Vitamin K status, all-cause mortality, and cardiovascular disease in adults with chronic kidney disease: the chronic renal insufficiency cohort

Authors: SHEA, KYLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BARGER, KATHRYN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, JIFAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FELDMAN, HAROLD - University Of Pennsylvania; TOWNSEND, RAYMOND - University Of Pennsylvania; CHEN, JING - Tulane School Of Medicine; FLACK, JOHN - Southern Illinois School Of Medicine; HE, JIANG - Tulane School Of Medicine; JAAR, BERNARD - Johns Hopkins University; KANSAL, MAYANK - University Of Illinois; ROSAS, SYLVIA - Harvard Medical School; WEINER, DANIEL - Tufts Medical Center

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/8/2021
Publication Date: 3/4/2022
Citation: Shea, K., Barger, K., Booth, S.L., Wang, J., Feldman, H.I., Townsend, R.R., Chen, J., Flack, J., He, J., Jaar, B.G., Kansal, M., Rosas, S.E., Weiner, D.E. 2022. Vitamin K status, all-cause mortality, and cardiovascular disease in adults with chronic kidney disease: the chronic renal insufficiency cohort. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqab375.
DOI: https://doi.org/10.1093/ajcn/nqab375

Interpretive Summary: Patients with chronic kidney disease frequently develop vascular calcification, which contributes to an increased risk for cardiovascular disease and all-cause mortality. Vitamin K-dependent proteins are involved in inhibiting vascular calcification. We investigated the association of vitamin K status with atherosclerotic cardiovascular disease and all-cause mortality in 3066 adults with chronic kidney disease. Vitamin K status was estimated using two blood measures: phylloquinone concentrations and uncarboxylated matrix gla protein (ucMGP) concentrations. Phylloquinone is the primary form of vitamin K in blood. UcMGP is a measure of vitamin K function, and concentrations increase when vitamin K status is low. On average, participants were 61 years old and were followed for 9.5 years. We found those with low circulating phylloquinone or high ucMGP had a 20-28% higher risk for death from all causes compared to those with high circulating phylloquinone or low ucMGP. However, the risk of atherosclerotic cardiovascular disease did not differ according to vitamin K status. Additional studies are needed to clarify why vitamin K status was associated with risk for death but not cardiovascular disease in adults with chronic kidney disease.

Technical Abstract: Background: Vascular calcification contributes to cardiovascular disease (CVD) and mortality in individuals with chronic kidney disease (CKD). Vitamin K-dependent proteins function as calcification inhibitors in vascular tissue. Objectives: We sought to determine the association of vitamin K status with mortality and CVD events in adults with CKD. Methods: Plasma dephospho-uncarboxylated matrix gla protein((dp)ucMGP), which increases when vitamin K status is low, and plasma phylloquinone (vitamin K1), which decreases when vitamin K status is low, were measured in 3066 Chronic Renal Insufficiency Cohort participants (median age equals 61 y, 45% female, 41% non-Hispanic black, median estimated glomerular filtration rate [eGFR] equals 41 mL/min/1.73m2). The association of vitamin K status biomarkers with all-cause mortality and atherosclerotic-related CVD was determined using multivariable Cox proportional hazards regression. Results: There were 1122 deaths and 599 atherosclerotic CVD events over the median 12.8 follow-up years. All-cause mortality risk was 21-29% lower among participants with plasma (dp)ucMGP <450 pmol/L (n equals 2361) compared with those with plasma (dp)ucMGP equals 450 pmol/L (adjusted HRs [95% CIs]: <300 pmol/L equals 0.71 [0.61, 0.83], 300-449 pmol/L equals 0.77 [0.66, 0.90]) and 16-19% lower among participants with plasma phylloquinone equals0.50 nmol/L (n equals 2421) compared to those with plasma phylloquinone <0.50 nmol/L (adjusted HRs: 0.50, 0.99 nmol/L equals 0.84 [0.72, 0.99], equals 1.00 nmol/L equals 0.81 [0.70, 0.95]). The risk of atherosclerotic CVD events did not significantly differ across plasma (dp)ucMGP or phylloquinone categories. Conclusions: Two biomarkers of vitamin K status were associated with a lower all-cause mortality risk but not atherosclerotic CVD events. Additional studies are needed to clarify the mechanism underlying this association and evaluate the impact of improving vitamin K status in people with CKD.