Vitamin K Deficiency in Chronic Kidney Disease: Evidence Is Building Up

adds an important piece of understanding to the framework of the deranged vitamin K metabolism in CKD. A reduced GGCX activity in the kidneys and in the aorta (but not in the liver) of uremic animals was previously found by Kaesler et al. [3] , indicating that uremia per se affects the vitamin K system. In addition, supplementation of phylloquinone or menaquinone (MK-4) at pharmacological doses restored the abnormal vitamin K cycle activity and slowed the progression of vascular calcification [3] . Additional evidence is now available from studies in humans. An observational, prospective study of 167 CKD patients (stages 3–5) highlighted that patients with the CG/GG genotype of vitamin K epoxide reductase complex subunit 1 (the enzyme target of warfarin) had a higher risk of coronary artery calcification progression and poorer survival [4] . Taken together, these findings are consistent with the higher prevalence of vascular calcifications in hemodialysis patients, as well as with the observation of warfarin-associated increased calcifications in patients with CKD [5] . A reduced dietary intake may be an important additional cause of vitamin K deficiency in CKD patients, as indicated by previous studies, in part due to the dietary limitations imposed by the uremic status. Recently, we confirmed a low vitamin K 1 intake in hemodialysis patients on a Mediterranean diet, compared to control subjects with normal renal function [6] . Participants completed a food journal of 7 consecutive days for the estimaVitamin K has important biological actions, mediated by the activation of vitamin K-dependent proteins ( VKDPs), such as blood coagulation factors and other proteins involved in bone metabolism and in the inhibition of vascular calcifications. Table 1 summarizes the physiological function of the main VKDPs and the consequences of vitamin K deficiency in patients with chronic kidney disease (CKD) and normal renal function. Vitamin K deficiency may result in the following: (a) anticoagulation with warfarin, a well-known inhibitor of vitamin K 2,3-epoxide reductase, vitamin K recycling (VKOR), an enzyme that recycles oxidized vitamin K to its reduced form; (b) inadequate dietary intake of vitamin K. There are 2 main forms of vitamin K: K 1 or phylloquinone, found in green vegetables, and K 2 or menaquinones (MK-n), found in specific food (such as natto, in Japan) or derived from the metabolic activity of intestinal bacteria. MK-4 is the unique menaquinone produced by systemic conversion of phylloquinone to vitamin K 2 through the action of prenyltransferase domain-containing protein 1 (UBIAD1) [1] . In this issue of the AJN, McCabe et al. [2] highlight, in a rat model of adenine-induced renal failure, how CKD can negatively affect vitamin K metabolism, generating a decreased expression of VKOR and utilization (γ-glutamyl carboxylase, Ggcx) enzymes in thoracic aorta. In addition, the uremic status was associated with a decrease in the kidney level of the phylloquinone to MK-4 bioconversion enzyme, UBIAD1. Thus, this study Published online: November 15, 2016 Nephrology American Journal of