLDL-cholesterol levels.

Vitamin K homologs as potential biomarkers for disease activity in patients with rheumatoid arthritis.
            (Khojah et al., 2016)  Download
The aim of this study was to evaluate the possible role of vitamin K homologs as potential biomarkers for disease activity in patients with rheumatoid arthritis (RA). In this study, 42 patients with RA and 40 healthy controls were enrolled. Serum levels of vitamin K homologs were measured using a high-performance liquid chromatography-fluorescence method. Different biochemical and clinical markers for disease activity were measured and correlated with serum levels of vitamin K homologs. There were no significant differences between RA patients and healthy subjects in demographic data. Patients with RA showed significantly higher levels of biochemical markers compared with healthy subjects (p < 0.001). These markers included rheumatoid factor (RF), anticyclic citrullinated polypeptide (anti-CCP), undercarboxylated osteocalcin (ucOC), matrix metalloproteinase (MMP-3), C-reactive protein (CRP), and disease activity score assessing 28 joints with erythrocyte sedimentation rate (DAS28-ESR). In addition, serum levels of vitamin K homologs were reduced in RA patients, and the levels of menaquinone-4 (MK-4) and menaquinone-7 (MK-7) were moderately to strongly inversely correlated with the clinical articular features in RA patients, whereas phylloquinone (PK) levels were weakly correlated. Serum levels of MK-4, MK-7 and PK were strongly inversely correlated with ucOC, MMP-3 and DAS28-ESR in RA patients. In contrast, serum levels of MK-4, MK-7 and PK were weakly correlated with CRP, RF and anti-CCP. These results suggest that serum levels of vitamin K homologs may be considered as potential biomarkers for disease activity. In addition, the results confirm the role of vitamin K deficiency in the etiology of RA.

Use of vitamin K antagonists and risk of prostate cancer: Meta-analysis and nationwide case-control study.
            (Kristensen et al., 2018)  Download
Use of vitamin K antagonists (VKAs) has been suggested to reduce the risk of prostate cancer. We conducted a nested case-control study using Danish demographic and health data registries and summarized existing evidence in a meta-analysis. The case-control study included all Danish men aged 40-85 years with incident histologically verified prostate adenocarcinoma between 2005 and 2015 (cases). For each case, we selected 10 age-matched controls. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CI) for prostate cancer associated with long-term VKA use adjusted for concomitant drug use, medical history, and socioeconomic status. We included 38,832 prostate cancer cases of which 1,089 (2.8%) had used VKAs for 3 or more years compared to 10,803 (2.8%) controls yielding a crude OR of 1.01 (95% CI, 0.95-1.08). Multivariable adjustment for covariates had limited influence on the association (OR, 1.03; 95% CI, 0.97-1.10). We observed no dose-response relationship (e.g. OR for 5-10 years of use, 1.06 95% CI, 0.97-1.16). We included 8 studies in the meta-analysis reporting effect estimates from 0.51 (95% CI, 0.23-1.13) to 1.10 (95% CI, 0.94-1.40). Using random effect methods, a pooled effect estimate of 0.86 (95% CI, 0.70-1.05) was obtained; however, there was considerable across-study heterogeneity (I2 : 93.9%). In conclusion, we did not observe a reduced risk of prostate cancer associated with VKA use in this nationwide study and, taken together with previous study findings, a major protective effect of VKAs against prostate cancer seems unlikely.


Crosstalk between Vitamins A, B12, D, K, C, and E Status and Arterial Stiffness.
            (Mozos et al., 2017)  Download
Arterial stiffness is associated with cardiovascular risk, morbidity, and mortality. The present paper reviews the main vitamins related to arterial stiffness and enabling destiffening, their mechanisms of action, providing a brief description of the latest studies in the area, and their implications for primary cardiovascular prevention, clinical practice, and therapy. Despite inconsistent evidence for destiffening induced by vitamin supplementation in several randomized clinical trials, positive results were obtained in specific populations. The main mechanisms are related to antiatherogenic effects, improvement of endothelial function (vitamins A, C, D, and E) and metabolic profile (vitamins A, B12, C, D, and K), inhibition of the renin-angiotensin-aldosterone system (vitamin D), anti-inflammatory (vitamins A, D, E, and K) and antioxidant effects (vitamins A, C, and E), decrease of homocysteine level (vitamin B12), and reversing calcification of arteries (vitamin K). Vitamins A, B12, C, D, E, and K status is important in evaluating cardiovascular risk, and vitamin supplementation may be an effective, individualized, and inexpensive destiffening therapy.

Anti-arthritis effects of vitamin K(2) (menaquinone-4)--a new potential therapeutic strategy for rheumatoid arthritis.
            (Okamoto et al., 2007)  Download
Vitamin K(2) (menaquinone-4, MK-4) has been reported to induce apoptosis in hepatocellular carcinoma, leukemia and myelodysplastic syndrome cell lines. The effects of MK-4 on the development of arthritis have never been addressed thus far. In the present study, we investigated the effect of MK-4 upon the proliferation of rheumatoid synovial cells and the development of arthritis in collagen-induced arthritis. We analyzed the effect of MK-4 on the proliferation of fibroblast-like synoviocytes using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The pro-apoptotic effect of MK-4 upon fibroblast-like synoviocytes was investigated with annexin V staining and DNA fragmentation and caspase 3/7 assays. Moreover, we analyzed the effect of MK-4 on the development of collagen-induced arthritis in female dark agouti rats. Our results indicated that MK-4 inhibited the proliferation of fibroblast-like synoviocytes and the development of collagen-induced arthritis in a dose-dependent manner. We conclude that MK-4 may represent a new agent for the treatment of rheumatoid arthritis in the setting of combination therapy with other disease-modifying antirheumatic drugs.


 

Vitamin K and rheumatoid arthritis.
            (Okamoto, 2008)  Download
Vitamin K2 [menaquinone-4 (MK-4)] has been reported to induce apoptosis in hepatocellular carcinoma, leukemia, and MDS cell lines. The effects of MK-4 on the development of arthritis have never been addressed so far. In this study, we investigated the effect of MK-4 upon the proliferation of rheumatoid synovial cells and the development of arthritis in collagen-induced arthritis (CIA). We analyzed the effect of MK-4 on the proliferation of fibroblast-like synoviocytes (FLSs) using the 3-(4,5-demethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The proapoptotic effect of MK-4 upon FLS was investigated with annexin V staining and DNA fragmentation and caspase 3/7 assays. Moreover, we analyzed the effect of MK-4 on the development of CIA in female dark agouti rats. Our results indicated that MK-4 inhibited the proliferation of FLS and the development of CIA in a dose-dependent manner. We concluded that MK-4 may represent a new agent for the treatment of RA in the setting of combination therapy with other disease-modifying antirheumatic drugs.

Low vitamin K intakes in community-dwelling elders at an early stage of Alzheimer's disease.
            (Presse et al., 2008)  Download
An increasing body of evidence points to a role for vitamin K in brain physiology through its participation in sphingolipid metabolism and biological activation of the vitamin K-dependent protein Gas6. One hypothesis is that vitamin K may also play a role in the pathogenesis of Alzheimer's disease. A recent study found that patients with early-stage Alzheimer's disease consumed less vitamin K than did cognitively intact control subjects. To learn more about the dietary intakes and food sources of vitamin K in these patients, a detailed analysis was conducted. Dietary vitamin K intakes were assessed from 5 nonconsecutive days of food records collected from 31 community-dwelling patients with early-stage Alzheimer's disease and in 31 age- and sex-matched cognitively intact control subjects. Mean vitamin K intake on a person-day basis was 63+/-90 microg/day in patients and 139+/-233 microg/day in control subjects. Vitamin K intakes were significantly less in participants with Alzheimer's disease (P<0.0001), even after adjusting for energy intakes (P=0.0003). Vegetables, fats, and fruits contributed more than 70% of total vitamin K intake in both groups. The main source of vitamin K was green vegetables, which contributed 33% and 49% to total intakes in patients and control subjects, respectively. This lower consumption of green vegetables in participants with Alzheimer's disease explained their lower vitamin K intakes overall. Despite their limitations, results are in line with the most recent research in both vitamin K and Alzheimer's disease and suggest a need to consider vitamin K in future investigations on the role of diet in Alzheimer's disease.


 

Vitamin K deficiency and osteopenia in elderly women with Alzheimer's disease.
            (Sato et al., 2005)  Download
OBJECTIVE:  To analyze the relation between vitamin K status and bone mineral density (BMD) in women with Alzheimer's disease (AD). DESIGN:  Cross-sectional study. SETTING:  Outpatient departments of neurology and neuropsychiatry at a hospital in Japan. Participants One hundred women with AD (mean age, 79.8 y) and 100 age-matched community dwelling controls (mean age, 80.6 y). INTERVENTIONS:  Not applicable. MAIN OUTCOME MEASURES:  Patients were divided into 2 groups according to the degree of dementia: the mild AD group was composed of patients with a score in Mini-Mental State Examination (MMSE) of 16 and above (n=42); patients in the severe AD group had MMSE scores below 15 (n=58). We assessed body mass index (BMI). BMD was measured by computed x-ray densitometry. Serum concentrations of vitamin K 1 , 25-hydroxyvitamin D (25[OH]D 3 ), intact parathyroid hormone (PTH), and Glu osteocalcin (OC) were measured. RESULTS:  BMI was significantly lower in women with more severe AD. Metacarpal BMD ( P <.02) and serum concentrations of vitamin K 1 ( P <.03) and 25(OH)D 3 ( P <.001) were significantly lower in the severe AD group than in the mild AD group. Serum levels of intact PTH and Glu OC in severely demented patients were higher than those with mild dementia ( P <.001). Serum PTH concentration correlated negatively with serum 25(OH)D 3 level ( r =-.241, P =.016). Serum concentration of vitamin K 1 correlated positively with that of 25(OH)D 3 ( r =.423, P <.001) and MMSE score ( r =.353, P <.001), and negatively with Glu OC ( r =-.580, P <.001). CONCLUSIONS:  In female AD patients, nutritional vitamin K 1 deficiency may reduce production of fully carboxylated OC, which in turn may cause reduced BMD. Lower BMIs in more severe AD may imply the presence of general malnutrition in such a patient group.

Extremes in vitamin K status of bone are related to bone ultrasound properties in children with juvenile idiopathic arthritis.
            (van Summeren et al., 2008)  Download
OBJECTIVE:  Osteopenia is a common complication of juvenile idiopathic arthritis (JIA). In adults, low bone density and increased fracture risk are associated with low vitamin K status of bone. The vitamin K-dependent protein osteocalcin plays an important role in bone metabolism. Its activity depends upon post-translational carboxylation in which vitamin K is an essential co-factor. Hence, vitamin K deficiency leads to under-carboxylated (i.e., inactive) osteocalcin (ucOC). Little is known about the vitamin K status and bone health in children with juvenile idiopathic arthritis (JIA). We studied the vitamin K status of bone and its association with bone mass properties in children with JIA compared to healthy children. METHODS:  We performed a cross sectional study in 55 children with JIA and 54 healthy controls between 6-18 years of age. Bone markers, ultrasound bone mass properties and vitamin K status of bone were determined. RESULTS:  Overall, no differences in vitamin K status of bone were found between the study groups. Among children with JIA, a high ratio of ucOC/cOC indicating low vitamin K status was associated with low bone ultrasound parameters, whereas children with a high vitamin K status had markedly higher bone properties. This association was independent of physical activity, age, gender and BMI. CONCLUSION:  These results suggest that vitamin K may be one of multiple risk factors for low bone mass in children with JIA, in addition to other recognized determinants of bone mass. The question remains whether JIA patients would benefit from increased dietary vitamin K intake.

Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial.
            (Westenfeld et al., 2012)  Download
BACKGROUND:  Vascular calcification is a predictor of cardiovascular morbidity and mortality. Hemodialysis patients experience severe vascular calcifications. Matrix Gla protein (MGP) is a central calcification inhibitor of the arterial wall; its activity depends on vitamin K-dependent γ-glutamate carboxylation. Uncarboxylated MGP, formed as a result of vitamin K deficiency, is associated with cardiovascular disease. Recent studies suggest poor vitamin K status in hemodialysis patients. We therefore aimed to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin K-dependent proteins in hemodialysis patients, assessed by circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and uncarboxylated prothrombin (PIVKA-II [protein induced by vitamin K absence II]). STUDY DESIGN:  Interventional randomized non-placebo-controlled trial with 3 parallel groups. SETTING & PARTICIPANTS:  53 long-term hemodialysis patients in stable conditions, 18 years or older. 50 healthy age-matched individuals served as controls. INTERVENTIONS:  Menaquinone-7 (vitamin K(2)) treatment at 45, 135, or 360 μg/d for 6 weeks. OUTCOMES:  Plasma levels of dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II. MEASUREMENTS:  Plasma levels were assessed using enzyme-linked immunosorbent assays. RESULTS:  At baseline, hemodialysis patients had 4.5-fold higher dephosphorylated-uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls. PIVKA-II levels were elevated in 49 hemodialysis patients. Vitamin K(2) supplementation induced a dose- and time-dependent decrease in circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II levels. Response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving 135 μg and 360 μg of menaquinone-7, respectively. LIMITATIONS:  Small sample size. CONCLUSIONS:  This study confirms that most hemodialysis patients have a functional vitamin K deficiency. More importantly, it is the first study showing that inactive MGP levels can be decreased markedly by daily vitamin K(2) supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K supplementation.

 


References

Allison, AC (2001), ‘The possible role of vitamin K deficiency in the pathogenesis of Alzheimer’s disease and in augmenting brain damage associated with cardiovascular disease.’, Med Hypotheses, 57 (2), 151-55. PubMed: 11461163
Aoun, M, et al. (2017), ‘High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: risk factors and response to vitamin K’, BMC Nephrol, 18 (1), 191. PubMed: 28592319
Dahlberg, S, J Ede, and U Schött (2017), ‘Vitamin K and cancer.’, Scand J Clin Lab Invest, 77 (8), 555-67. PubMed: 28933567
Dihingia, A, et al. (2018), ‘Prophylactic role of vitamin K supplementation on vascular inflammation in type 2 diabetes by regulating the NF-κB/Nrf2 pathway via activating Gla proteins.’, Food Funct, 9 (1), 450-62. PubMed: 29227493
Karamali, M, et al. (2017), ‘The Effects of Calcium, Vitamins D and K co-Supplementation on Markers of Insulin Metabolism and Lipid Profiles in Vitamin D-Deficient Women with Polycystic Ovary Syndrome.’, Exp Clin Endocrinol Diabetes, 125 (5), 316-21. PubMed: 28407660
Khojah, HM, et al. (2016), ‘Vitamin K homologs as potential biomarkers for disease activity in patients with rheumatoid arthritis.’, J Bone Miner Metab, PubMed: 27722902
Kristensen, KB, et al. (2018), ‘Use of vitamin K antagonists and risk of prostate cancer: Meta-analysis and nationwide case-control study.’, Int J Cancer, PubMed: 30246248
Mozos, I, D Stoian, and CT Luca (2017), ‘Crosstalk between Vitamins A, B12, D, K, C, and E Status and Arterial Stiffness.’, Dis Markers, 2017 8784971. PubMed: 28167849
Okamoto, H, et al. (2007), ‘Anti-arthritis effects of vitamin K(2) (menaquinone-4)--a new potential therapeutic strategy for rheumatoid arthritis.’, FEBS J, 274 (17), 4588-94. PubMed: 17681015
Okamoto, H (2008), ‘Vitamin K and rheumatoid arthritis.’, IUBMB Life, 60 (6), 355-61. PubMed: 18484089
Presse, N, et al. (2008), ‘Low vitamin K intakes in community-dwelling elders at an early stage of Alzheimer’s disease.’, J Am Diet Assoc, 108 (12), 2095-99. PubMed: 19027415
Sato, Y, et al. (2005), ‘Vitamin K deficiency and osteopenia in elderly women with Alzheimer’s disease.’, Arch Phys Med Rehabil, 86 (3), 576-81. PubMed: 15759247
van Summeren, MJ, et al. (2008), ‘Extremes in vitamin K status of bone are related to bone ultrasound properties in children with juvenile idiopathic arthritis.’, Clin Exp Rheumatol, 26 (3), 484-91. PubMed: 18578975
Westenfeld, R, et al. (2012), ‘Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial.’, Am J Kidney Dis, 59 (2), 186-95. PubMed: 22169620