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

Miles D. Witham; Jennifer S. Lees; Myra White; Margaret Band; Samira Bell; Donna J. Chantler; Ian Ford; Roberta L. Fulton; Gwen Kennedy; Roberta C. Littleford; Ian V. McCrea; Deborah McGlynn; Maurizio Panarelli; Maximilian R. Ralston; Elaine Rutherford; Alison Severn; Nicola Thomson; Jamie P. Traynor; Allan D. Struthers; Kirsty Wetherall; Patrick B. Mark

doi:10.1681/ASN.2020020225

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Visual Abstract

Significance Statement

Among patients with CKD, vascular calcification is common and is an independent contributor to increased vascular stiffness and vascular risk. The authors investigated whether supplementation with vitamin K, a cofactor for proteins that inhibit vascular calcification, could improve arterial stiffness in patients with CKD, in a parallel-group, double-blind, randomized, placebo-controlled trial involving patients aged 18 or older with CKD stage 3b or 4. Vitamin K2 supplementation for 12 months did not improve vascular stiffness, as measured by pulse wave velocity. An updated meta-analysis including these new results confirmed a lack of efficacy of vitamin K supplementation on these end points. Longer treatment periods or therapies other than vitamin K may be required to improve vascular calcification and reduce arterial stiffness and cardiovascular risk in patients with CKD.

Abstract

Background Vascular 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.

Methods To 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.

Results We 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.

Conclusions Vitamin 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 number Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com)

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