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.

Figure 1.

Dialysis patients are deficient in vitamin K. Distribution of PIVKA-II in hemodialysis patients. According to the upper limit of the normal range (dotted line, 2 ng/ml), 64% of dialysis patients display vitamin K deficiency (as indicated by increased PIVKA-II levels).

Figure 2.

Reduced levels of dp-cMGP in dialysis patients with more calcifications. Serum levels of dp-cMGP in patients with high versus low calcification score (Adragao score and total calcification score). The Adragao score counts vascular calcifications of the pelvis (four quadrants) and hands (four quadrants), whereas the extended total calcification score uses the Adragao score plus calcification of both carotid arteries, AV fistula with neighboring arteries, and aortic and mitral heart valves (*P < 0.05).

Figure 3.

Low dp-cMGP levels predict all-cause and cardiovascular mortality in dialysis patients. Kaplan-Meier analysis of all-cause (left) and cardiovascular (right) mortality in patients with low and high levels of dp-cMGP (grouped according to median), log-rank test: P = 0.008 and P = 0.003, respectively.

Figure 4.

With adjustment, low dp-cMGP remains a significant mortality predictor in dialysis patients. Effect of low levels of dp-cMGP on all-cause and cardiovascular mortality determined by Cox regression analysis (crude, adjusted for age, and multivariable adjusted hazard ratios). The multivariable adjusted analysis included age, gender, diabetes mellitus, dialysis vintage, body mass index, presence of vascular disease at the start of the study, and the serum parameters calcium, phosphate, and high-sensitive CRP.

Figure 5.

Vitamin K2 supplementation reduces dp-ucMGP but not dp-cMGP levels in dialysis patients. Plasma levels of dp-ucMGP and dp-cMGP at baseline and after 6 weeks of treatment with vitamin K2 (135 μg MK-7). (A) Changes in dp-ucMGP levels (**P < 0.01), whereas B depicts dp-cMGP levels (not significant) before (baseline) and after vitamin K2 substitution (vit K2), respectively.