The Role of Vitamin K in Vascular Calcification

Cozzolino, Mario; Fusaro, Maria; Ciceri, Paola; Gasperoni, Lorenzo; Cianciolo, Giuseppe

doi:10.1053/j.ackd.2019.10.005

Cited by 34 publications

(25 citation statements)

References 43 publications

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“…Considering the increasingly recognised role of vitamin K in VC (11,19,24,41,42), VF (24,43) and mortality (24,44), in patients with CKD, it is critical that those burdened with co-morbid diseases requiring multiple medications are monitored for the presence of drugs that could interfere with the potential absorption and action of vitamin K and VKDPs.…”

Section: Discussionmentioning

confidence: 99%

Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study

Fusaro

Cozzolino

Plebani

et al. 2020

Journal of Bone and Mineral Research

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BACKGROUND: Hyperphosphatemia is a risk factor for vascular calcifications (VCs) and VCs belong to mineral bone disorders (MBD) in chronic kidney disease (CKD) patients. Vitamin Kdependent proteins such as Matrix Gla Protein (MGP) and Bone Gla Proteins (BGP or osteocalcin) can inhibit VCs and regulate bone mineralization. OBJECTIVE: To evaluate whether the phosphate binder, sevelamer, could influence vitamin K levels in hemodialysis (HD) patients. METHODS: In a secondary analysis of the VItamin K Italian (VIKI) study, we evaluated the relationship between vitamin K status, VFs and VCs in 387 HD patients with/without sevelamer. Levels of serum vitamin 25(OH)D, alkaline phosphatase (ALP), vitamin k vitamers: K1 and K2 or menaquinone (MK, including: MK4, MK5, MK6 and MK7), total and undercarboxylated (uc) forms for both BGP and MGP were determined. RESULTS: No significant differences were observed between sevelamer-treated and untreated patients for main clinical characteristics. Lower MK4 levels (0.45 vs. 0.6 ng/mL, p=0.01) and a higher MK4 deficiency was observed in sevelamer-treated patients (13.5% vs. 5.4%, p=0.005). Multivariate logistic regression revealed that MK4 deficiency was associated with sevelamer use (Odds Ratio; OR: 2.64, 95% CI: 1.25-5.58, p=0.011) and aortic calcification (OR: 8.04, 95% CI: 1.07-60.26, p=0.04). In the same multivariate logistic regression model, sevelamer significantly amplified the effect of total BGP levels on the odds of fractures so that in sevelamer-treated patients, the OR of VFs was about 3 times higher in patients with total BGP <150 µg/L compared to those with total BGP ≥150 µg/L (OR: 3.15, 95% CI: 1.46-6.76, p=0.003), whereas no such effect was found in those untreated (total BGP <150 µg/L vs. total BGP ≥150 µg/L: OR: 1.21, 95% CI: 0.66-2.23, p=0.54] (p=0.049 for effect modification by sevelamer). CONCLUSION: These data suggest that sevelamer could interfere with MK4 levels in HD patients and its use in patients with low BGP levels (<150 µg/L) could increase bone fragility in CKD patients.

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Section: Discussionmentioning

confidence: 99%

Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study

Fusaro

Cozzolino

Plebani

et al. 2020

Journal of Bone and Mineral Research

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“…Measuring Vitamin K plasma levels is difficult due its low circulating concentration, the non-polar nature of the molecule and the interference of lipids. Moreover analytical variability, diet, inflammation, and the coexistence of chronic disease may further influence plasma levels of vitamin K subtypes [21]. Functional tests can be performed to estimate vitamin K blood levels indirectly.…”

Section: Vitamin K and Gla Proteinsmentioning

confidence: 99%

“…Observational and interventional clinical studies suggest that CKD patients often develop subclinical vitamin K deficiency [50][51][52], a condition that may determine a higher risk of morbidity and mortality in this population. Dietary recommendations aimed at restricting potassium and phosphate intake (e.g., reduced consumption of leafy green vegetables and dairy products, rich in vitamin K1 and K2, respectively) may play a pivotal role in promoting this deficit [17,21,50,53].…”

Section: Vitamin K Deficiency Mgp and Oc Metabolism In Ckd Patientsmentioning

confidence: 99%

Current Therapy in CKD Patients Can Affect Vitamin K Status

et al. 2020

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Chronic kidney disease (CKD) patients have a higher risk of cardiovascular (CVD) morbidity and mortality compared to the general population. The links between CKD and CVD are not fully elucidated but encompass both traditional and uremic-related risk factors. The term CKD-mineral and bone disorder (CKD-MBD) indicates a systemic disorder characterized by abnormal levels of calcium, phosphate, PTH and FGF-23, along with vitamin D deficiency, decreased bone mineral density or altered bone turnover and vascular calcification. A growing body of evidence shows that CKD patients can be affected by subclinical vitamin K deficiency; this has led to identifying such a condition as a potential therapeutic target given the specific role of Vitamin K in metabolism of several proteins involved in bone and vascular health. In other words, we can hypothesize that vitamin K deficiency is the common pathogenetic link between impaired bone mineralization and vascular calcification. However, some of the most common approaches to CKD, such as (1) low vitamin K intake due to nutritional restrictions, (2) warfarin treatment, (3) VDRA and calcimimetics, and (4) phosphate binders, may instead have the opposite effects on vitamin K metabolism and storage in CKD patients.

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“…For this reason, vitamin K2 is more effective in carboxylating extrahepatic vitamin K-dependent proteins than vitamin K1 [3]. Besides their role in the coagulation cascade, vitamin K-dependent proteins are involved in (patho)physiological calcification of the vasculature [4] and the bones [5,6]. Matrix Gla Protein (MGP) is a vitamin K-dependent protein that inhibits vascular calcification and plays a regulatory role in the bones [7].…”

Section: Introductionmentioning

confidence: 99%

Six months vitamin K treatment does not affect systemic arterial calcification or bone mineral density in diabetes mellitus 2

et al. 2020

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Purpose Vitamin K-dependent proteins are involved in (patho)physiological calcification of the vasculature and the bones. Type 2 diabetes mellitus (DM2) is associated with increased arterial calcification and increased fractures. This study investigates the effect of 6 months vitamin K2 supplementation on systemic arterial calcification and bone mineral density (BMD) in DM2 patients with a history of cardiovascular disease (CVD). Methods In this pre-specified, post hoc analysis of a double-blind, randomized, controlled clinical trial, patients with DM2 and CVD were randomized to a daily, oral dose of 360 µg vitamin K2 or placebo for 6 months. CT scans were made at baseline and follow-up. Arterial calcification mass was quantified in several large arterial beds and a total arterial calcification mass score was calculated. BMD was assessed in all non-fractured thoracic and lumbar vertebrae. Results 68 participants were randomized, 35 to vitamin K2 (33 completed follow-up) and 33 to placebo (27 completed follow-up). The vitamin K group had higher arterial calcification mass at baseline [median (IQR): 1694 (812–3584) vs 1182 (235–2445)] for the total arterial calcification mass). Six months vitamin K supplementation did not reduce arterial calcification progression (β [95% CI]: − 0.02 [− 0.10; 0.06] for the total arterial calcification mass) or slow BMD decline (β [95% CI]: − 2.06 [− 11.26; 7.30] Hounsfield units for all vertebrae) when compared to placebo. Conclusion Six months vitamin K supplementation did not halt progression of arterial calcification or decline of BMD in patients with DM2 and CVD. Future clinical trials may want to pre-select patients with very low vitamin K status and longer follow-up time might be warranted. This trial was registered at clinicaltrials.gov as NCT02839044

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The Role of Vitamin K in Vascular Calcification

Cited by 34 publications

References 43 publications

Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study

Sevelamer Use, Vitamin K Levels, Vascular Calcifications, and Vertebral Fractures in Hemodialysis Patients: Results from the VIKI Study

Current Therapy in CKD Patients Can Affect Vitamin K Status

Six months vitamin K treatment does not affect systemic arterial calcification or bone mineral density in diabetes mellitus 2

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