Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis

J Am Soc Nephrol. 2017 Jun;28(6):1717-1722. doi: 10.1681/ASN.2016060651. Epub 2017 Jan 3.

Abstract

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K-dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P=0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses (β=-8.99; P=0.04). In conclusion, vitamin K deficiency-mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.

Keywords: calcific uremic arteriolopathy; calcium-binding protein; renal dialysis; vascular calcification; vitamin K; warfarin.

MeSH terms

  • Calciphylaxis / epidemiology
  • Calciphylaxis / etiology*
  • Calcium-Binding Proteins / metabolism*
  • Carboxylic Acids / metabolism*
  • Extracellular Matrix Proteins / metabolism*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Risk
  • Vitamin K / physiology*

Substances

  • Calcium-Binding Proteins
  • Carboxylic Acids
  • Extracellular Matrix Proteins
  • matrix Gla protein
  • Vitamin K