Vitamin K metabolism in a rat model of chronic kidney disease

Authors: MCCABE, KRISTIN - Queen'S University - Canada; BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; FU, XUEYAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WARD, EMILIE - Queen'S University - Canada; ADAMS, MICHAEL - Queen'S University - Canada; HOLDEN, RACHEL - Queen'S University - Canada

Submitted to: The American Journal of Nephrology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/18/2016
Publication Date: 11/16/2016
Citation: McCabe, K.M., Booth, S.L., Fu, X., Ward, E., Adams, M.A., Holden, R.M. 2016. Vitamin K metabolism in a rat model of chronic kidney disease. The American Journal of Nephrology. 45:4-13. doi: 10.1159/000451068.

Interpretive Summary: The major form of vitamin K found in the diet and in circulation is phylloquinone. Phylloquinone is converted to menaquinone-4 (MK-4) in certain tissues, including the kidney. Both phylloquinone and menaquinone-4 confer function on vitamin K-dependent proteins. Patients with chronic kidney disease have very high levels of inactive vitamin K-dependent proteins measured in circulation. It is not known if these these high levels of non-functional proteins reflect low vitamin K intakes or an alteration of vitamin K metabolism. In the present study, we assessed tissue concentrations of phylloquinone and MK-4 and the expression of vitamin K-related genes in an experimental rat model of chronic kidney disease. We found that rats with both mild and severe chronic kidney disease had lower amounts of phylloquinone measured in liver, spleen, and heart compared to rats without the chronic renal disease. In contrast, these rats had higher levels of MK-4 measured in the kidney. Among the rats fed high levels of phylloquinone in their diet, there was an increase in tissue levels of both phylloquinone and MK-4. However, the relative increase in phylloquinone compared to MK4 was different when compared among tissues, which suggests that the conversion of phylloquinone to MK-4 may be a regulated process in some tissues. There was a decrease in expression of the vitamin K-related enzymes. Taken together, these findings suggest that chronic kidney disease impacts vitamin K metabolism and that this occurs early in the disease course. Our findings suggest that vitamin K metabolism is altered in the presence of chronic kidney disease and provides further support that sub-clinical vitamin K deficiency may represent a modifiable risk factor for vascular health in this population.

Technical Abstract: Background: Patients with chronic kidney disease (CKD) have very high levels of uncarboxylated, inactive, extra-hepatic vitamin K-dependent proteins measured in circulation, putting them at risk for complications of vitamin K deficiency. The major form of vitamin K found in the liver is phylloquinone (K1). Menaquinone-4 (MK-4) is the form of vitamin K that is preferentially found in extra-hepatic tissues. Methods: In the present study, we assessed tissue concentrations of K1 and MK-4 and the expression of vitamin K-related genes in a rat model of adenine-induced CKD. Results: It was found that rats with both mild and severe CKD had significantly lower amounts of K1 measured in liver, spleen and heart and higher levels of MK-4 measured in kidney cortex and medulla. All animals treated with high dietary K1 had an increase in tissue levels of both K1 and MK-4; however, the relative increase in K1 differed suggesting that the conversion of K1 to MK-4 may be a regulated/limiting process in some tissues. There was a decrease in the thoracic aorta expression of vitamin K recycling (Vkor) and utilization (Ggcx) enzymes, and a decrease in the kidney level of vitamin K1 to MK-4 bioconversion enzyme Ubiad1 in CKD. Conclusion: Taken together, these findings suggest that CKD impacts vitamin K metabolism, and this occurs early in the disease course. Our findings that vitamin K metabolism is altered in the presence of CKD provides further support that sub-clinical vitamin K deficiency may represent a modifiable risk factor for vascular and bone health in this population.