title: Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial.
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 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]).
  
  
  METHODS
  Interventional randomized non-placebo-controlled trial with 3 parallel groups.
  
  
  METHODS
  53 long-term hemodialysis patients in stable conditions, 18 years or older. 50 healthy age-matched individuals served as controls.
  
  
  METHODS
  Menaquinone-7 (vitamin K(2)) treatment at 45, 135, or 360 μg/d for 6 weeks.
  
  
  RESULTS
  Plasma levels of dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cardiology, Pulmonary Diseases, Vascular Medicine, University Hospital Düsseldorf, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Westenfeld
authors.forename: Thilo
authors.initials: T
authors.lastname: Krueger
authors.forename: Georg
authors.initials: G
authors.lastname: Schlieper
authors.forename: Ellen C M
authors.initials: EC
authors.lastname: Cranenburg
authors.forename: Elke J
authors.initials: EJ
authors.lastname: Magdeleyns
authors.forename: Stephan
authors.initials: S
authors.lastname: Heidenreich
authors.forename: Stefan
authors.initials: S
authors.lastname: Holzmann
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002135:Calcium-Binding Proteins / Q000097:blood; D015897:Comorbidity; D019587:Dietary Supplements; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000097:blood; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000453:epidemiology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D006435:Renal Dialysis; D016037:Single-Blind Method; D016896:Treatment Outcome; D061205:Vascular Calcification / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control; D024482:Vitamin K 2 / Q000008:administration & dosage* / Q000627:therapeutic use*; D014813:Vitamin K Deficiency / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D060749:alpha-2-HS-Glycoprotein / Q000378:metabolism; D000097568:Matrix Gla Protein
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D015675:Osteocalcin; D011498:Protein Precursors; D011516:Prothrombin; D024482:Vitamin K 2; D060749:alpha-2-HS-Glycoprotein; D000097568:Matrix Gla Protein; C008208:acarboxyprothrombin