Vitamin K status in chronic kidney disease: a report of a study and a mini-review

Abstract

Hepatic vitamin K-dependent proteins (e.g., Factors II, VII, IX and X) form part of the clotting cascade. Factor II (FII)/Prothrombin incorporates 10 Glu residues on the N-terminal region that are γ-carboxylated to Gla residues by the action of γ-glutamyl carboxylase to confer biological activity. Vitamin K is also required for the normal function of Matrix Gla Protein (MGP)--one of several non-clotting-related extra-hepatic vitamin K-dependent proteins. MGP is known to have protective action against vascular calcification--indeed it is a powerful tissue-bound inhibitory mechanism and can be found in blood vessel walls. The mature protein is also dependent on activation by γ-glutamyl carboxylase enzyme to convert Glu residues in its amino acid sequence to Gla. This reaction can only take place when the enzyme is activated in the presence of vitamin K. It is of great potential interest to investigate whether subtle deficiencies of vitamin K may, through its effect on the action of MGP, be a contributing factor to vascular calcification in CKD patients, in whom CV disease is greatly accelerated and in whom vascular calcification is not only common, but progresses aggressively, and is something for which as yet there is no clinically applicable remedy.

Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients

“…This was not the case in our population (data not shown) but our sample of prevalent VKA treated patients (n = 23) was probably too small. Several authors have suggested that VKA treatment is a risk factor for vascular calcifications or calciphylaxis in HD patients but this assertion deserves further study [24, 32, 35, 39–46]. Third, the Kauppila method is not the most sensitive way of detecting vascular calcifications and we did not directly measure neither vitamin K levels nor other vitamin K dependent protein like PIVKA-II (protein induced by vitamin K absence II).…”

“…This high concentration of dp-ucMGP in HD patients is not fully understood. These patients are clearly sensitive to vitamin K deficiency, and this is likely because the recommended diet in HD patients is deficient in vitamin K [19–22, 24]. However, decreased excretion or catabolism of MGP associated with decreased glomerular filtration is also a plausible explanation for the molecular weight of MGP (11 kDa) [7, 33].…”

“…There are several in vitro and in vivo data suggesting a direct link between the decreased availability of vitamin K and vascular calcification, based on the role of this vitamin in the activation of MGP [9, 18]. Various authors have described a decreased availability of vitamin K (both K 1 and K 2) in patients with chronic kidney disease (CKD) [19–24]. As a result, the level of the inactive form, dp-ucMGP, has been found to increase in these patients, in comparison with non-CKD patients [7, 10, 21, 22, 25].…”

The Association of dp-ucMGP with Cardiovascular Morbidity and Decreased Renal Function in Diabetic Chronic Kidney Disease

“…This is why currently, the most reliable markers of vitamin K status are considered circulating dp-ucMGP and proteins induced by vitamin K absence or antagonism (PIVKA), which is a collective marker of all undercarboxylated, inactive vitamin K dependent proteins [ 53 ]. The prevalence of vitamin K deficiency (measured by PIVKA) augments in parallel with progression of CKD [ 54 ] and reaches 83–97% in HD patients [ 35 , 55 ]. Moreover, in these populations, subclinical vitamin K deficiency (assessed either by PIVKA or dp-ucMGP) has been repeatedly associated with increased VC and CV disease [ 56 , 57 ].…”

Influence of Kidney Function on Risk of Supratherapeutic International Normalized Ratio–Related Hemorrhage in Warfarin Users: A Prospective Cohort Study

“…This is supported by the influence of decreased kidney function on the carboxylation of matrix Gla-protein, another vitamin K-dependent protein. 44–46 The slower rate of INR decline, together with other factors (e.g. uremia, platelet dysfunction) known to be associated with kidney disease, could explain the higher risk of hemorrhagic complications.…”