Menadiol Sodium Diphosphate

Premature cardiovascular disease and death with a functioning graft are leading causes of death and graft loss respectively in kidney transplant recipients (KTR). Vascular stiffness and calcification are markers of cardiovascular disease that are prevalent in KTR and associated with subclinical vitamin K deficiency. We performed a single-centre, phase II, parallel-group, randomised, double-blind, placebo-controlled trial (ISRCTN22012044) to test whether vitamin K supplementation reduced vascular stiffness (MRI-based aortic distensibility) or calcification (coronary artery calcium score on computed tomography) in KTR over 1 year of treatment. The primary outcome was between-group difference in vascular stiffness (ascending aortic distensibility). KTR were recruited between September 2017 and June 2018, and randomised 1:1 to vitamin K (Menadiol diphosphate 5mg; n=45) or placebo (n=45) thrice-weekly. Baseline demographics, clinical history and immunosuppression regimens were similar between groups. There was no impact of vitamin K on vascular stiffness (treatment effect -0.23 (95% CI -0.75 to 0.29) x10^-3 mmHg^-1 ; p=0.377), vascular calcification (treatment effect -141 (95% CI -320 to 38) units; p=0.124), nor any other outcome measure. In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce vascular stiffness or calcification over 1 year. Improving vascular health in KTR is likely to require a multifaceted approach.

Renal transplant recipients (RTRs) exhibit increased vascular stiffness and calcification; these parameters are associated with increased cardiovascular risk. Activity of endogenous calcification inhibitors such as matrix gla protein (MGP) is dependent on vitamin K. RTRs commonly have subclinical vitamin K deficiency. The Vitamin K in kidney Transplant Organ Recipients: Investigating vEssel Stiffness (ViKTORIES) study assesses whether vitamin K supplementation reduces vascular stiffness and calcification in a diverse population of RTR.

ViKTORIES (ISRCTN22012044) is a single-centre, phase II, parallel-group, randomised, double-blind, placebo-controlled trial of the effect of vitamin K supplementation in 90 prevalent RTR. Participants are eligible if they have a functioning renal transplant for >1 year. Those on warfarin, with atrial fibrillation, estimated glomerular filtration rate <15 mL/min/1.73 m² or contraindications to MRI are excluded. Treatment is with vitamin K (menadiol diphosphate) 5 mg three times per week for 1 year or matching placebo. All participants have primary and secondary endpoint measures at 0 and 12 months. The primary endpoint is ascending aortic distensibility on cardiac MR imaging. Secondary endpoints include vascular calcification (coronary artery calcium score by CT), cardiac structure and function on MR, carotid-femoral pulse wave velocity, serum uncarboxylated MGP, transplant function, proteinuria and quality of life. The study is powered to detect 1.0×10^-3 mm Hg^-1 improvement in ascending aortic distensibility in the vitamin K group relative to placebo at 12 months. Analyses will be conducted as between-group differences at 12 months by intention to treat.

This trial may identify a novel, inexpensive and low-risk treatment to improve surrogate markers of cardiovascular risk in RTR.