Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Abstract

The mechanisms for vascular calcification and its associated cardiovascular mortality in patients with ESRD are not completely understood. Dialysis patients exhibit profound vitamin K deficiency, which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). Here, we tested whether distinct circulating inactive vitamin K-dependent proteins associate with all-cause or cardiovascular mortality. We observed higher levels of both desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) among 188 hemodialysis patients compared with 98 agematched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r ϭ 0.62, P Ͻ 0.0001). We found increased PIVKA-II levels in 121 (64%) dialysis patients, indicating pronounced vitamin K deficiency. Kaplan-Meier analysis showed that patients with low levels of dp-cMGP had an increased risk for all-cause and cardiovascular mortality. Multivariable Cox regression confirmed that low levels of dp-cMGP increase mortality risk (all-cause: HR, 2.2; 95% CI, 1.1 to 4.3; cardiovascular: HR, 2.7; 95% CI, 1.2 to 6.2). Furthermore, patients with higher vascular calcification scores showed lower levels of dp-cMGP. In 17 hemodialysis patients, daily supplementation with vitamin K2 for 6 weeks reduced dp-ucMGP levels by 27% (P ϭ 0.003) but did not affect dp-cMGP levels. In conclusion, the majority of dialysis patients exhibit pronounced vitamin K deficiency. Lower levels of circulating dp-cMGP may serve as a predictor of mortality in dialysis patients. Whether vitamin K supplementation improves outcomes requires further study. 22: 387-395, 201122: 387-395, . doi: 10.1681 Dialysis patients show an increased total and cardiovascular mortality. 1 Cardiovascular calcifications are well-established mortality predictors in ESRD patients. 2 Calcification is not only a passive but an actively regulated process dependent on calcification inhibitors. 3 Fetuin-A, a liver-derived protein, acts as a systemic calcification inhibitor, 4 and low serum levels have been shown to predict mortality in dialysis patients. 5 Matrix gla protein (MGP) is produced by vascular smooth muscle cells and acts locally in the vascular wall. 6 MGP can be modified by ␥-glutamate carboxylation and serine phosphorylation. The function of phosphorylation is not yet known, but recent data suggest that it plays a role in regulating the secretion of proteins into the extracellular environ- J Am Soc Nephrol

Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes

“…Five studies [10][11][12][13]24 reported on the association between mortality and dp-ucMGP in patients with aortic stenosis, 12 chronic 10 or end-stage kidney disease, 24 chronic heart failure, 11 or overt vascular disease. 13 The associations between all-cause mortality and dp-ucMGP were positive, 10-13 except in patients with advanced renal dysfunction, in whom this association was not significant.…”

Serum myostatin levels are negatively associated with abdominal aortic calcification in older men: the STRAMBO study

“…Lower levels of calcification inhibitors (fetuin-A, matrix GLA protein) were observed in vascular diseases, whereas OPG levels were elevated (44,45,46). So far, myostatin has not been implicated in mineral homeostasis crucial for the pathophysiology of vascular calcification.…”

Cardiovascular Calcification and Bone: A Comparison of the Effects of Dietary and Serum Vitamin K and its Dependent Proteins

“…By contrast, in CKD and T2D patients serum ucMGP levels correlated inversely with CAC and peripheral arterial calcification scores 42,43 although plasma dp-ucMGP levels were positively correlated with calcification scores 43 and mortality 44 , but not with risk of CHD or stroke after 11.5 years 45 . Similarly, a large study of asymptomatic subjects found that higher dp-ucMGP was associated with higher mortality, including cardiovascular mortality, but lower coronary event incidence 46 , possibly reflecting the protective effect of coronary calcification by stabilising plaque. Likewise, lower levels of dp-cMGP were associated with a higher calcification score and all-cause and CV mortality in CKD 47 .…”