Effect of Vitamin K-2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial

Ralf Westenfeld, Thilo Krueger*, Georg Schlieper, Ellen C. M. Cranenburg, Elke J. P. Magdeleyns, Stephan Heidenreich, Stefan Holzmann, Cees Vermeer, Willi Jahnen-Dechent, Markus Ketteler, Juergen Floege, Leon J. Schurgers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

198 Citations (Web of Science)

Abstract

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 gamma-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 mu g/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 mu g and 360 mu g 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. Am J Kidney Dis. 59(2):186-195.
Original languageEnglish
Pages (from-to)186-195
JournalAmerican Journal of Kidney Diseases
Volume59
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Dialysis
  • vascular calcification
  • vitamin K
  • matrix Gla protein (MGP)
  • osteocalcin
  • protein induced by vitamin K absence II (PIVKA-II)

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