title: Investigating the effects of vitamin K on vascular health and disease
Creators: name: Lees, Jennifer S.
Publisher: name: University of Glasgow
Year: 2020
Subjects: subject: vitamin K, cardiovascular, vascular stiffness, vascular calcification, kidney disease, CKD, kidney transplant.

description: Patients with chronic kidney disease are exposed to risk of cardiovascular disease that 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 for age and gender in patients with chronic kidney disease. 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 vitamin K deficiency is seen in patients with chronic kidney disease 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 chronic kidney disease. The hypothesis of this thesis is that vitamin K deficiency drives vascular stiffness and calcification in excess for age and gender in patients with established kidney disease, and that this is one contributing mechanism for the excess cardiovascular risk seen in patients with CKD. I explored whether vitamin K deficiency was associated with cardiovascular events and mortality in population studies. I reviewed whether vitamin K deficiency was evident and associated with vascular stiffness and calcification in human studies, and whether supplementation with vitamin K regressed existing (or slow progression of) vascular stiffness and calcification in these patients. These hypotheses were explored in two main ways: 1. Two-part systematic review and meta-analysis of the published data describing: i) the relationship between vitamin K status markers, specifically high levels of uncarboxylated (inactive) vitamin K dependent proteins, and incident cardiovascular disease and mortality; ii) the effect of vitamin K supplementation on vascular stiffness and calcification in controlled trials in adults. 2. A randomised, double-blind, placebo-controlled trial of vitamin K supplementation in prevalent kidney transplant recipients to assess the effects on vascular stiffness and calcification. Participants were recruited at least 1 year after receiving a functioning kidney transplant and randomly allocated, in a 1:1 ratio, to receive vitamin K (menadiol diphosphate 5mg) or placebo three times per week, over a treatment and follow-up period of 1 year. There was a baseline visit, a safety check blood test at 1 month and two further visits at 6 and 12 months. 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. Secondary endpoints included vascular calcification (non-contrast computed tomography coronary artery calcium score), left ventricular mass index (cardiac magnetic resonance imaging), transplant function, and other clinical and biochemical markers of vascular health, again as between-group differences 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 were analysed. In the published data, and across all population groups, high levels of uncarboxylated (inactive) vitamin K dependent proteins were weakly associated with a combined endpoint of incident cardiovascular disease and mortality (log hazard ratio 0.45 (95% CI 0.07 – 0.83); p=0.019), but with evidence of publication bias in favour of studies demonstrating a positive association between vitamin K deficiency and cardiovascular or mortality outcome. High levels of uncarboxylated (inactive) vitamin K dependent proteins were not associated with incident cardiovascular disease alone (log hazard ratio 0.26 (95% CI -0.13 - 0.66), p=0.20) or death alone (log hazard ratio 0.64 (95% CI -0.02 - 1.29), p=0.06). In a subgroup of patients considered to be from high-risk populations including CKD, vitamin K deficiency was associated with combined outcome of cardiovascular disease or death (log hazard ratio 0.55 (95% CI 0.10 – 1.00); p=0.016) and an increased risk of death (log hazard ratio 0.87 (95% CI 0.13 – 1.62); p=0.022), but not with cardiovascular disease alone; however, there was again evidence of publication bias in favour of positive results. In published reports across all adult populations, vitamin K supplementation was associated with a significant improvement in progression of vascular calcification (3 studies, n=407; mean difference -9.14% (95% CI (-17.8 - -0.52); p=0.038), a non-significant trend towards improvement in vascular stiffness (3 studies, n=445; mean difference -3.70 (95% CI -7.77 - 0.37) %, p=0.075), and a convincing reduction in vitamin K deficiency markers. In the randomised, controlled trial, very few participants (kidney transplant recipients) displayed dietary habits in line with government recommendations, particularly in relation to consumption of fruit and vegetables and other sources of dietary fibre. Those who did had lower body mass index and were more likely to maintain healthier dietary habits overall, including lower consumption of processed foods and higher intake of fish. Both low vegetable (and thus vitamin K) intake and high intake of processed foods are likely to contribute to subclinical vitamin K deficiency, vascular stiffness and calcification in this cohort at high risk of cardiovascular disease. 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 immunosuppression 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. The population of participants was comparable to the prevalent UK transplant population in terms of age, gender and transplant function but had a lower prevalence of vascular disease and diabetes as their primary cause of kidney disease. In this group of 90 participants, 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 and excess vascular calcification were common in kidney transplant recipients, but there was no consistent, reversible factor associated with baseline or progressive vascular stiffness or calcification. This analysis offered no target for intervention to reduce the progression of vascular stiffness and calcification and the associated risk of cardiovascular disease. These results 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. With increasing interest in and availability of large population datasets including biobank resources, it may be possible to identify novel calcification inhibitors or other biomarkers of vascular risk as targets for intervention to reduce vascular risk in patients with chronic kidney disease.