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

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.

Copyright © 2017 by the American Society of Nephrology.

Figures

Figure 1.

Relative cMGP concentration is reduced in calciphylaxis. (A) Reduced relative cMGP concentration is observed in calciphylaxis cases compared with matched controls. (B) This reduction in relative cMGP concentration was also observed in calciphylaxis cases who were not taking warfarin compared with controls who were not taking warfarin.

Figure 2.

Vitamin K deficiency is more prevalent in calciphylaxis cases compared with matched controls. Vitamin K deficiency was defined as a plasma PIVKA-II of ≥2 ng/ml. (A) A comparison of the prevalence of vitamin K deficiency in all calciphylaxis cases and controls. (B) A comparison of the prevalence of vitamin K deficiency in cases and controls who were not taking warfarin.