Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD

J Am Soc Nephrol. 2011 Feb;22(2):387-95. doi: 10.1681/ASN.2010040339.

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.

MeSH terms

  • Adult
  • Aged
  • Biomarkers / blood
  • Calcinosis / blood
  • Calcium-Binding Proteins / blood*
  • Extracellular Matrix Proteins / blood*
  • Female
  • Humans
  • Kidney Failure, Chronic / blood
  • Kidney Failure, Chronic / mortality*
  • Male
  • Middle Aged
  • Phosphorylation
  • Proportional Hazards Models
  • Prospective Studies
  • Protein Precursors / blood
  • Prothrombin
  • Renal Dialysis / mortality
  • Vitamin K 2 / administration & dosage

Substances

  • Biomarkers
  • Calcium-Binding Proteins
  • Extracellular Matrix Proteins
  • Protein Precursors
  • matrix Gla protein
  • Vitamin K 2
  • acarboxyprothrombin
  • Prothrombin