The interplay between mineral metabolism, vascular calcification and inflammation in Chronic Kidney Disease (CKD): challenging old concepts with new facts

The importance of calcium (Ca) and phosphate (P) minerals in CKD: balance and regulation

P and Ca are absolutely essential for life but its balance and regulation are tightly controlled because both positive and negative balances have detrimental clinical implications. In patients with CKD, a negative balance of Ca and P favors bone mineral loss and osteoporosis, increased risk for bone fragility and fractures. On the other hand, a positive balance favors soft tissue calcification, consequent cardiovascular events, and interrelates with high morbidity and mortality.

Ca and P homeostasis

Ca and P are absorbed from the diet in the intestine, stored in the skeleton, and reabsorbed and excreted by the kidneys (extensively reviewed elsewhere [17–19]). In healthy adults, normal daily intake of Ca and P is considered in the range of 800–1000 mg and 700-2000 mg, respectively. The majority of Ca and P stores in the body are in the bone (approximately 99% and 85%, respectively), while the remaining is present in the extracellular and intracellular spaces, including the circulating fractions (approximately 0.1%). In adulthood, normal total serum Ca is approximately 8.5–10 mg/dL and includes the ionized and complexed fractions, as well as the protein-bound fraction. Normal serum P levels are considered between 2.5–4.5 mg/dL. Among the many factors that can influence Ca and P homeostasis, high dietary Ca and P intake are related with increased serum Ca and P, which are associated with poor clinical outcomes including increased CVD risk [20–23].

In normal physiology, Ca and P homeostasis are regulated through hormonal control of a four-tissue axis involving intestine, bone, kidney, and parathyroid gland, that tightly control serum ionized Ca and P levels within a narrow range.

The two primary hormones involved in calcium balance are parathyroid hormone (PTH) and 1,25 vitamin D (1,25D) (Figure 1). PTH secretion is stimulated by hypocalcemia and suppressed by hypercalcemia. Low levels of serum ionized Ca are sensed by the calcium-sensing receptors (CaSR) on the parathyroid gland, which stimulates PTH synthesis and secretion. In order to raise serum Ca to normal levels, PTH exerts effects at multiple levels such as: (i) stimulating bone osteoclast activity to increase Ca efflux from bone; (ii) increasing Ca reabsorption in the kidney; (iii) stimulating 1,25D production, which in turns increases intestinal Ca absorption and Ca efflux from bone. Hypercalcemia suppresses PTH secretion and stimulates CaSR activity to enhance renal Ca excretion.

Figure 1. Overview of calcium (Ca) and phosphate (P) homeostatic regulation. Red lines represent the main mechanisms of Ca regulation in a situation of hypocalcemia. Decreased Ca levels in serum increase 1,25D and PTH. Increased levels of 1,25D increase Ca absorption at the intestine and stimulate mineral exchange in bone increasing Ca efflux. Increased PTH stimulate mineral exchange in bone increasing Ca efflux, and increase Ca reabsorption in the kidney. Indirectly, high levels of PTH stimulate 1,25D with consequent increase in Ca absorption. Overall, the concerted action of PTH and 1,25D lead to increased serum Ca levels until the normal range by increasing Ca reabsorption at the intestine, increasing Ca from mineral exchange in bone, and increasing Ca reabsorption in the kidneys. Blue lines represent the main mechanisms of P regulation in a situation of hyperphosphatemia. High levels of serum P increase FGF-23 production in bone, which exerts several effects to promote a decrease in serum P. FGF-23 decreases P reabsorption and increases P excretion in the kidneys, and indirectly decreases P absorption at the intestine and P efflux from bone mineral exchange, through the inhibition of 1,25D and PTH.

The primary regulator of P homeostasis is the kidney which adjusts the excretion to the dietary load of P. The main hormones implicated in regulation of serum P are fibroblast growth factor 23 (FGF-23) with its cofactor Klotho, PTH, and 1,25D (Figure 1). FGF-23 is primarily a phosphaturic hormone, produced by osteoblasts and osteocytes under physiological conditions, and secreted from bone in response to increased serum P and 1,25D. FGF23 exerts several effects to promote a decrease in serum P such as (i) inhibiting P reabsorption in the kidney by suppression of type II sodium phosphate cotransporters; (ii) decreasing P absorption by inhibiting 1,25D production; (iii) suppressing PTH and expression of the CaSR and vitamin-D receptor in the parathyroid gland. In addition, FGF-23 increases Ca reabsorption in the kidneys, probably to compensate for low Ca absorption due to induced 1,25D deficiency. PTH increases phosphate excretion by stimulating FGF-23 production and reducing type II sodium phosphate cotransporters.

Special attention and concerns have been raised in recent years in relation to the possible excess of P intake in the general population, and its correlation with disturbances in bone and mineral metabolism, compromising bone health [24]. In addition to a high protein diet, the increased consumption of processed food and the use of food additives containing high levels of inorganic phosphates, have been linked to acute spikes or transient increases in serum P. This might be partially explained by the high rate of absorption efficiency, particularly of inorganic P present in food additives, and the circadian fluctuation in serum P. In fact, short term high P diets have been shown to significantly increase circulating levels of FGF-23 and bone related markers in human and mice, while decrease bone mineral density in mice [25]. Increased FGF-23 levels in individuals with normal renal function have been related with renal P wasting and impaired bone mineralization [26]. Excessive intake of P has been linked to increased levels of serum P, which in turn is suggested to be the main stimulus for phosphorus homeostasis disruption. Consequently, in both healthy and renal disease individuals (detailed below), current dietary habits might contribute to current worldwide burdens of osteoporosis and renal dysfunction.

Dysregulation of mineral metabolism in CKD: the mineralization paradox behind CKD-MBD

In the CKD context, the ability to filter and excrete P is progressively compromised as kidney function declines, leading to a progressive dysregulation of the intricate set of feedback loops that tightly regulate Ca and P homeostasis. Hyperphosphatemia is usually defined as serum P >=5.0 mg/dL, and hypercalcemia as serum Ca >=10 mg/dL [27,28]. However, P accumulation has been suggested to occur since early stages of CKD, prior to the development of hyperphosphatemia. This situation is prevented by the adaptive and compensatory mechanisms that increase P excretion through the increased phosphaturic action mediated by FGF-23/klotho axis and PTH. In fact, increased serum P, although still within the normal range, has been correlated with adverse cardiovascular and renal outcomes and overall survival in early stage CKD patients [29–34]. In stages 2–5 CKD patients, the reported thresholds of serum P shown to predict adverse outcomes ranged between 3.5 and 4.6mg/dL. FGF-23 levels increase since stage 2 and continue to rise as CKD progresses. In addition, a gradual increase in serum P can be observed since the beginning of stage 3. When GFR is below 30 mL/min/1.73 m2, the adaptive mechanisms are unable to sustain serum P in the normal range due to an imbalance between P intake and renal excretion capacity. As kidney function declines, FGF-23 and then PTH levels increases in CKD, exerting opposing effects on vitamin D metabolism. Although PTH stimulates 1,25D production, increasing FGF-23 creates a state of 1,25D deficiency that decreases serum Ca and further increases PTH. In CKD stage 5, FGF-23 levels are normally several hundred folds above the normal range [30,35]. Since hypocalcemia stimulates PTH production and decreased levels of 1,25D results in failure to inhibit PTH synthesis, an excessive rise in PTH release often accompanied by parathyroid hyperplasia, is common in CKD patients and referred as secondary hyperparathyroidism (SHPT) [36]. As kidney function declines, phosphate retention occurs, and hyperphosphatemia has been consistently associated with CKD progression and cardiovascular outcomes. However, a state of hypocalcemia is often associated with these patients, despite it is quite uncommon in CKD stage 3 and early stage 4, and more often observed in stage 5 [34,37]. One important issue is that the levels of ionized serum Ca might not reflect Ca balance in the organism [19]. Since only 0.1% of total body Ca is present in circulation, the determination of Ca balance or total body Ca content, or adequacy of Ca load, cannot be infer by serum Ca levels. Indeed, the constant stimulation of Ca and P efflux from bone, the increased Ca reabsorption and the decreased urinary Ca excretion capacity might originate a positive calcium balance. At physiological pH, free Ca is able to bind to excessive P and facilitate P removal, although the resulting calcium-phosphate mineral (CaP) does not precipitate directly from solution into hydroxyapatite that can be deposited within soft tissues. Instead, it passes through a series of phases including the transition from an initial unstable amorphous calcium phosphate (ACP-1) into a more stable and less soluble form of amorphous calcium phosphate phase (ACP-2).

Of note, the concept of calcium-phosphate product, often referred as CaxP, widely used in the literature, is obtained by simply multiplying serum Ca and P levels and does not entirely reflect the aggregation of Ca and P in soft tissues, here referred as CaP. This emphasizes the significant difference between Ca homeostasis and balance. While compensatory mechanisms are crucial to counteract hyperphosphatemia in short-term, these adaptive responses may increase the risk of undesirable and detrimental effects resulting from a positive calcium balance. Ultimately, this will lead to a process of soft tissue calcification, increasing the cardiovascular risk. These adaptive mechanisms are effective in maintaining serum P and Ca within the normal range until late stages of CKD. This situation constitutes a major risk for CKD patients since the accumulation of P, Ca and CaP progresses since early stages of disease development. Often, at the time of diagnosis, bone loss might be significant and soft tissue calcification already established. This process is often referred as the mineralization paradox in CKD (Figure 2). Clinical studies have shown that the development of VC is correlated with a decrease in bone mineral density, the incidence of bone fractures and mortality in CKD patients [38,39]. Current Kidney Disease Improving Global Outcomes guidelines defined that CKD-MBD should be used to describe the broader clinical syndrome encompassing mineral, bone, and calcific cardiovascular abnormalities that develop as a complication of CKD [8].

Figure 2. Schematic representation of the mineralization paradox in CKD. As kidney functional declines, P retention occurs and FGF-23 highly increases, with consequent decrease in 1,25D levels. Dysregulated levels of 1,25D lead to increased levels of PTH and decreased levels of serum Ca. Low levels of serum Ca maintained by low 1,25D, constantly stimulate PTH production, often resulting in secondary hyperparathyroidism (SHPT) and bone resorption leading to decreased bone mineralization. However, increased Ca efflux from bone, and increased Ca reabsorption and decreased excretion in the kidneys originate a positive Ca balance, correlated with increased vascular calcification.

The crosstalk between vascular calcification and inflammation: a plausible explanation for the burden of CVD in CKD

In addition to the complexity of mechanisms involved on VC initiation and progression, it is currently accepted that it cannot be regarded as an isolated pathological process, with several studies providing compelling evidence that VC is highly interconnected with inflammation. In fact, it has been suggested that pathological calcification and chronic inflammation are involved in a positive feed-back loop driving disease progression [153–155].

In CKD, persistent microinflammation has been recognized as an important pathophysiological component, contributing for cardiovascular disease and mortality. Increased C-reactive protein (CRP), which is a predictor of cardiovascular risk factors and death in the general population, has been long associated with increased vascular calcification and mortality in hemodialysis patients [156–159]. Inverse correlations between GFR and levels of proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α, clearly demonstrate the role of inflammation on CKD development [160]. In a cohort of hemodialysis patients, a pattern of high proinflammatory cytokines IL-1β, IL-6, and TNF-α, in combination with low anti-inflammatory parameters including IL-2, IL-4, IL-5, IL-12, were associated with decreased survival [161]. In fact, several of these inflammation-related biomolecules have been proposed as biomarkers for cardiovascular mortality in CKD, although differing in their predictive value [162,163]. The high levels of inflammatory molecules in CKD might be explained, at least in part, with increased production at tissue level such as at the vascular wall. In atherosclerotic lesions, the accumulation of macrophages within the vascular wall has been consistently co-localized with calcium deposits and associated with various phases of calcification [164,165]. More pronounced macrophage infiltration and higher CRP were described in coronary artery lesions of CKD [166]. Early stages of CKD are already associated with up-regulation of proinflammatory and pro-osteogenic molecules in the vascular wall and calcification of the aortic media [167]. In fact, several lines of evidence indicate that inflammation triggers and precedes osteogenic conversion of VSMCs and the release of calcifying EVs, promoting the calcification process. It is likely that the effect of inflammation on VC occurs at multiple and interconnected levels. It has been proposed that inflammation might regulate VC, at least in part, through activation of an endoplasmic reticulum stress pathway, which in turn may increase inorganic phosphate uptake, leading to increased VSMCs osteogenic differentiation and increased mineral deposition [168]. Activated macrophages at sites of tissue damage also produce high levels of matrix metalloproteinases, cysteine endoproteases and cytokines, which will enhance elastin and collagen degradation. These processes leading to remodelling and structural changes of the ECM, will contribute to create a nidus for CaP crystal growth [169–171]. Also, macrophages have been shown to regulate VC through the release of osteogenic factors capable of inducing VSMCs osteogenic differentiation [172,173]. Among the many soluble factors released by activated macrophages and known to be elevated in CKD, TNFα and also IL-1β are reported to enhance VSMCs osteogenic activity by increasing BMP2 production [173]. In a scenario of reduced MGP and GRP levels (or functionality) to inhibit BMP2 osteogenic signaling, VSMCs osteogenic differentiation is potentiated, and further aggravated through the release of calcifying competent EVs lacking MGP and GRP inhibitors. Also interesting is the possible direct role of macrophages on vascular calcification, through the release of calcifying EVs containing hydroxyapatite nucleation sites, and capable of mineralization [174]. These macrophage- released EVs are loaded with mineralization related factors, and have an increased Ca content and alkaline phosphatase activity. Interestingly, GRP was shown to be present, at protein and mRNA levels, in EVs released by THP-1 differentiated macrophages [94]. Although additional studies are required to understand the role of GRP in macrophage-derived EVs with calcifying capacity, it is licit to speculate that GRP might also be involved on the inhibition of mineral nucleation. In fact, GRP was shown to be synthetized and γ-carboxylated in the majority of human immune system cells, including monocytes and macrophages [94], and the anti-inflammatory properties of GRP have been highlighted. Treatments with exogenous GRP or GRP overexpression were both shown to be able to decrease the pro-inflammatory response of THP-1 monocytes/ macrophages and of articular cells, by down-regulating pro-inflammatory molecules such as TNFα, IL-1β and nuclear factor kappa B [93,94]. A similar down-regulation of mediators of inflammation and inflammatory cytokines was observed when basic calcium phosphate (BCP) crystals were coated with GRP, clearly indicating GRP as a crosstalk agent between inflammatory and calcifying processes [93,94]. In fact, while macrophages are key players signaling ECM degradation, calcification and cells differentiation, a multitude of CaP crystals have been shown to promote pro-inflammatory responses, which again will affect VC, in a calcification-inflammation pathological feeding cycle (Figure 3). Micro-calcifications have been proposed to be involved in macrophage recruitment in early stages of atherosclerosis development [164], and BCP crystals stimulate macrophages to produce pro-inflammatory cytokines affecting VSMCs differentiation [94,175,176]. BCP crystals were shown to directly interact with macrophages, inducing an increased production of TNFα, IL-1β and IL-8, which in turn stimulate the activation of endothelial cells and recruitment of mononuclear cells [175], amplifying the immune response. Coating of BCP particles with fetuin-A and GRP, resembling CPPs, was shown to decrease pro-inflammatory responses when compared to naked crystals [93,94,140], and synthetic secondary CPP particles were shown to induce an up-regulation of TNFα accompanied by increased calcification [138,139]. More recently, a link between inflammation and calcification in CKD was highlighted. CPPs isolated from CKD stage 5 patients, containing reduced levels of GRP and fetuin-A, were shown to be highly osteogenic driven factors, with the capacity to increase VSMCs calcification by promoting osteogenic differentiation and inflammation [108]. Importantly, the dual capacity of GRP to act as an anti-inflammatory agent and an inhibitor of vascular calcification, was clearly demonstrated when the calcification/osteogenic differentiation and inflammatory status induced in VSMCs was rescued by supplementation of those CKD5-CPPs with GRP [108]. While the role of fetuin-A in inflammation has also been demonstrated, functioning as an acute phase reactant protein (reviewed in [91,177]), the research data on the role of MGP in inflammation is still quite incipient. Only a few studies have reported a possible association between increased levels of MGP and reduced inflammation, by inhibiting BMP-induced inflammatory pathway [178,179]. More recently, results from a mouse experimental colitis model shown that MGP was implicated on the suppression of T cells proliferation and cytokine production in Crohn’s disease [180]. Also, the association between circulating levels of MGP and inflammatory markers is still quite limited and inconsistent [181–183]. While an inverse association between dp-ucMGP (reflecting vitamin K status) and inflammatory markers is shown in some observational studies [184], long term vitamin K2 supplementation do not show a correlation [185]. In fact, the association between vitamin K levels, either K1 or K2, and inflammation is still debatable [186,187].

Figure 3. The vascular calcification-inflammation cycle. Calcium-phosphate (CaP) mineral is present in secondary calciprotein particles (CPP-II), in calcifying extracellular vesicles (cEVs) and in the extracellular matrix (ECM) of blood vessels. All these forms of CaP mineral are able to induce pro-inflammatory responses in immune and VSMs cells, and the osteogenic differentiation of VSMCs. In turn, macrophage pro-inflammatory responses contribute to increased vascular calcification through the release of cEVs and inducing osteogenic differentiation of VSMCs, while osteogenic VSMCs drive ECM calcification through the release of cEVs and increase in macrophage pro-inflammatory responses, in a vicious cycle.

In this context, it is also noteworthy the proposed function of vitamin K as an anti-inflammatory agent, as mediated by a direct vitamin K effect rather than through VKDPs functionalization [188–190]. In this regard it is interesting to note that the anti-inflammatory function of GRP seems to be independent of its γ-carboxylation status [93,94]. Considering the conflicting results and the reduced number of available randomized studies addressing causality between vitamin K status and inflammation [191–193], additional studies are required to establish the direct role of vitamin K in inflammation, particularly concerning the inflammation/vascular calcification cycle in CKD-CVD outcomes.

Remarkably, this inflammation/vascular calcification crosstalk described in CKD pathology, share many similarities with the aging process in the general population, including the inflammaging and VSMCs senescence [194,195]. Inflammaging is a recently adopted term do define a state of low grade chronic inflammatory condition, associated with a significant risk factor for morbidity and mortality in the elderly (reviewed in [196]). Cellular senescence, in general, has been proposed as a potential mechanism of aging and age-related diseases, which can be triggered by a number of mechanisms and leading to an altered secretome, termed the senescence-associated secretory phenotype (SASP) (reviewed in [195,197]). In the particular case of VSMCs, senescence has been shown to enhance vascular calcification and inflammation, with pro-calcific and pro-inflammatory SASPs [195,198,199]. These SASPs share substantial similarities with the osteochondrogenic phenotype of VSMCs under uremic conditions, including the overexpression of bone-related, inflammation and extracellular matrix degradation markers. Also, microvesicles isolated from elderly people and from senescent endothelial cells, characterized by high levels of calcification-related proteins and increased calcium content, were shown to promote calcification of VSMCs [200]. In fact, VSMCs senescence and associated SASP have been suggested to contribute for chronic vascular inflammation and calcification, loss of arterial function, and the development of age-related diseases [195–197]. Thus, it has been suggested that altered vascular health under CKD settings might represent an example of premature aging [194,195]. In this context, it could be conceivable that new knowledge about molecular mechanisms, such as the crosstalk between VC and inflammation, in CKD, might shed new horizons on the aging process, and vice-versa. It is clear that several biomolecules, including mineralization inhibitors such as GRP, act in a highly complex and coordinated network between inflammation and calcification processes, and that a deeper knowledge of this complex crosstalk is crucial to the development of new therapies and biomarkers that will benefit the populations at high risk for cardiovascular diseases.

Abbreviations

CKD: Chronic kidney disease; CVD: Cardiovascular disease; Ca: Calcium; P: Phosphate; MBD: Mineral and bone disorder; VC: Vascular calcification; CaP: Calcium-phosphate mineral; GFR: Glomerular filtration rate; VSMCs: Vascular smooth muscle cells; ECM: Extracellular matrix; EVs: Extracellular vesicles; PBs: Phosphate binders; PTH: Parathyroid hormone; 1,25D: 1,25 vitamin D; CaSR: Calcium-sensing receptors; FGF-23: Fibroblast growth factor 23; SHPT: Secondary hyperparathyroidism; VKDPs: Vitamin K-dependent proteins; Glu: Glutamic acid; Gla: γ-carboxyglutamic acid; MGP: Matrix Gla protein; CBPBs: Calcium-based phosphate binders; KDIGO: Kidney Disease Outcomes Quality Initiative Guidelines; CPPs: Calciprotein p-articles; GRP: Gla-rich protein; MGP-/-: Knockout mice for MGP; GRP-/-: Knockout mice for GRP; CPP-I: Primary calciprotein particles; CPP-II: Secondary calciprotein particles; BMP2: Bone morphogenetic protein 2; Dp-ucMGP: Dephosphorylated and uncarboxylated matrix Gla protein; CRP: C-reactive protein; IL: Interleukin; TNF-α: Tumor necrosis factor alpha; BCP: Basic calcium phosphate; SASP: Senescence-associated secretory phenotype.

Acknowledgements

N. Araújo is the recipient of the Portuguese Science and Technology Foundation (FCT) fellowship SFRH/BD/111824/2015.

Conflicts of Interest

Dina Simes and Carla Viegas are cofounders of GenoGla Diagnostics. The authors declare that there is no conflict of interests regarding the publication of this paper.

Funding

This research was funded by the Portuguese Society of Nephrology (SPN) through project funding 2016, and by the Portuguese national funds from FCT - Foundation for Science and Technology through project UID/Multi/04326/2019.

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