Effect of Vitamin K2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial

doi:10.1053/j.ajkd.2011.10.041

American Journal of Kidney Diseases

Volume 59, Issue 2, February 2012, Pages 186-195

https://doi.org/10.1053/j.ajkd.2011.10.041 Get rights and content

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 K₂) 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 K₂ 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 K₂ supplementation. Our study provides the rationale for intervention trials aimed at decreasing vascular calcification in hemodialysis patients by vitamin K supplementation.

Section snippets

Trial Design

The study was a prospective randomized blinded intervention study. Of 75 patients consecutively screened for the study participation, 55 were eligible, included, and randomly assigned (Fig 2A). The rest of the patients were excluded because of a history of thrombosis or other coagulation disorders or coumarin use. After randomization, but before entering the supplementation phase, 2 patients refused to continue the protocol. Three additional patients discontinued the study, and final data were

Baseline Characteristics and Biochemical Parameters

Of 53 patients enrolled, 50 patients completed the study (Fig 2A). One patient discontinued the intervention due to bowel discomfort (45-μg group), one underwent kidney transplant, and one patient died of myocardial infarction (both in the 360-μg group; Fig 2A). The latter was assumed to have occurred independently of the present study protocol. Baseline differences between the control group and patients were significant for diabetes mellitus, coronary artery disease (absent in controls), and

Discussion

In this study, we confirm and extend our recent pilot data that hemodialysis patients show significant vitamin K deficiency. This was evidenced by 4.5-fold increased dephosphorylated-uncarboxylated MGP levels, 3.2-fold increased uncarboxylated osteocalcin levels, and detectable concentrations of PIVKA-II in most hemodialysis patients. Moreover, in the present study, we assessed the dose dependency of vitamin K₂ supplementation to improve the carboxylation status of vitamin K–dependent proteins.

Acknowledgements

Support: None.

Financial Disclosure: The authors declare that they have no relevant financial interests.

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Cited by (244)

No Detectable Coagulation Activation After Vitamin K (MK-7) Supplementation in Patients on Dialysis With Functional Vitamin K Deficiency: A One-Year Randomized, Placebo-Controlled Study
2024, Journal of Renal Nutrition
Patients on dialysis treatment have poor functional vitamin K status, and this may increase the risk of vascular calcification. Vitamin K supplementation may therefore be relevant in patients on dialysis, but the procoagulant effects have not been studied. We evaluated effects of menaquinone-7 (MK-7) supplementation on biomarkers of coagulation in patients on dialysis.
Double-blinded, placebo-controlled study in 123 patients on dialysis randomized to 52 weeks of vitamin K (MK-7, 360 μg/daily, n = 61) or placebo (n = 62). Measurements at baseline and after 52 weeks of intervention included thrombin generation (endogenous thrombin potential, peak thrombin concentration, time to peak, and lag time); clot activities of vitamin K-dependent coagulation factors (F) II, VII, IX, and X; prothrombin fragment 1 + 2 (F1+2); and proteins induced by vitamin K absence II (PIVKA-II). Between-group differences (vitamin K vs. placebo) at 52 weeks were determined with an analysis of covariance. Within-group changes in vitamin K and placebo groups were analyzed with a paired t-test. Vascular adverse events and serious adverse events were registered based on hospital records, laboratory data, and participant interviews and compared between groups using Fisher’s exact test or Pearson’s Chi-Squared test.
A between-group difference at 52 weeks was observed for PIVKA-II (P < .001). PIVKA-II decreased significantly from baseline to 52 weeks in the vitamin K group, but not in the placebo group. We observed no between-group differences or within-group changes for biomarkers of coagulation, except for FVII clot activity which was reduced in the placebo group (P = .04), and no between-group differences in adverse events and serious adverse events.
One year of vitamin K supplementation in patients on dialysis has no detectable effects on biomarkers of coagulation activation, clot activities of vitamin K-dependent coagulation factors, and vascular events or death, indicating no procoagulant effects of this treatment.
Randomized Controlled Clinical Trial of the Effect of Treatment with Vitamin K2 on Vascular Calcification in Hemodialysis Patients (Trevasc-HDK)
2023, Kidney International Reports
Vitamin K deficiency among patients on hemodialysis (HD) affects the function of matrix GLA protein (MGP), a potent vitamin K-dependent inhibitor of vascular calcification (VC).
We conducted a single-center randomized controlled trial (RCT) on maintenance HD patients to examine if vitamin K2 supplementation can reduce progression of coronary artery calcification (CAC) over an 18-month study period. Patients were randomized to vitamin K2 group receiving menaquinone-7360 μg 3 times/wk or control group. The primary outcome was CAC scores at the end of the study period. The secondary outcomes were aortic valve calcification (AVC), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), dephosphorylated undercarboxylated MGP (dp-ucMGP) levels, major adverse cardiac events (MACE), and vascular access events.
Of the 178 patients randomized, follow-up was completed for 138 patients. The CAC scores between the 2 groups were not statistically different at the end of 18 months (relative mean difference [RMD] 0.85, 95% CI 0.55–1.31). The secondary outcomes did not differ significantly in AVC (RMD 0.82, 95% CI 0.34–1.98), cfPWV (absolute mean difference [AMD] 0.55, 95% CI −0.50 to 1.60), and AIx (AMD 0.13, 95% CI −3.55 to 3.80). Supplementation with vitamin K2 did reduce dp-ucMGP levels (AMD −86, 95% CI −854 to −117). The composite outcome of MACE and mortality was not statistically different between the 2 groups (Hazard ratio = 0.98, 95% CI 0.50–1.94).
Our study did not demonstrate a beneficial effect of vitamin K2 in reducing progression of VC in this population at the studied dose and duration.
Vitamin K2 as a potential therapeutic candidate for the prevention of muscle cramps in hemodialysis patients: A prospective multicenter, randomized, controlled, crossover pilot trial
2022, Nutrition
Citation Excerpt :
Its effects are carried out through vitamin K-dependent proteins, osteocalcin, and the matrix Gla protein [26–29]. Vitamin K2 supplementation is believed to be a promising intervention to counteract the development and progression of arterial calcification [30]. Earlier, we conducted a study on vitamin K2 supplementation in dialysis patients to investigate its effects on vascular calcification and artery stiffness.
Muscle cramps occur in 33% to 78% of patients with dialysis. The etiology of muscle cramps is poorly understood, and no clear evidence-based prevention or treatment strategies exist. Improved interventions are urgently needed. The aim of this study was to investigate the effect of vitamin K2 in reducing the frequency and severity of muscle cramps in hemodialysis (HD) patients.
This multicenter, randomized, placebo-controlled, crossover clinical trial was conducted from June 2019 to May 2020. Each participant received vitamin K2 (360 µg/d) or placebo for two 4-wk phases, and then crossed to the alternative arm for two 4-wk phases after a 2-wk washout. The primary endpoint was the frequency of muscle cramps during HD. The secondary endpoints were severity and duration of muscle cramps during HD.
A total of 523 patients with maintenance HD were screened for muscle cramps, including 41 patients with muscle cramps refractory to conventional interventions, were enrolled. Nineteen patients in the vitamin K2-initial group and 20 in the placebo-initial group completed the protocol, and were included in the final analysis. Vitamin K2 reduced the frequency, duration, and severity of muscle cramps in HD patients (all P < 0.05). The frequency, duration, and severity of muscle cramps in HD patients increased again after crossing over to the placebo. There were no serious adverse events. One patient experienced gastrointestinal discomfort when taking vitamin K2.
This pilot trial demonstrated that vitamin K2 supplementation could decrease the frequency, duration, and severity of muscle cramps in HD patients.
Vitamin K status, all-cause mortality, and cardiovascular disease in adults with chronic kidney disease: The Chronic Renal Insufficiency Cohort
2022, American Journal of Clinical Nutrition
Vascular calcification contributes to cardiovascular disease (CVD) and mortality in individuals with chronic kidney disease (CKD). Vitamin K-dependent proteins function as calcification inhibitors in vascular tissue.
We sought to determine the association of vitamin K status with mortality and CVD events in adults with CKD.
Plasma dephospho-uncarboxylated matrix gla protein ((dp)ucMGP), which increases when vitamin K status is low, and plasma phylloquinone (vitamin K1), which decreases when vitamin K status is low, were measured in 3066 Chronic Renal Insufficiency Cohort participants (median age = 61 y, 45% female, 41% non-Hispanic black, median estimated glomerular filtration rate [eGFR] = 41 mL/min/1.73m²). The association of vitamin K status biomarkers with all-cause mortality and atherosclerotic-related CVD was determined using multivariable Cox proportional hazards regression.
There were 1122 deaths and 599 atherosclerotic CVD events over the median 12.8 follow-up years. All-cause mortality risk was 21–29% lower among participants with plasma (dp)ucMGP <450 pmol/L (n = 2361) compared with those with plasma (dp)ucMGP ≥450 pmol/L (adjusted HRs [95% CIs]: <300 pmol/L = 0.71 [0.61, 0.83], 300–449 pmol/L = 0.77 [0.66, 0.90]) and 16–19% lower among participants with plasma phylloquinone ≥0.50 nmol/L (n = 2421) compared to those with plasma phylloquinone <0.50 nmol/L (adjusted HRs: 0.50, 0.99 nmol/L = 0.84 [0.72, 0.99], ≥1.00 nmol/L = 0.81 [0.70, 0.95]). The risk of atherosclerotic CVD events did not significantly differ across plasma (dp)ucMGP or phylloquinone categories.
Two biomarkers of vitamin K status were associated with a lower all-cause mortality risk but not atherosclerotic CVD events. Additional studies are needed to clarify the mechanism underlying this association and evaluate the impact of improving vitamin K status in people with CKD.
The study of bioavailability and endogenous circadian rhythm of menaquinone-7, a form of vitamin K 2, in healthy subjects
2023, British Journal of Nutrition
Vascular calcification inhibitors and cardiovascular events in peritoneal dialysis patients
2024, Therapeutic Apheresis and Dialysis

View all citing articles on Scopus

: Originally published online December 12, 2011.

: Trial registration: ClinicalTrials.gov; study number: NCT01407601

^⁎: R.W. and T.K. contributed equally to this work.

^†: J.F. and L.J.S. contributed equally to this work.

View full text

Original InvestigationPathogenesis and Treatment of Kidney DiseaseEffect of Vitamin K2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial

Background

Study Design

Setting & Participants

Interventions

Outcomes

Measurements

Results

Limitations

Conclusions

Section snippets

Trial Design

Baseline Characteristics and Biochemical Parameters

Discussion

Acknowledgements

Am J Kidney Dis

Bone

Biochim Biophys Acta

Am J Clin Nutr

Am J Clin Nutr

Am J Kidney Dis

J Biol Chem

J Nutr

Lancet

Blood

Blood

Am J Cardiol

Blood

Atherosclerosis

J Nutr

Am J Clin Nutr

Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads

Proc Natl Acad Sci U S A

Mechanisms, pathophysiology, and therapy of arterial stiffness

Arterioscler Thromb Vasc Biol

Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia

Curr Opin Nephrol Hypertens

Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease

Hypertension

Media calcification and intima calcification are distinct entities in chronic kidney disease

Clin J Am Soc Nephrol

Original Investigation
Pathogenesis and Treatment of Kidney Disease
Effect of Vitamin K₂ Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial