Vitamin K gets significant attention with regard to its influence on clotting factors. However, a growing body of evidence suggests a link between vitamin K status and calcification and bone and heart health. This is noteworthy considering that cardiac events continue to be the leading cause of death for those with chronic kidney disease (CKD).1 Considering vitamin K status may provide additional options for preventing complications and understanding their underlying causes.
Vitamin K is actually a collection of fat-soluble cofactors that activate vitamin K-dependent proteins (VKDP) primarily dealing with bone and vascular health (including blood clotting and preventing calcification). Vitamin K1, or phylloquinone, is found abundantly in green leafy vegetables. Vitamin K2, or menaquinones (MK), are produced by intestinal bacteria and found in fermented foods like cheese and natto (fermented soybeans), and liver.2 There are several known types of MK, and their effects may differ. For example, supplementation with MK-4, which can be converted from phylloquinones, increases prothrombin time/international normalized ratio (PT-INR), whereas MK-7 does not seem to have this impact.2,3,4
Studies across of patients with CKD stages 3-5 those on hemodialysis and peritoneal dialysis have found significant numbers of patients with vitamin K deficiency or subclinical deficiency. There are several suggested causes for low vitamin K levels in these populations:2
- Increased nutrient need to reduce calcification
- Low intake related to an over-restrictive traditional renal diet (specifically potassium restriction)
- Medications such as omeprazole and antibiotics that contribute to dysbiosis and reduce vitamin K production from gut bacteria. Warfarin use is also associated with increased calcification and lower vitamin K levels
- Uremia possibly due to reduced vitamin K cycle enzyme activity
Vascular calcification is a significant concern in those with CKD, affecting as many as 79% of those with non-dialysis-dependent CKD. Coronary artery calcification has been found in as many as 88% of patients older than 20 years undergoing hemodialysis.
Poor vitamin K status has been linked to an increased risk of calcification in CKD. There are multiple pathways proposed for this correlation, such as altered activity and function of smooth muscle cells and reduced production of matrix Gla protein that leads to increased calcification activity as well as reduced ability to inhibit calcification. Thus, it is suggested that low vitamin K2 may contribute to increased risk of atherosclerosis, calcification, higher bone breaks, and bone disease.5
Given the high frequency of vitamin K deficiency and correlation with serious issues, assessing vitamin K status and deficiency risk and improving vitamin K status is a worthy consideration in patients with CKD.
There are various options for assessing vitamin K status, albeit some are not easily available. Additionally, adequate amounts of intake or supplementation are not well established in the CKD population. Consequently, a multidisciplinary approach and clinical judgment should play a significant role in any vitamin K intervention.
Direct measurements of vitamin K are one approach, but patients’ lipid levels and smoking status may obscure results. Indirect methods may provide a more reliable option. These include measuring osteocalcin, matrix Gla protein, and dephosphorylated-carboxylated MGP (dp-cMGP). Osteocalcin and matrix Gla protein, however, have limitations in patients with advanced secondary hyperparathyroidism due to bone resorption and for those with later stages of CKD due to more retention of osteocalcin fragments. Measuring dp-cMGP may be more reliable, but testing may not be as readily available.6
In the absence of testing, use of clinical judgment combined with a review of deficiency risk factors can assist in assessing vitamin K status. Vitamin K2 supplementation, especially with MK-7, shows mixed results with regards to reducing calcification and improving cardiac related outcomes, although increased intake seems to consistently show benefit. Researchers postulate that higher vitamin K doses for longer periods of time than allowed in studies may be needed to see results.1 It is also worth considering, as it is with many vitamins, dietary sources of vitamin K have a synergistic effect with supplementation that contributes to improved outcomes. In light of this, dietitians can play a key role in supporting physicians and other nephrology providers in assessing vitamin K status, supporting gut health to ensure optimal K2 production as well as digestion and absorption of nutrients, and liberating patients from the restrictions of a traditional renal diet that evidence continues to show is not heart-healthy and creates more fear and confusion for patients with CKD.7
While it is clear that additional research needs to be done to clarify vitamin K’s role in CKD and the when’s and how’s of replenishing vitamin K, nephrology providers can act now, using clinical judgment to manage patients’ vitamin K status. As providers use clinical judgment to support all aspects of kidney care, they increase the practice-based evidence that expands the evidence base of effective interventions to improve CKD outcomes using all available tools.8
Lindsey Zirker, MS, RD, is a renal dietitian and Director of Clinical Services for the Kidney Nutrition Institute in Titusville, Florida. She specializes in autoimmune kidney disease and advanced practice medical nutrition therapy for people with kidney disease.
- Grzejszczak P, Kurnatowska I. Role of vitamin K in CKD: Is its supplementation advisable in CKD patients? Kidney Blood Press Res.2021;46(5):523-530. Doi:10.1159/000526611
- Cozzolino M, Mangano M, Galassi A, Ciceri P, Messa P, Nigwekar S. Vitamin K in chronic kidney disease. Nutrients. 2019;11(1):168. doi:10.3390/nu11010168
- Bus K, Szterk A. Relationship between structure and biological activity of various vitamin K forms. Foods. 2021;10(12):3136. doi:10.3390/foods10123136
- Ren R, Liu J, Cheng G, Tan J. Vitamin K2 (Menaquinone-7) supplementation does not affect vitamin K-dependent coagulation factors activity in healthy individuals. Medicine (Baltimore). 2021;100(23):e26221. doi:10.1097/MD.0000000000026221
- Levy DS, Grewal R, Le TH. Vitamin K deficiency: an emerging player in the pathogenesis of vascular calcification and an iatrogenic consequence of therapies in advanced renal disease. Am J Physiol Renal Physiol. 2020;319(4):F618-F623. doi:10.1152/ajprenal.00278.2020.
- Evenepoel P, Claes K, Meijers B, et al. Poor Vitamin K status is associated with low bone mineral density and increased fracture risk in end-stage renal disease. J Bone Miner Res. 2019;34(2):262-269. doi:10.1002/jbmr.3608
- Biruete A, Jeong JH, Barnes JL, Wilund KR. Modified nutritional recommendations to improve dietary patterns and outcomes in hemodialysis patients. J Ren Nutr. 2017;27(1):62-70. doi:10.1053/j.jrn.2016.06.001
- Frieden T. Why the ‘gold standard’ of medical research is no longer enough. STATnews. August 2, 2017.