title: 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 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.
authors.affiliation: Department of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule, Pauwelsstrasse 30, 52074 Aachen, Germany. gschlieper@ukaachen.de
authors.forename: Georg
authors.initials: G
authors.lastname: Schlieper
authors.forename: Ralf
authors.initials: R
authors.lastname: Westenfeld
authors.forename: Thilo
authors.initials: T
authors.lastname: Krüger
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Cranenburg
authors.forename: Elke J
authors.initials: EJ
authors.lastname: Magdeleyns
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Brandenburg
authors.forename: Zivka
authors.initials: Z
authors.lastname: Djuric
authors.forename: Tatjana
authors.initials: T
authors.lastname: Damjanovic
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.forename: Nada
authors.initials: N
authors.lastname: Dimkovic
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002114:Calcinosis / Q000097:blood; D002135:Calcium-Binding Proteins / Q000097:blood*; D016326:Extracellular Matrix Proteins / Q000097:blood*; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D006435:Renal Dialysis / Q000401:mortality; D024482:Vitamin K 2 / Q000008:administration & dosage; D000097568:Matrix Gla Protein
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D011498:Protein Precursors; D011516:Prothrombin; D024482:Vitamin K 2; D000097568:Matrix Gla Protein; C008208:acarboxyprothrombin