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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 (?=-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.

SUBMITTER: Nigwekar SU

PROVIDER: S-EPMC5461787 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Nigwekar Sagar U SU Bloch Donald B DB Nazarian Rosalynn M RM Vermeer Cees C Booth Sarah L SL Xu Dihua D Thadhani Ravi I RI Malhotra Rajeev R

Journal of the American Society of Nephrology : JASN 20170103 6

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 hem ...[more]

PMID: 28049648

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Project description:Background Vascular calcification is strongly related to the risk of mortality and cardiovascular (CV) diseases. In vascular calcification, matrix Gla protein (MGP), a small vitamin K-dependent protein, is an important mineralization inhibitor. Recent studies showed that circulating MGP is associated with mortality risk. However, the longitudinal association between urinary excretion of MGP and all-cause mortality was not established. Materials and methods Urinary MGP was measured in 776 randomly recruited Flemish population (mean age: 51.2 years; 50.9% women) at baseline (during 2005–2010) using capillary electrophoresis coupled with mass spectrometry. Plasma inactive MGP [desphospho-uncarboxylated MGP (dp-ucMGP)] levels were quantified in 646 individuals by ELISA kits. Mortality status was ascertained through the Belgian Population Registry until 2016. The longitudinal association with mortality was determined by the multivariate-adjusted Cox proportional hazards regression models. The multivariate linear regression models were used to identify determinants of urinary MGP level. Results Over the 9.2 years, 47 (6.06%) participants died, including 15 CV deaths. For a doubling of urinary MGP, the hazard ratios (HRs) were 1.31 (95% CI: 1.01–1.69, P = 0.040) for all-cause mortality and 2.05 (95% CI: 1.11–3.79, P = 0.023) for CV mortality with adjustment for covariates, including estimated glomerular filtration rate and urine microalbumin. The addition of urinary MGP to the basic models improved the reclassification as suggested by the increased net reclassification improvement [64.01% (95% CI: 32.64–98.63)] and integrated discrimination improvement [2.33% (95% CI: 0.24–4.71)]. Circulating inactive MGP, total cholesterol, urine microalbumin, and smoking were significantly associated with urinary MGP levels (P ≤ 0.041), independent of sex and age. Conclusion Elevated urinary MGP was associated with an increased risk of all-cause mortality and CV mortality and improved the risk reclassification for all-cause mortality. These findings suggested that urinary MGP might be useful in mortality risk assessment in the general population. However, these observations need to be replicated in larger studies with a longer follow-up time.

Dataset Information

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

Publications

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

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