CKD: Micronutrients: Vitamin K Supplementation (2020)
Click here to see the explanation of recommendation ratings (Strong, Fair, Weak, Consensus, Insufficient Evidence) and labels (Imperative or Conditional). To see more detail on the evidence from which the following recommendations were drawn, use the hyperlinks in the Supporting Evidence Section below.
CKD: Anticoagulant Medication and Vitamin K Supplementation
In adults with CKD 1-5D or posttransplantation, it is reasonable that patients receiving anticoagulant medicines known to inhibit vitamin K activity (e.g., warfarin compounds) do not receive vitamin K supplements (OPINION).
Risks/Harms of Implementing This Recommendation
There are no obvious risks and harms associated with this recommendation.
Conditions of Application
The United States Institute of Medicine states that the Adequate Intake of vitamin K is 120 and 90 micrograms per day for adult men and women, respectively (DRI 2001; Shearer et al 2014). These values are based on median vitamin K intakes reported in the NHANES III data. Globally, dietary recommendations for vitamin K usually vary from 50 to 120 micrograms/day (Fusaro et al 2017). These recommendations do not differentiate phylloquinone from menaquinone intake. At the time the US Institute of Medicine recommendations were set, the food composition databases on which these recommendations were made only contained the phylloquinone content of foods. Hence, these current recommendations are based on phylloquinone, which is the major form of vitamin K in Western diets.
A study of the NHANES data indicated that 72.1% of adults with mild-moderate CKD (eGFR-EPI 58 mL/min/1.73m2) had vitamin K intake below the recommended adequate Intake (AI) level (mean, 97.5 µg/day; 95%CI, 89.7-105.3) (Cheung et al 2015). Studies in Italy confirmed that daily intake of vitamin K1 in MHD patients is commonly below recommended levels (Fusaro et al 2017). Several observational studies in advanced CKD (stages 3-5) or MHD patients indicated that serum vitamin K1 (phylloquinone) and vitamin K2 (menaquinone) concentrations were frequently low and that serum levels of other uncarboxylated compounds which, when elevated, indicated vitamin K deficiency were increased (Thamratnopkoon et al 2017; Westenfeld et al 2012).
The recommended dietary vitamin K intake for patients with CKD 1-5, including those with the nephrotic syndrome, those who are undergoing MHD or PD or those who are post-transplant recipients were not defined and were based on that derived for the general population. In MHD patients, vitamin K intake and serum vitamin K levels are often low or undetectable, and serum uncarboxylated osteocalcin and PIVKA-II are commonly elevated (Westenfeld et al 2012, Elliott et al 2014).
- Suggested vitamin intake should be based on recommendations for the general population (ex: Recommended Dietary Allowance) unless there are specific considerations requiring modification.
- Patients receiving antibiotics who have poor intake and at higher risk of bleeding (e.g., surgical patients) may be considered for vitamin K supplements, particularly if they have acute kidney injury or chronic kidney disease(Pineo et al 1973). However, the foregoing conclusions were essentially based on observational studies of small number of patients. Increasing age, platelet count and serum urea and creatinine and lower serum albumin concentrations were associated with more severe elevation in prothrombin time in patients taking antibiotics (Pineo et al 1973, Williams et al 1991). Vitamin K supplements may return prothrombin time to normal in such patients (Williams et al 1991). However, the foregoing conclusions were essentially based on observational studies of small number of patients.
- The RDN may provide dietary assessment/counseling related to excess dietary intake of Vitamin K or irregular excess intake of foods containing high vitamin K; and providing education regarding dietary sources of vitamin K.
Potential Costs Associated with Application
There are no obvious costs associated with this recommendation.
Vitamin K is a fat-soluble vitamin that acts as a cofactor for gamma-glutamyl carboxylase which enables the carboxylation of vitamin K-dependent proteins producing coagulation factors. Coagulation factors II, VII, IX and X are the most well-known vitamin K-dependent proteins, and deficiency in these factors can lead to impairment in blood clotting. Vitamin K also enables normal calcification processes to proceed in bone and soft tissues. Matrix Gla protein (MGP) is a vitamin K-dependent protein produced by vascular smooth muscle cells (VSMCs) that is a powerful inhibitor of vascular calcification in culture media and of intimal atherosclerotic plaque calcification. After carboxylation, MGP binds to calcium crystals, inhibiting further crystal growth. MGP binds to bone morphogenetic protein-2 (BMP-2) thereby blocking the differentiation of VSMCs towards osteochondrogenic type cells. Vitamin K participates in the enzymatic carboxylation of proteins controlling bone calcium deposition (e.g., osteocalcin) and also plays an important role in normal bone formation and structure.
Hence Vitamin K, by facilitating carboxylation of certain proteins, has major effects on blood clothing, preventing soft tissue calcification, including vascular calcification and controlling bone calcium crystal formation.
Two classes of vitamin K compounds are primarily responsible for vitamin K activity, phylloquinone (vitamin K1) and menaquinones (vitamin K2) (Harshman et al 2014). Phylloquinone is found primarily in foods, especially green and leafy vegetables (e.g., spinach, kale, cabbage, broccoli), plant based oils found in many food products, and cow’s milk. There are more than 10 menaquinones which differ in the number of isoprenoid units in its side chain. Most menaquinones are produced by bacteria. Menaquinone 4 is different and appears to be produced in vivo from phylloquinone (Harshman et al 2014; Card et al 2014). Menaquinones are found in dairy products (yogurt) meats, and fermented foods, and also synthesized in the intestine by colonic bacteria. The Intestinal absorption of vitamin K requires biliary and pancreatic secretions and occurs in the small intestine where vitamin K is incorporated into chylomicrons. The role of the menaquinones in vitamin K function and nutritional needs is still not completely understood. Large doses of vitamin E may induce vitamin K deficiency (Card et al 2014).
Vitamin K Levels
Only one short term randomized controlled study has been published that examined the effects of vitamin K supplements on vitamin K status in MHD patients (Westenfeld et al 2012). No such studies have been carried out in other stages of CKD or in PD patients or those post-transplant. The study involved small number of patients who received, by random assignment, supplements of 45, 135 or 360 micrograms per day of vitamin K2 (menaquinone-7) for only six weeks. In general, there was a dose dependent increase in serum vitamin K2 and decrease in serum dpucMGP, ucosteocalcin and PIVKD-II. Mean serum vitamin K2 rose to previously reported normal values with the 45 µg/day dose and to modestly above normal values with the 135 and 360 µg/day doses. Serum dpucMGP, ucosteocalcin and PIVKD-II decreased most with the 360 µg/day dose, but concentrations still tended to be above normal with this dose.
There are currently several clinical trials of vitamin K supplements in MHD patients, and more information regarding vitamin K supplementation should be available within the near future (Caluwe et al 2014; Holden et al 2015; Krueger et al 2014).(Clinical Trials Identifier: NCT01528800; NCT01742273; NCT2610933; NCT02870829; UMIN000011490; UMIN000017119). There is a paucity of data on the long-term safety of different vitamin K intakes and especially of vitamin K supplements and of the value, if any, of taking different vitamin K compounds. Individuals receiving vitamin K supplements should not receive anticoagulant medicines that inhibit vitamin K activity (e.g., warfarin compounds).
Recommendation Strength Rationale
The recommendation regarding vitamin K supplementation is based on Consensus/expert opinion.
- Risks/Harms of Implementing This Recommendation
The recommendations were created from the evidence analysis on the following questions. To see detail of the evidence analysis, click the blue hyperlinks below (recommendations rated consensus will not have supporting evidence linked).
What is the effect of vitamin K supplementation on vitamin K levels in adults with CKD 1-5D and post-transplant?
What is the effect of vitamin K supplementation on dephosphorylated-uncarboxylated MGP levels in adults with CKD 1-5D and post-transplant?
Westenfeld R, Krueger T, Schlieper G, Cranenburg E, Magdeleyns E, Heidenreich S, Holzmann S, Vermeer C, Jahnen-Dechent W, Ketteler M, Floege J, Schurgers L. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. American Journal of Kidney Diseases : the official journal of the National Kidney Foundation 2012; 59:186-95
References not graded in Academy of Nutrition and Dietetics Evidence Analysis Process
Caluwe R, Vandecasteele S, Van Vlem B, Vermeer C, De Vriese AS. Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study. Nephrol Dial Transplant. 2014;29(7):1385-90. PMID: 24285428
Card DJ, Gorska R, Cutler J, Harrington DJ. Vitamin K metabolism: current knowledge and future research. Mol Nutr Food Res. 2014;58(8):1590-1600. PMID: 24376012
Cheung CL, Sahni S, Cheung BM, Sing CW, Wong IC. Vitamin K intake and mortality in people with chronic kidney disease from NHANES III. Clin Nutr. 2015;34(2):235-40. PMID: 24745600
In: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington (DC)2001.
Elliott MJ, Booth SL, Hopman WM, Holden RM. Assessment of potential biomarkers of subclinical vitamin K deficiency in patients with end-stage kidney disease. Can J Kidney Health Dis. 2014;1:13. PMID: 25780608
Fusaro M, D'Alessandro C, Noale M, et al. Low vitamin K1 intake in haemodialysis patients. Clin Nutr 2017;36(2):601-7. PMID: 27234935
Harshman SG, Saltzman E, Booth SL. Vitamin K: dietary intake and requirements in different clinical conditions. Curr Opin Clin Nutr Metab Care. 2014;17(6):531-8. PMID: 25232640
Holden RM, Booth SL, Day AG, et al. Inhibiting the progression of arterial calcification with vitamin K in HemoDialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease. Can J Kidney Health Dis. 2015;2:17. PMID: 26075081
Krueger T, Schlieper G, Schurgers L, et al. Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol. Nephrol Dial Transplant. 2014;29(9):1633-1638.
Pineo GF, Gallus AS, Hirsh J. Unexpected vitamin K deficiency in hospitalized patients. Can Med Assoc J. 1973;109(9):880-3. PMID: 4750303
Shearer MJ, Newman P. Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res. 2014;55(3):345-62. PMID: 24489112
Thamratnopkoon S, Susantitaphong P, Tumkosit M, et al. Correlations of Plasma Desphosphorylated Uncarboxylated Matrix Gla Protein with Vascular Calcification and Vascular Stiffness in Chronic Kidney Disease. Nephron. 2017;135(3):167-72. PMID: 27951533
Usui Y, Tanimura H, Nishimura N, Kobayashi N, Okanoue T, Ozawa K. Vitamin K concentrations in the plasma and liver of surgical patients. Ame J Clin Nutr. 1990;51(5):846-52. PMID: 2333843
Williams KJ, Bax RP, Brown H, Machin SJ. Antibiotic treatment and associated prolonged prothrombin time. J Clin Pathol. 1991;44(9):738-41. PMID: 1918399