January 2019
Mario Cozzolino, Michela Mangano, Andrea Galassi, Paola Ciceri, Piergiorgio Messa, and Sagar Nigwekar
Abstract
Vitamin K is a composite term referring to a group of fat-soluble vitamins that function as a cofactor for the enzyme γ-glutamyl carboxylase (GGCX), which activates a number of vitamin K-dependent proteins (VKDPs) involved in haemostasis and vascular and bone health.
Accumulating evidence demonstrates that chronic kidney disease (CKD) patients suffer from subclinical vitamin K deficiency, suggesting that this represents a population at risk for the biological consequences of poor vitamin K status. This deficiency might be caused by exhaustion of vitamin K due to its high requirements by vitamin K-dependent proteins to inhibit calcification.
1. Introduction
There are two forms of vitamin K: K1 (phylloquinone, PK) mainly found in green vegetables, and K2 (including different menaquinones, MKs) derived from intestinal bacteria and fermented food (cheeses and “natty”, a Japanese soybean product) [1,2]. Liver is also a rich source of menaquinones [3]. We know about more than 12 different types of MKs, from MK-4 to MK-15, but the most common MKs in humans are the short-chain MK-4; it is the only MK produced by systemic conversion of phylloquinone to menaquinones [4].
Vitamin K is a non-polar molecule; after its intestinal absorption, vitamin k is solubilised by bile salt and pancreatic juice; vitamin K is then packaged into chylomicrons which are secreted into the lymphatic system [5]. For this reason lipids, in particular triglycerides, interfere with vitamin K measurement.
Vitamin K is as a substrate for an enzyme, the vitamin K-dependent carboxylase, that converts specific glutamic acid residues of a small number of proteins to glutamic carboxyl (Gla) residues by the addition of a CO2.
Vitamin K is necessary to introduce carboxyl groups into glutamic acid residues in blood coagulation factors (II, VII, IX, X) to yield Gla residues [6]; Gla-containing proteins include osteocalcin (OC), synthesized by the osteoblasts in bone, and matrix Gla protein (MGP), synthesized by chondrocytes and vascular smooth muscle cells (VSMCs), involved in bone mineralization and inhibition of vascular calcifications, respectively.
2. Vitamin K Deficiency
Indirect functional tests can be assessed to detect vitamin k levels, such as the prothrombin time or measurement of undercarboxylated proteins OC and MGP, which are more sensitive in detecting subclinical vitamin K deficiency than prothrombin time [6].
This measurement is possible because vitamin K-dependent proteins (VKDP) cannot attain their carboxylation status (and they remain undercarboxylated) in the presence of vitamin K deficiency; this condition causes the loss of their capacity to bind calcium, so that bone metabolism may be impaired and the process of vascular calcification enhanced [7].
A high percentage of undercarboxylated OC (uOC) reflects vitamin K intake and the long-term vitamin K status. Osteocalcin levels are also influenced by vitamin D, which is required for the production of uOC, and by parathyroid hormone (PTH), which is frequently elevated in CKD patients [6,8,9]. Therefore, chronic kidney disease (CKD) patients with hyperparathyroidism will present high serum uOC, but this does not necessarily mean that they are vitamin K deficient.
A good alternative to evaluate vitamin K status is through the inactive form of MGP, even if inactive MGP may only reflect the vitamin K status at the vascular level and not at bone or liver.
Indeed, randomized controlled studies have shown that vitamin K therapy decreases undercarboxylated unphosphorylated MGP (uc-dp-MGP) levels [9,10,11]; in contrast, anti-vitamin K (AVK) treatment increased the amount of inactive uc-dp-MGP [12] and stopping that treatment decreased uc-dp-MGP [13]. All these data suggest that uc-dp-MGP could be a good marker of vitamin K status [6].
