|Nigwekar, Sagar - Massachusetts General Hospital|
|Bloch, Donald - Massachusetts General Hospital|
|Nazarian, Rosalynn - Massachusetts General Hospital|
|Vermeer, Cees - Maastricht University|
|Booth, Sarah - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Thadhani, Ravi - Massachusetts General Hospital|
|Malhotra, Rajeev - Massachusetts General Hospital|
Submitted to: Journal of the American Society of Nephrology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/23/2016
Publication Date: 1/3/2017
Citation: Nigwekar, S.U., Bloch, D.B., Nazarian, R.M., Vermeer, C., Booth, S.L., Thadhani, R.I., Malhotra, R. 2017. Vitamin K-dependent carboxylation of matrix gla protein influences the risk of calciphylaxis. Journal of the American Society of Nephrology. doi: 10.1681/asn.2016060651.
Interpretive Summary: Calciphylaxis is a syndrome of abnormal calcification of the blood vessels, which can lead to blood clot formation and inadequate oxygenation of tissues. This disease usually occurs in patients with renal disease and often results in death. Matrix Gla protein (MGP) is a protein that inhibits abnormal calcification. This ability to inhibit calcification requires the presence of vitamin K. In the absence of vitamin K, MGP is not activated to a functional form. Both functional and non-functional forms of MGP are measurable in blood. We investigated how the MGP functionality influences the risk of calciphylaxis in adult patients with renal disease and receiving dialysis. Our study included 20 patients with renal disease receiving dialysis who were diagnosed with calciphylaxis. Each patient with calciphylaxis was matched by age, sex, race, and use of vitamin K antagonists with another patient with renal disease who did not have calciphylaxis. The patients with calciphylaxis had higher plasma levels of the non-functional form of MGP compared to the patients who had no calciphylaxis. Furthermore, the portion of MGP in plasma that was functional was lower in patients with calciphylaxis. Each unit reduction in functional MGP concentration was associated with a more than two-fold increase in calciphylaxis risk. In conclusion, the vitamin K deficiency that is associated with reduced functional MGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.
Technical 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 (beta= -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.