Hepatic and Vascular Vitamin K Status in Patients with High Cardiovascular Risk

Nikolas Rapp,Stephan J L Bakker,Leon J Schurgers,Alexander Schuh,Pieter Evenepoel,Nadine Kaesler,Vincent M Brandenburg,Robert Stöhr

doi:10.3390/nu13103490

Abstract

Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.

Highlights

The unequivocal role of vitamin K is to mediate the posttranslational gamma-glutamyl carboxylation of specific, protein bound glutamate (Glu) residues into gamma-carboxyglutamate (Gla) residues
We performed a post hoc analysis on data collected in the frame of 4 different cohort studies including: HD patients scheduled for kidney transplantation (NCT01886950, Leuven, Belgium); HD patients with calcific uremic arteriolopathy (CUA) (German calciphylaxis registry, Aachen [12]); patients with aortic valve calcification enrolled in a randomized controlled trial to placebo versus vitamin K1 supplementation (“Vitamin K Supplementation for Inhibition of the Progress in Aortic Valve Calcification”, NCT00785109 [8]); and patients with atrial fibrillation (AF) randomized to rivaroxaban versus phenprocoumon
We investigated the correlation between dp-ucMGP and PIVKA-II levels in the various cohorts

Summary

Introduction

The unequivocal role of vitamin K is to mediate the posttranslational gamma-glutamyl carboxylation of specific, protein bound glutamate (Glu) residues into gamma-carboxyglutamate (Gla) residues. Proteins carrying these residues are called vitamin K-dependent proteins (VKDP). The undercarboxylated fraction of VKDP can be measured in the blood, which, as a marker, reflects functional vitamin K status more robustly than direct vitamin K measurements [5]. While menaquinones are the prevalent active form in extra hepatic tissue, and the vessel wall [7], there is currently no data available that points to any of the surrogate markers showing correlation with a specific vitamin K subtype. Increasing the supplementation with vitamin K substantially increases the carboxylation status of these marker proteins [8,9], while application of vitamin K antagonists (VKA) or oral anticoagulant therapy (OAT)

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