Vascular Calcification in Chronic Kidney Disease

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1		Stefanos Roumeliotis	+ 57 word(s)	57	2022-03-01 07:37:29	\|
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This entry is adapted from the peer-reviewed paper 10.3390/nu14050925

Chronic Kidney Disease (CKD) patients are at high risk of presenting with arterial calcification or stiffness, which confers increased cardiovascular mortality and morbidity. In recent years, it has become evident that VC is an active process regulated by various molecules that may act as inhibitors of vessel mineralization.

cardiovascular disease chronic kidney disease end-stage kidney disease vitamin k vascular calcification matrix gla protein

1. Introduction

Cardiovascular (CV) disease is highly prevalent among Chronic Kidney Disease (CKD) patients and remains the major cause of early morbidity and mortality sustained by this population. Pre-dialysis CKD patients are at a much greater risk of experiencing a fatal CV event than of progression to end-stage kidney disease (ESKD) requiring dialysis ^[1] and in ESKD the CV risk is further exacerbated ^[2].

This increased CV risk in ESKD patients cannot be solely attributed to traditional risk factors such as hypertension, diabetes, and dyslipidemia. Additionally, these patients are overexposed to novel uremia-specific factors including oxidative stress ^[3]^[4], inflammation, disorders of mineral metabolism, and endothelial dysfunction ^[5]. Furthermore, calcification of arteries and cardiac valves is very common in ESKD, triggering the onset and development of arterio- or atherosclerosis and subsequent CV disease. Therefore, the increased CV death rates of ESKD patients may partially reflect the accelerated rate of arterial calcification observed in these patients.

2. Vascular Calcification in Chronic Kidney Disease

Calcification of the arteries starts early in life and gradually increases with age; it is a common condition in the healthy aged. The presence and degree of vascular calcification (VC) are independent and each is a strong predictor of CV morbidity and mortality. As deposition and accumulation of calcium and hydroxyapatite in any artery of the human body increases the risk of developing CV disease by 3.5 times and CV death by 3.9 times ^[6], it has been suggested that their biological age is partially determined by the health status of their arteries ^[7]. There are four distinct histopathologic patterns of arterial calcification: calcification of the intima, calcification of the media, calcification of cardiac valves, and calciphylaxis. VC can exist in any one of these forms or in combinations of them. In CKD, all these patterns might occur either alone or in combination, and the degree of VC progressively increases along with disease deterioration to ESKD ^[8]^[9]. Compared to the general population, the prevalence of arterial microcalcification is 45 times greater in CKD patients ^[10]. Even in early stages of CKD, calcification of the media or intima is present in 50–90% of all cases ^[11] and the prevalence and degree of VC are more increased in ESKD. Eight out of ten HD patients present with VC, which is tightly correlated with the duration of dialysis ^[12]; every year on dialysis confers a 15% increased risk of developing calcification of the coronary arteries ^[13]. However, although the deleterious effects of VC in CKD and ESKD patients have been known for a long time the pathophysiology of this process was not fully elucidated until recently. For more than a century, arterial calcification was believed to be a passive, progressive and untreatable process of calcium accumulation in the arterial walls. However, three decades ago this perspective changed significantly and it became evident that the calcification of arteries is not a degenerative but rather an active process starting with the osteoblastic differentiation of vascular smooth muscle cells (VSMCs) ^[14], a process similar to bone formation. Moreover, it became clear that the onset and development of VC is regulated by various molecules normally involved in the regulation of bone metabolism, which can act as either promoters or inhibitors of arterial calcification. Therefore, VC is the result of the disruption of balance between inhibitors and promoters in favor of the latter. In advanced CKD, the consequences of kidney dysfunction (particularly mineral dysregulation, inflammation and accumulation of uremic toxins) favor the osteogenic transition of vascular smooth muscle cells, through the activity of cytokines and enzymes such as Fibroblast Growth Factor-23 ^[15]^[16], osteocalcin ^[17]^[18]^[19], sclerostin ^[20]^[21]^[22], bone-morphogenetic proteins ^[16]^[23]^[24]^[25], osteoprotegerin ^[22]^[26]^[27]^[28], RUNX2 ^[16] and calcium-sensing receptor ^[29]^[30] that trigger the osteoblastic differentiation of VSMCs, thus promoting the onset and development of VC ^[31]^[32]^[33]^[34]. In addition, accumulation of uremic toxins and enhanced oxidative stress and inflammation suppress the concentration and expression of calcification inhibitors, such as Klotho ^[15]^[16]^[35] and pyrophosphates ^[36]^[37]^[38]. Although VC is highly prevalent in ESKD patients, 15% of HD patients do not exhibit calcification of the vasculature even years after initiation of dialysis ^[39] due to the protection of natural calcification inhibitors. Therefore, scientific research is focused on the pathophysiology of calcification inhibitors in CKD, especially their activation pathways.

3. Matrix Gla Protein as a Calcification Inhibitor

Matrix Gla Protein (MGP) is a 12 kDa protein containing 84 amino-acids, four or five glutamate (Glu) and three serine residues which is secreted by VSMCs in the arterial wall and expressed in the bones, heart, kidneys, cartilage and arteries. MGP was the first identified inhibitor of VC in experimental studies and has the ability to prevent as well as to reverse calcification of the vessel walls ^[40]^[41]^[42] through several pathways. MGP binds directly to free circulating calcium, phosphorus, and hydroxyapatite crystals and forms neutralized, inactive complexes that lose their ability to accumulate within the arterial walls ^[36]. MGP additionally activates the phagocytosis of these complexes by arterial macrophages and abrogates the expression of the calcification bone morphogenetic protein -2 (BMP-2) by antagonizing the binding of BMP-2 to its receptor ^[43]^[44]^[45]^[46]^[47]. Finally, MGP has the ability to remove calcium and extracellular matrix from the vessel walls ^[48]. The function and clinical importance of this inhibitor of VC was first recognized by Luo et al., who found that MGP-deficient animals (knockout models, MGP^--/--), develop to term but die within eight weeks due to accelerated VC leading to blood vessel rupture in the aorta ^[41]. Moreover, data from genetic studies suggest that mutations and polymorphisms of the MGP gene lead to non-functional or partially-functional MGP, respectively, and are associated with ectopic calcification of the cartilage and the arteries as well as with CV mortality in CKD ^[49]^[50]. Therefore, a genetic basis underlying the pathogenesis of arterial calcification in CKD through de-activation of MGP might occur in CKD.

MGP belongs to the family of vitamin K-dependent proteins (VKDPs), a group of seventeen proteins involved in the regulation of bone metabolism, blood coagulation, and arterial calcification. All VKDPs have inactive Glu residues that undergo γ-carboxylation to γ-carboxyglutamate (Gla), a process requiring vitamin K as a co-factor. The carboxylation of Glu causes significant alterations in the molecular structure of VKDPs, leading to their activation. In contrast to the other VKDPs, after γ-carboxylation ΜGP needs to undergo another activation step, phosphorylation of its serine residues, which again requires vitamin K as a co-factor. Therefore, while the fully inactive form of MGP is the dephosphorylated, uncarboxylated MGP (dp-ucMGP) MGP exists in the partially inactive forms of dephosphorylated carboxylated MGP (dp-cMGP) and phosphorylated uncarboxylated MGP (p-ucMGP) as well. After carboxylation and phosphorylation, MGP is fully activated and can act as a powerful calcification inhibitor via the aforementioned molecular pathways. On the other hand, dp-ucMGP cannot bind to calcium/phosphate particles, hydroxyapatite, or BMP-2 and therefore loses the ability to act as an inhibitor of VC ^[51]^[52]^[53]^[54]. Because vitamin K is an essential co-factor for both activation steps of MGP, in vitamin K deficiency MGP is deactivated and the circulating levels of dp-ucMGP are further increased. Accumulated data from in vitro and in vivo studies has coherently detected local concentrations of dp-ucMGP around calcification sites such as atheromatic lesions and plaques, and circulating levels of dp-ucMGP are strongly correlated with the degree of VC ^[55]^[56]. Moreover, in experimental models, vitamin K deficiency (achieved by the use of the vitamin K antagonist warfarin) was accompanied by an abrupt increase in dp-ucMGP and accelerated calcification; after supplementation with high doses of vitamin K, however, MGP was activated, dp-ucMGP levels were suppressed, and calcification status was reduced by 37% ^[42]. The importance of this entry was that it showed for the first time that supplementation with vitamin K might prevent or even reverse VC.

4. Vitamin K Deficiency in CKD as a Predictor of Calcification and Adverse Events

By activating VKDPs, vitamin K (a group of fat-soluble vitamins) is implicated in the regulation of bone metabolism, blood coagulation, and vascular health. Vitamin K exists in three vitamers, phylloquinone (or K1), menaquinone (K2), and menadione (K3); there are several sub-forms of K2 depending on the number of isoprenyl units and the length of the side-chain. Among these, the K2 subtype with the longest side chain, the longest half-life, and the optimal bioavailability in humans is menaquinone-7 (MK-7). For this reason, MK-7 is considered to be the optimal form of vitamin K for supplementation, and is commercially used for supplementation ^[57]. However, all vitamers and sub-forms of vitamin K can act as co-factors for the activation of MGP.

4.1. Association between Vitamin K Status and Arterial Calcification/Stiffness in CKD

Epidemiological data in the general population (NHANES II ^[58]) as well as ERGO ^[59], the Danish Diet, Cancer and Health Study ^[60], EPIC ^[61], and the PREVEND study ^[62] have all suggested that poor vitamin K status is independently associated with VC, mortality, and CV disease. Subclinical vitamin K depletion is highly prevalent in ESKD patients and has been associated with VC, vascular stiffness, mortality, and CV disease. The increased prevalence of vitamin K depletion in ESKD patients can be due to any of several different reasons. In this stage, ESKD patients are given strict dietary recommendations that include restriction of dairy products rich in phosphate (and vitamin K2) and green vegetables rich in potassium (and vitamin K1) ^[17]. The uremic environment can directly decrease the activity of vitamin K-recycling molecules and enzymes ^[63]; finally, certain drug agents that are commonly used by ESKD patients, such as phosphate binders, can further exacerbate vitamin K deficiency ^[64]. Because CKD patients suffer from accelerated calcification, several researchers have aimed to investigate the possible association between poor vitamin K status as assessed by dp-ucMGP and VC. In pre-dialysis CKD, data from a few observational studies showed that dp-ucMGP was associated with various surrogate markers of arterial calcification or stiffness. Schurgers et al. reported that in 107 patients in CKD stages 2–5, circulating dp-ucMGP gradually increased with CKD stage and was strongly and independently correlated with aortic calcification score as assessed by spiral computed tomography ^[65]. Likewise, in another cross-sectional study that enrolled 83 patients in CKD stages 3 to 5, dp-ucMGP was augmented according to CKD severity ^[66]. Moreover, plasma dp-ucMGP was independently associated with VC as assessed by abdominal aortic calcification, and was not associated with markers of vascular stiffness such as pulse-wave velocity (PWV) and cardio-ankle vascular index. However, in 67 patients with diabetic CKD dp-ucMGP failed to correlate with carotid intima-media thickness (cIMT) ^[50]. The biggest study to date was conducted by Puzantian et al. ^[67]; in 137 patients with various degrees of kidney function, subclinical vitamin K deficiency as assessed by increased levels of dp-ucMGP was an independent predictor of carotid–femoral PWV, and there was a progressive increase in dp-ucMGP as kidney function deteriorated.

In HD populations, two independent studies showed that plasma dp-ucMGP was predictive of vitamin K status and significantly correlated with abdominal aortic calcification ^[68]^[69], whereas in a cohort of 120 maintenance HD patients, Hermans et al. found that ucMGP was associated with duration of dialysis and aortic augmentation index ^[70]. Similarly, Fain et al. showed that in a cohort of 37 HD patients dp-ucMGP was an independent predictor of arterial stiffness and endothelial dysfunction as assessed by PWV and flow mediated dilation, respectively, even after adjustment for duration of dialysis, gender, age, diabetes, blood pressure, and history of CV disease ^[71]. Moreover, in a cohort of 188 HD patients, patients with more severe degrees of VC as assessed by Adragao and total calcification score had significantly lower plasma dp-cMGP levels, whereas dp-ucMGP was not correlated with the extent of VC ^[72]. Fusaro et al. conducted a multicenter, cross-sectional study (VIKI) that included 387 HD patients from eighteen Italian dialysis centers; they found that HD patients with calcification of the iliac arteries exhibited significantly decreased circulating levels of vitamin K2 and MK-7, while no difference was found regarding vitamin K1 and MK-4 levels ^[73]. Furthermore, a close link between vitamin K deficiency and calciphylaxis has been suggested as well. In a cohort of 40 HD patients (20 presenting with calciphylaxis and 20 without) Nigwekar et al. found that every 0.1-unit decrease in cMGP levels doubled the risk of calciphylaxis ^[74].

In order to assess a possible association between vitamin K status and CV outcomes, Chen et al. performed a meta-analysis of 21 studies and 222,592 participants and showed that increased dietary intake of either vitamin K1 or K2 was linked with a moderately reduced risk of coronary heart disease, although not with mortality. Moreover, increased circulating dp-ucMGP (which is representative of vitamin K depletion) was predictive of both all-cause and CV mortality, while uncarboxylated osteocalcin (another VKDP implicated in bone and vascular health) was not ^[75].

4.2. Association between Vitamin K Status and Clinical Hard Endpoints in CKD and ESKD

Following the accumulating data supporting a close association between subclinical vitamin K deficiency and arterial calcification/stiffness in the CKD population, several investigators have aimed to assess whether poor vitamin K status is predictive of adverse events, including mortality, CV disease, and deterioration of kidney function. Schurgers et al. were the first to show that dp-ucMGP plasma levels were predictive of all-cause mortality in a cohort of 107 pre-dialysis CKD patients ^[65]. Similarly, in a group of 66 patients with diabetic CKD circulating dp-ucMGP was associated with CV morbidity, mortality, and deterioration of kidney function ^[50]^[76]. In agreement with these results, Kayzer et al., enrolled 518 stable kidney transplant recipients, followed them for a median period of 9.8 years, and found that increased plasma dp-ucMGP was an independent predictor of all-cause mortality and transplant failure ^[77]. Finally, in a study by Schlieper et al. dp-ucMGP was an independent predictor of mortality in 188 maintenance HD patients ^[72].

4.3. The Effect of Exogenous Vitamin K Supplementation on MGP Forms in CKD and ESKD

As it has been shown in experimental animal uremic models that supplementation with vitamin K could potentially reverse arterial calcification through activation of MGP, an attractive hypothesize is that exogenous supplementation with vitamin K might ameliorate CV disease in CKD patients through activation of MGP. While the daily recommended amount of vitamin K for healthy subjects is 90–120 μg ^[78], the exact dosage of vitamin K intake for activation of MGP in populations with vitamin K deficiency, such as CKD patients, has not yet been defined. In a study by Schlieper et al., the authors reported that in 17 HD patients, daily supplementation with 135 μg of MK-7 for 1.5 months caused a modest 27% reduction in dp-ucMGP levels ^[72]. Following these results, two randomized, interventional, non-placebo-controlled, dose-finding studies were conducted in dialysis patients. Westenfeld et al. randomly divided 53 maintenance HD patients into daily intake groups of 45, 135 or 360 μg MK-7 for 1.5 month, and found that dp-ucMGP was time- and dose-dependently reduced in all three groups (a 17.9%, 36.7% and 61.1% reduction in the 45, 135 and 360 groups, respectively) ^[79]. Similarly, Caluwe et al. enrolled a larger sample size of 200 HD patients and randomly divided them to three parallel groups receiving 360, 720 and 1080 μg of MK-7 thrice weekly (which translates roughly to 154, 308 or 464 μg/day) for two months, and found that dp-ucMGP was decreased by 17%, 33% and 46%, respectively, in the three groups ^[80]. These two studies showed that even 460 μg of vitamin K2 per day failed to restore vitamin K status (as reflected by the reduction rate of dp-ucMGP) in dialysis patients, and provided the rationale for designing randomized controlled trials (RCTs) in dialysis patients. Moreover, the response rates were better in the study by Westenfeld et al., which was attributed to the fact that the patients enrolled by Caluwe et al. were much older (64.6 versus 70.8 years of mean age). In agreement with these results, a pre- and post-intervention clinical study in 50 maintenance HD patients showed that daily supplementation with 360 μg/day of MK-7 for one month was accompanied by a significant 86% decrease in circulating dp-ucMGP, with type 2 diabetes patients exhibiting the lowest response rates ^[69]. Therefore, as it is well established that VC is highly prominent in diabetics and the elderly these studies suggest that the effect of vitamin K intake on MGP is highly dependent on the dose, the duration of supplementation, and the population.

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Stefanos Roumeliotis

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