Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD

• Published in: Journal of the American Society of Nephrology 2011-02, Vol.22 (2), p.387-395
• Main Authors: SCHLIEPER, Georg, WESTENFELD, Ralf, DIMKOVIC, Nada, FLOEGE, Jürgen, SCHURGERS, Leon J, KRÜGER, Thilo, CRANENBURG, Ellen C, MAGDELEYNS, Elke J, BRANDENBURG, Vincent M, DJURIC, Zivka, DAMJANOVIC, Tatjana, KETTELER, Markus, VERMEER, Cees
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biological and medical sciences; Biomarkers - blood; Calcinosis - blood; Calcium-Binding Proteins - blood; Clinical Research; Extracellular Matrix Proteins - blood; Female; Humans; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - mortality; Male; Matrix Gla Protein; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Phosphorylation; Proportional Hazards Models; Prospective Studies; Protein Precursors - blood; Prothrombin; Renal Dialysis - mortality; Renal failure; Vitamin K 2 - administration & dosage
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2010040339

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 age-matched subjects with normal renal function. Levels of dp-ucMGP correlated with those of protein induced by vitamin K absence II (PIVKA-II; r = 0.62, P < 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 = 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.