In the article “Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies”, Kremer et al. measured plasma levels of dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) in patients with chronic renal failure (CRF) and correlated these with plasma creatinine [1]. MGP is a vitamin K-dependent calcification inhibitor that may undergo two activation steps—phosphorylation and carboxylation—creating four MGP variants: 1. dp-ucMGP; 2. phosphorylated-carboxylated (p-c)MGP; 3. p-ucMGP; and 4. dp-cMGP [2]. Circulating dp-ucMGP reflects vitamin K status with high and low dp-ucMGP levels representing vitamin K deficiency and sufficiency, respectively [2].
Kremer et al. demonstrated that dp-ucMGP positively correlates with creatinine in CRF patients and concluded that dp-ucMGP should therefore be corrected for kidney function [1]. However, a correlation between a biomarker and kidney function does not automatically imply that it should be corrected for creatinine. Adjustment would only be appropriate if the rise is caused by a fall in renal function. Rennenberg et al., however, demonstrated that the average renal fractional extraction of MGP is independent of kidney function in hypertensive patients [3]. Theoretically, it could be the case that MGP variants in CRF are differentially excreted in urine, but Kremer et al. did not provide convincing evidence for this [1].
The correlation between dp-ucMGP and creatinine in CRF likely reflects a mechanistic link. Vascular calcification is prevalent in CRF due to disorders in mineral metabolism and increases as the glomerular filtration rate declines [4]. Calcium deposition leads to MGP upregulation to protect blood vessels from further mineralization [5]. MGP, however, is only functional after vitamin K-dependent carboxylation [6]. Activation of synthesized MGP may lead to depletion of vitamin K stores and subsequent vitamin K deficiency, which is reflected by increased dp-ucMGP levels. Adequate levels of cMGP are crucial to maintain the patency of blood vessels [5]. In a state of vitamin K deficiency, there is insufficient cMGP activity in the kidneys, exacerbating vascular deterioration and renal failure [7].
We conclude that the correlation between dp-ucMGP and creatinine is far more likely the result of vitamin K deficiency than a function of a decreased glomerular filtration rate. Regardless of any renal influence on dp-ucMGP levels, elevated dp-ucMGP levels should, in our opinion, be normalized by vitamin K administration and not through adjusting for creatinine.
Author Contributions
Writing—original draft preparation, R.J.; writing—review and editing, J.W. and C.V. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
R.J. discloses a patent on vitamin K in COVID-19 (WO 2021/206560). R.J. and J.W. have a scientific collaboration with Kappa Bioscience AS, a manufacturer of vitamin K2 (MK-7). C.V. declares no competing interest.
References
- Kremer, D.; Groothof, D.; Keyzer, C.A.; Eelderink, C.; Knobbe, T.J.; Post, A.; van Londen, M.; Eisenga, M.F.; TransplantLines Investigators; Schurgers, L.J.; et al. Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies. Nutrients 2021, 13, 3069. [Google Scholar] [CrossRef] [PubMed]
- Wei, F.F.; Trenson, S.; Verhamme, P.; Vermeer, C.; Staessen, J.A. Vitamin K-Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity. Hypertension 2019, 73, 1160–1169. [Google Scholar] [CrossRef] [PubMed]
- Rennenberg, R.J.; Schurgers, L.J.; Vermeer, C.; Scholte, J.B.; Houben, A.J.; de Leeuw, P.W.; Kroon, A.A. Renal handling of matrix Gla-protein in humans with moderate to severe hypertension. Hypertens. Res. 2008, 31, 1745–1751. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Palit, S.; Kendrick, J. Vascular calcification in chronic kidney disease: Role of disordered mineral metabolism. Curr. Pharm. Des. 2014, 20, 5829–5833. [Google Scholar] [CrossRef] [PubMed]
- Price, P.A.; Buckley, J.R.; Williamson, M.K. The amino bisphosphonate ibandronate prevents vitamin D toxicity and inhibits vitamin D-induced calcification of arteries, cartilage, lungs and kidneys in rats. J. Nutr. 2001, 131, 2910–2915. [Google Scholar] [CrossRef] [PubMed]
- Schurgers, L.J.; Cranenburg, E.C.; Vermeer, C. Matrix Gla-protein: The calcification inhibitor in need of vitamin K. Thromb. Haemost. 2008, 100, 593–603. [Google Scholar] [PubMed]
- Roumeliotis, S.; Roumeliotis, A.; Dounousi, E.; Eleftheriadis, T.; Liakopoulos, V. Vitamin K for the Treatment of Cardiovascular Disease in End-Stage Renal Disease Patients: Is there Hope? Curr. Vasc. Pharmacol. 2021, 19, 77–90. [Google Scholar] [CrossRef] [PubMed]
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