Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease

Abstract

The leading cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease, with vascular calcification being a key modifier of disease progression. A local regulator of vascular calcification is vitamin K. This γ-glutamyl carboxylase substrate is an essential cofactor in the activation of several extracellular matrix proteins that inhibit calcification. Warfarin, a common therapy in dialysis patients, inhibits the recycling of vitamin K and thereby decreases the inhibitory activity of these proteins. In this study, we sought to determine whether modifying vitamin K status, either by increasing dietary vitamin K intake or by antagonism with therapeutic doses of warfarin, could alter the development of vascular calcification in male Sprague-Dawley rats with adenine-induced CKD. Treatment of CKD rats with warfarin markedly increased pulse pressure and pulse wave velocity, as well as significantly increased calcium concentrations in the thoracic aorta (3-fold), abdominal aorta (8-fold), renal artery (4-fold), and carotid artery (20-fold). In contrast, treatment with high dietary vitamin K1 increased vitamin K tissue concentrations (10-300-fold) and blunted the development of vascular calcification. Thus, vitamin K has an important role in modifying mechanisms linked to the susceptibility of arteries to calcify in an experimental model of CKD.

Vascular Calcification in Patients with Nondialysis CKD over 3 Years

“…More interestingly, hyperparathyroidism was an independent predictor for kidney progression, which had not been fully shown previously (30), whereas low vitamin D levels were associated to all-cause mortality and ESRD after adjusting for age and eGFR, respectively. Lastly, we would like to draw attention to the independent association observed between the use of oral anticoagulants and VC, which has been previously reported (33)(34)(35). Although this association does not imply causation, it should be evaluated in future clinical trials designed to test anticoagulation strategies in the CKD population.…”

A current understanding of vascular calcification in CKD

“…Vitamin K antagonists, such as warfarin, are used commonly in CKD patients and interfere with the generation of active MGP (88). Adenine-induced CKD mice treated with therapeutic doses of warfarin develop significant vascular calcification, and warfarin use is associated with vascular calcification in the hemodialysis population (48,69). Circulating levels of dephosphorylated uncarboxylated (inactive) MGP have been found to increase with worsening stages of CKD, and these elevated levels are associated with the severity of aortic calcification.…”

Anticoagulation for Atrial Fibrillation in End-stage Kidney Disease

“…McCabe et al (23) similarly reported increased vascular calcification in rats with CKD on warfarin, which was also blunted by vitamin K. In a retrospective study of 108 haemodialysis (HD) patients, an association was found between duration of warfarin exposure and degree of aortic valve calcification after adjustment for dialysis vintage, calcium and calcitriol intake (24). Furthermore, a recent Japanese study found an 11-fold risk in HD patients on warfarin for calciphylaxis (uraemic calcific arteriolopathy), an uncommon complication of ESKD characterised by skin ulceration and necrosis with small vessel medial calcification and intimal proliferation (25).…”