Comment on Kremer et al. Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies. Nutrients 2021, 13, 3069.

In the article "Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies", Kremer et al. [...].

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.