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

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.

Index Words:  Dialysis , vascular calcification , vitamin K , matrix Gla protein (MGP) , osteocalcin , protein induced by vitamin K absence II (PIVKA-II)