The Circulating Inactive Form of Matrix Gla Protein Is a Surrogate Marker for Vascular Calcification in Chronic Kidney Disease

Schurgers, Leon J.; Barreto, Daniela Veit; Barreto, Fellype Carvalho; Liabeuf, Sophie; Renard, C.; Magdeleyns, Elke; Vermeer, Cees; Choukroun, Gabriel; Massy, Ziad A.

doi:10.2215/cjn.07081009

Cited by 266 publications

(292 citation statements)

References 42 publications

(47 reference statements)

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“…The increased dp-ucMGP levels in uremia found in our study are consistent with a recent study showing increasing dp-ucMGP levels with higher chronic kidney disease (CKD) stages. 15 In this study, the levels seemed to be even higher than those of our previous study, 15 which may be because of the fact that we studied ESRD patients with long dialysis vintage and little to no residual renal function. Additionally, it could also point to a more pronounced vitamin K deficiency in our cohort of patients with long dialysis vintage.…”

Section: Discussioncontrasting

confidence: 58%

“…Correlation with PIVKA-II (this study) Increased levels in CKD patients 15 and dialysis patients (this study)…”

Section: Mgp Species Studies Interpretationmentioning

confidence: 67%

“…Inactive species Most likely reflects vitamin K status of the vessel wall Increased levels associated with increased mortality risk in CKD patients but not in dialysis patients 15 Increased levels associated with increased mortality in aortic stenosis patients 16 dp-cMGP (nonphosphorylated, carboxylated MGP)…”

Section: Mgp Species Studies Interpretationmentioning

confidence: 99%

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Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Schlieper¹,

Westenfeld²,

Krüger³

et al. 2011

Journal of the American Society of Nephrology

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210

181

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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

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Section: Discussioncontrasting

confidence: 58%

“…Correlation with PIVKA-II (this study) Increased levels in CKD patients 15 and dialysis patients (this study)…”

Section: Mgp Species Studies Interpretationmentioning

confidence: 67%

See 1 more Smart Citation

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Schlieper¹,

Westenfeld²,

Krüger³

et al. 2011

Journal of the American Society of Nephrology

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210

181

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“…The biologically relevant concentrations of TS for this effect are unknown at the present time. A fourth mechanism may be related to STSinduced changes in serum inhibitors of vascular calcification (43,44), as described for the matrix-Gla-protein in previous studies with STS-treated rats (13). However, the concentrations required for this effect are unknown, too.…”

Section: Discussionmentioning

confidence: 92%

Sodium Thiosulfate Pharmacokinetics in Hemodialysis Patients and Healthy Volunteers

Farese¹,

Stauffer²,

Kalicki³

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Vascular calcification is a major cause of morbidity and mortality in dialysis patients. Human and animal studies indicate that sodium thiosulfate (STS) may prevent the progression of vascular calcifications. The pharmacokinetics of STS in hemodialysis patients has not been investigated yet.Design, setting, participants, & measurements STS was given intravenously to 10 hemodialysis patients onand off-hemodialysis. Additionally, STS was applied to 9 healthy volunteers once intravenously and once orally. Thiosulfate concentrations were measured by using a specific and sensitive HPLC method. ResultsIn volunteers and patients, mean endogenous thiosulfate baseline concentrations were 5.5 Ϯ 1.82 versus 7.1 Ϯ 2.7 mol/L. Renal clearance was high in volunteers (1.86 Ϯ 0.45 ml/min per kg) and reflected GFR. Nonrenal clearance was slightly, but not significantly, higher in volunteers (2.25 Ϯ 0.32 ml/min per kg) than in anuric patients (2.04 Ϯ 0.72 ml/min per kg). Hemodialysis clearance of STS was 2.62 Ϯ 1.01 ml/min per kg. On the basis of the nonrenal clearance and the thiosulfate steady-state serum concentrations, a mean endogenous thiosulfate generation rate of 14.6 nmol/min per kg was calculated in patients. After oral application, only 4% of STS was recovered in urine of volunteers, reflecting a low bioavailability of 7.6% (0.8% to 26%). ConclusionsGiven the low and variable bioavailability of oral STS, only intravenous STS should be prescribed today. The biologic relevance of the high hemodialysis clearance for the optimal time point of STS dosing awaits clarification of the mechanisms of action of STS.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes

Liu

Thijs

et al. 2015

Hypertension

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Matrix Gla-protein is a vitamin K–dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated matrix Gla protein (dp–ucMGP). The risk associated with dp–ucMGP in the population is unknown. In a Flemish population study, we measured circulating dp–ucMGP at baseline (1996–2011), genotyped MGP , recorded adverse health outcomes until December 31, 2012, and assessed the multivariable-adjusted associations of adverse health outcomes with dp–ucMGP. We applied a Mendelian randomization analysis using MGP genotypes as instrumental variables. Among 2318 participants, baseline dp–ucMGP averaged 3.61 μg/L. Over 14.1 years (median), 197 deaths occurred, 58 from cancer and 70 from cardiovascular disease; 85 participants experienced a coronary event. The risk of death and non-cancer mortality curvilinearly increased ( P ≤0.008) by 15.0% (95% confidence interval, 6.9–25.3) and by 21.5% (11.1–32.9) for a doubling of the nadir (1.43 and 0.97 μg/L, respectively). With higher dp–ucMGP, cardiovascular mortality log-linearly increased (hazard ratio for dp–ucMGP doubling, 1.14 [1.01–1.28]; P =0.027), but coronary events log-linearly decreased (0.93 [0.88–0.99]; P =0.021). dp–ucMGP levels were associated ( P ≤0.001) with MGP variants rs2098435 , rs4236 , and rs2430692. For non-cancer mortality and coronary events ( P ≤0.022), but not for total and cardiovascular mortality ( P ≥0.13), the Mendelian randomization analysis suggested causality. Higher dp–ucMGP predicts total, non-cancer and cardiovascular mortality, but lower coronary risk. For non-cancer mortality and coronary events, these associations are likely causal.

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The Circulating Inactive Form of Matrix Gla Protein Is a Surrogate Marker for Vascular Calcification in Chronic Kidney Disease

Cited by 266 publications

References 42 publications

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

Sodium Thiosulfate Pharmacokinetics in Hemodialysis Patients and Healthy Volunteers

Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes

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