Investigating the effects of vitamin K on vascular health and disease

Lees, Jennifer S. (2020) Investigating the effects of vitamin K on vascular health and disease. PhD thesis, University of Glasgow.

Abstract

Background:

Cardiovascular disease is common in chronic kidney disease (CKD), and is incompletely explained by atherosclerotic risk factors such as age, hypertension, dyslipidaemia and smoking. Vascular stiffness and calcification are often found together as surrogate markers of cardiovascular disease that are prevalent in excess in patients with CKD. Vitamin K is a co-factor for the activation of calcification inhibiting vitamin K dependent proteins, and so can be considered a calcification inhibitor in itself. Subclinical deficiency of vitamin K is seen in patients with CKD, including end-stage kidney disease and kidney transplantation, and is associated with vascular stiffness and calcification. Vitamin K supplementation has been proposed as a low-cost and safe intervention to improve vascular stiffness and calcification, and potentially reduce the incidence of cardiovascular disease amongst high-risk patient groups including those with CKD.

Hypothesis:

Vitamin K deficiency drives vascular stiffness and calcification in excess for age and gender in patients with established kidney disease, and vitamin K supplementation regresses existing (or slows) progression of) vascular stiffness and calcification.

Methods:

The hypothesis was explored in two main ways. First, we conducted a two-part systematic review and meta-analysis of the published data describing: i) the relationship between vitamin K status markers and incident cardiovascular disease and mortality; ii) the effect of vitamin K supplementation on vascular stiffness and calcification in controlled trials in adults.

Second, we conducted a phase II, single-centre, randomised, double-blind, placebo-controlled trial of vitamin K supplementation in prevalent adult kidney transplant recipients (transplant duration > 12 months) to assess the effects on vascular stiffness and calcification. The primary outcome measure was between-group difference in vascular stiffness (aortic distensibility on cardiac magnetic resonance imaging) at 12 months, adjusted for the baseline value, age and duration of end-stage kidney disease. Dietary and lifestyle data were collected at baseline to assess the potential impact of these factors on vascular health. Factors associated with baseline and progressive vascular stiffness, calcification and left ventricular mass index (LVMI) were analysed.

Results:

In the meta-analysis of published data, subclinical vitamin K deficiency (estimated from high levels of inactive vitamin K dependent proteins) was weakly associated with a combined endpoint of incident cardiovascular disease and mortality. This effect was maintained in a subgroup of patients considered to be from high-risk populations including CKD. In published reports across all adult populations, vitamin K supplementation was associated with a significant improvement in progression of vascular calcification, a non-significant trend towards improvement in vascular stiffness and a convincing reduction in vitamin K deficiency markers.

In the randomised, controlled trial, 90 participants with functioning kidney transplants were randomised 1:1 to vitamin K (n=45) or placebo (n=45) and included in the intention-to-treat analysis. Baseline demographics, clinical history and immuno suppression regimens were similar between groups: mean age 57.6 ± 9.6 years, 70% male, with median time after transplantation 7.8 (IQR 3.5- 13.9) years. Very few participants consumed adequate vitamin K-containing foods (especially green vegetables) to maintain dietary sufficiency. Vitamin K supplementation for 1 year did not reduce progression of vascular stiffness (ascending aortic distensibility: -0.2 (95% CI -0.5 - 0.2) vs -0.3 (95% CI -0.6 - 0.1) x10-3 mmHg-1 ; p=0.597), calcification (coronary artery calcium score: +184 (95% CI 52 - 315) vs +44 (95% CI -89 - 177) units; p=0.105) or any of the other pre-specified biochemical or clinical secondary endpoints. Achieved study power was 85%. Combining these new data with published and available unpublished reports, vitamin K supplementation was not associated with any identifiable improvement in vascular stiffness (mean difference -2.95 (95% CI -6.05 – 0.14) %; p=0.061) or calcification (mean difference -3.2 (95% CI -12.8 – 6.4) %; p=0.511), though with relatively few studies available for analysis.

Adjusted for age and gender, excess vascular stiffness, calcification and LVMI were common in kidney transplant recipients, but there was no consistent, reversible factor associated with baseline or progressive vascular stiffness, calcification or LVMI.

Conclusions:

The results in this thesis do not support vitamin K supplementation alone as a treatment strategy to reduce vascular stiffness and calcification across broad population groups. There may still be a role for vitamin K supplementation in high-risk groups as one part of a multi-faceted approach. Further work is required to identify whether combination therapy with other known calcification inhibitors may be beneficial, or whether targeting subclinical vitamin K deficiency with supplementation or dietary intervention could improve hard cardiovascular endpoints. In the meantime, major lifestyle change (with increased consumption of vegetables and improved exercise habits) is likely to be important to reduce cardiovascular risk.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: vitamin K, cardiovascular, vascular stiffness, vascular calcification, kidney disease, CKD, kidney transplant.
• Subjects: R Medicine > R Medicine (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Funder's Name: Kidney Research UK (KIDNEYRE), British Heart Foundation (BHF)
• Supervisor's Name: Mark, Professor Patrick B. and Jardine, Professor Alan G.
• Date of Award: 2020
• Embargo Date: 1 April 2023
• Depositing User: Dr Jennifer Lees
• Unique ID: glathesis:2020-81269
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 07 Apr 2020 08:18
• Last Modified: 10 Apr 2020 08:50
• Thesis DOI: 10.5525/gla.thesis.81269
• URI: https://theses.gla.ac.uk/id/eprint/81269

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