Vitamin K Supplementation to Improve Vascular Stiffness in CKD: The K4Kidneys Randomized Controlled Trial

Abstract

BackgroundVascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown.MethodsTo determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15–45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study.ResultsWe included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures.ConclusionsVitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD.Clinical Trial registry name and registration numberVitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com)

Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches

“…Since vitamin K deficiency represents a key feature in the development of VC, the effects of vitamin K substitution have been investigated. A recently published study comparing oral vitamin K2 substitution versus placebo in CKD patients showed no improvement in vascular stiffness or other measures of vascular health [139]. Vitamin K1 supplementation however is a promising and uncomplicated way to positively influence VC in CKD patients and, therefore, its effect on CV risk is under investigation in current clinical trials (Table 3) [135,140].…”

Role of Uremic Toxins in Early Vascular Ageing and Calcification

“…Moreover, warfarin treatment (a vitamin K antagonist) induced coronary artery disease and vulnerable plaques in mice and vitamin K administration reversed such VC progression, suggesting the role of vitamin K in VC development [ 178 ]. However, the association between vitamin K status and VC in clinical observations are inconclusive [ 179 , 180 , 181 ] and the recent K4Kidneys trial failed to confirm the beneficial role of vitamin K supplement in vascular health [ 182 ].…”

Management of Cardiovascular Disease in Kidney Disease Study: Rationale and Design

“…Among the variety of methods evaluated for the measurement of vascular stiffness, APWV has been proven to have the best reproducibility and outcome validation and is the recommended method to test vascular stiffness by major regulatory bodies [40]. Recent studies with vitamin K therapy and nutritional vitamin D supplements have shown that vascular stiffness as examined by the APWV is a difficult parameter to modulate [41, 42], and at present time, no directed therapy is available for reducing vascular stiffness. While in vitro and in vivo studies show that hydroxychloroquine has the potentials to positively impact endothelial dysfunction, vascular calcification and smooth muscle dysfunction are also important modifiers of the vascular stiffness in CKD that are unlikely to be affected by hydroxychloroquine.…”