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Keywords:

  • cardiovascular disease;
  • chronic kidney disease;
  • vascular calcification

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

The complex relationships between cardiovascular, renal, and bone disease are increasingly recognized but not yet clearly understood. Vascular calcification (VC) represents a common end point between these interlinked systems. It is highly prevalent in chronic kidney disease (CKD) and may be responsible for some of the excess cardiovascular events seen in this condition. There is much interest in developing therapeutic agents to stop its development or reverse its progression. Traditionally considered to be due to abnormalities in calcium and phosphate metabolism alone, VC is now known to be the product of active, dynamic processes within the vessel wall. Primary prevention of VC is possible through successful prevention or reversal of progressive renal dysfunction, hypertension and hyperlipidaemia, but is challenging given the increasing global prevalence of these risk factors. Secondary prevention of VC through tight control of calcium and phosphate, can be achieved by dietary or pharmacological means. Both the modification of haemodialysis duration or methods and the use of renal transplantation have an effect. Novel drugs such as cinacalcet were hoped to halt calcification but results have been mixed, and no intervention has yet been shown to reverse calcification reliably. A new range of experimental targets involved in the putative mediatory pathways between bone and vascular disease has emerged. Aiming to manipulate the active mechanisms involved in calcium deposition, these hold hope for reversal of calcification, but are still theoretical or in early animal or human experimentation.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

Cardiovascular diseases (CVD) are the leading cause of death globally [1]. Hyperlipidaemia, smoking, hypertension and diabetes are well established as the most powerful modifiable risk factors for CVD. In recent years renal dysfunction (chronic kidney disease (CKD)) has emerged as a factor of equal importance [2-5]. The prevalence of CKD, defined by reduced glomerular filtration rate (GFR) or albuminuria, is in the range of 10–13% in the general population [6], with an incidence and prevalence that is increasing at an alarming rate [6]. More than 80% of all cardiovascular deaths can be delayed using changes in life style and commonly prescribed drugs [7]. Despite this, many patients never receive the full benefits from these interventions because of frequent under-diagnosis, late presentation and consequent under-treatment [8, 9]. This is particularly an issue for subjects with CKD.

Cardiovascular disease in chronic kidney disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

Patients with mild to moderate chronic kidney disease are much more likely to develop CVD than to die from end stage renal failure (ESRF) [10]. The detrimental cardiovascular effects of declining renal function have been well described, for instance by Go et al. [11], who reported on the association between estimated GFR (eGFR) and the risks of death, cardiovascular events and hospitalization over 2.8 years. The adjusted hazard ratio for death was 1.2 with an eGFR of 45–59 ml min−1 m−2, 1.8 with eGFR of 30–44 ml min−1 m−2, 3.2 with eGFR of 15–29 ml min−1 m−2 and 5.9 with eGFR of <15 ml min−1 m−2 [11].

In acute coronary syndromes, the single most common cause of death worldwide [1], approximately 40% of the patients have at least moderate kidney dysfunction with an eGFR below 60 ml min−1 1.73 m–2 [12]. The 1 year mortality among these patients is about 25%, compared with 5% in patients with normal renal function [12]. The increased mortality in CKD patients after an acute coronary event is directly related to decreasing renal function, including very mild impairment [2, 13]. This is most likely caused by the range of vascular abnormalities that occur in CKD, for example in abnormal haemostasis and vascular function, but may in part be due to the fact that patients with renal impairment less often receive active treatment, such as early revascularization [14]. There is also a lack of specific guidelines, attributable in part to limited clinical data, as the majority of randomized trials in acute coronary syndromes so far have excluded CKD patients [15].

The cardio-renal concept

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

The frequent association seen clinically between cardiac and renal disease is sometimes referred to as the cardio-renal syndrome [16]. Conceptually it is most commonly thought of as the link between systolic heart failure and progressive renal dysfunction. However, the cardio-renal syndrome includes a multitude of pathogenic pathways including glucose metabolism, anaemia, inflammation, coagulation, mineral metabolism, sympathetic activation, renin-angiotensin-aldosterone system (RAAS) activation, endothelial dysfunction and lipid disturbances [17]. It is important to recognize that while systolic heart failure directly affects renal function, CKD reciprocally affects cardiac structure and function. Each condition may limit the therapeutic options available to treat the other, provoking debate between the nephrologist and cardiologist over diuretic and RAAS blocker dose in the context of ‘heart failure’ versus ‘kidney failure’.

Vascular disease is a common aetiological factor mediating the cardio-renal syndrome [18]. It progresses from lipid deposition in the vascular wall in early life, through to endothelial dysfunction, hypertension, inflammatory activation, atheroma formation and vascular calcification (VC) in adulthood [19]. In some individuals it causes ischaemic heart disease and heart failure, while in others it predominantly affects the renal arterioles and glomeruli, causing renal dysfunction. Once prevalent in one organ, the disease hastens the development of vascular disease in other [16, 17] partly explaining why kidney disease, even at the very earliest and otherwise asymptomatic stages, is a strong independent risk factors for the development of CVD [20].

Calcification in cardiovascular disease and chronic kidney disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

In the general population VC occurs most commonly in the context of advanced atherosclerosis where microcalcification forms within the vascular smooth muscle cells (VSMCs) of the tunica intima. This process is driven by the inflammatory and apoptotic processes of atherosclerosis [21] and results in vessel narrowing and dysfunction, increasing the likelihood of a thrombotic event.

Calcification also occurs within the tunica media in association with ageing, usually termed Monckeberg's sclerosis. The exact aetiology is unknown, however this process occurs decades earlier in the CKD population. It was previously thought to be caused by abnormalities in calcium and phosphate concentrations alone [22], but the role of active processes that transform VSMCs to an osteoblastic phenotype is now recognized [23]. Ultrastructural analysis has suggested that the microcalcifications may originate from nanocrystals and they often exhibit a ‘core-shell’ structure, suggesting that apoptotic cells also play an initiating role [24].

Medial calcification increases arterial stiffness [25] more than other forms of VC, promoting left ventricular hypertrophy (LVH) and fatal arrhythmias [26]. In CKD, medial calcification develops concurrently with classical atherosclerosis [27], which is itself accelerated [28]. The synergistic effect is an excess in cardiovascular mortality, particularly sudden cardiac death [26].

VC is detectable using several methods including plain radiographs of the chest and abdomen [29, 30], while valvular calcification can best be visualized using echocardiography. VC predicts death regardless of the site measured, modality used to visualize it or whether it is measured in CKD patients or the general population [25, 27, 29, 31, 32].

The gold standard non-invasive measure is currently coronary computed tomography (CT) scanning, most commonly multi-detector CT, giving the coronary artery calcium (CAC) score in Agatston units. Calcium scoring is primarily used for risk stratification in asymptomatic patients, while contrast-enhanced CT is primarily used in patients with acute or chronic chest pain. Neither technique can reliably distinguish between intimal or medial calcification. Despite this caveat a high CAC score predicts cardiovascular events in CKD [33], and in the general population where it moderately improves the accuracy of traditional risk factor based risk prediction, such as the Framingham risk score (FRS) [34]. Recent US guidelines for asymptomatic patients advise that a single measurement is reasonable to risk stratify further intermediate FRS individuals [35]. A recent review cautioned against the use of serial measurements due to the relatively high radiation dose (8–18 mSv) [36]. The role of CAC measurement in CKD has not yet been defined and there have been no randomized controlled trials incorporating CAC in risk prediction algorithms in either population.

Reciprocity between calcium in the skeleton, vessels and valves

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

Ectopic calcification in CKD develops concurrently in the vessels and heart valves [30] and occurs in the context of a syndrome of metabolic abnormalities. There is a complex relationship between the bone and the vascular systems, in which both parallel and reciprocal changes in mineralization have been observed, the so-called bone-vascular axis [22]. Though this interaction is poorly understood and causal links have not yet been established, CKD is thought to induce a state of low bone turnover, reducing the bone's ability to buffer mineral metabolite (calcium and phosphate) change and promoting VC [37]. Empirically, bone mineral density is inversely associated with CAC score [38] and low bone turnover is associated with CAC progression in haemodialysis patients [39]. Over and above the links between calcium deposition in the vessels and bone there is also a more complex relationship between bone and cardiovascular health which is not well defined. This is illustrated by the fact that left ventricular mass in CKD patients is independently associated with not only aortic calcification, but also lower mean femoral bone mineral density [40].

Several factors unique to renal failure exacerbate VC and are potential therapeutic targets. These factors often co-exist and create what has been referred to as a ‘perfect storm’ for the development of VC. These are outlined in the Table 1.

Table 1. The many different influences on vascular calcification, and the relevant biological pathways or pathomechanisms
ParameterAssociationsPossible mechanisms
Phosphate

    Higher concentrations associated with:

  • more extensive CAC in CKD patients [96]
  • death and CV events in CKD patients [97]
  • death and CV events in the general population [98]
  • coronary artery occlusion and higher CAC score in normal renal function [99]
  • Stimulates VSMC transformation to an osteoblastic phenotype [100]
  • Stimulates calcification of VSMC extracellular matrix [101]
  • Promotes of VSMC apoptosis [102]
  • Inhibits vessel wall macrophage differentiation to osteoclast-like cells, disrupting a potential innate regulatory mechanism [103]
Fibroblast growth factor-23 (FGF-23)
  • Deficiency associated with VC in animal and human studies
  • Raised concentrations correlate with CAC in children on haemodialysis [104] and aortic calcification in adults [105]
  • Phosphaturic – initially mitigates effect of hyperphosphataemia [106]
  • Inhibits renal synthesis of 1,25 vitamin D (overall effect unknown)
  • Possible undefined phosphate-independent inhibitory effect [107]
  • Raised concentrations in advanced CKD may reflect resistance (e.g. fewer nephrons to respond)
Klotho

    A transmembrane protein which acts as an essential co-factor for FGF-23 at its receptor:

  • Knockout mice display a CKD / pro-calcification phenotype
  • CKD patients have low free urinary klotho [108], and low levels of expression are found in CKD kidneys
  • Indirect action via FGF-23 (see above) [109]
  • In its free form following cleavage of the extracellular domain it has a direct phosphaturic effects on Na-PO4 channels in the proximal convoluted tubule [108]
  • Direct effect on VSMCs, suppressing PO4 entry in to VSMCs [108]
Vitamin D

    An evolving picture of sometimes conflicting results:

  • Induces VC in excess, in animal and clinical models [110]
  • Physiological dose protective in animal CKD model [111]
  • Deficiency linked to VC, arterial stiffness and CV mortality in CKD [112]
  • Low and high concentrations associated with VC in children on haemodialysis (‘U’ shaped relationship) [113]

    A likely mixture of pro-calcific:

  • Direct effect on VSMC
  • Promoting VC by raising PO4 and Ca
  • Over-suppression of PTH leading to adynamic bone disease and low bone turnover

    And protective:

  • Pleiotropic anti-inflammatory and immunomodulatory effects across the cardiovascular system [113]
  • Inhibit the production of renin and myocyte proliferation [114]
  • Prevents hyperparathyroidism and hyperphosphataemia
Matrix GLA-protein (MGP)
  • Deficiency and under-activated MGP associated with VC in animals [115, 116]

    Precise mechanism not clear but known to:

  • Inhibit bone morphogenetic proteins (BMP) type 2 and 4, thereby blocking induction of VSMC osteoblastic phenotype
  • Directly bind hydroxyapatite [117]
Warfarin

    Commonly prescribed in CKD (e.g. higher incidence of atrial fibrillation [118]):

  • Use results in phenotype similar to that seen in MGP-deficient mice [119] (see above).
  • Human data link is weaker: a few small, observational studies link use to valvular calcification e.g. [120]
  • Strongest risk factor for calcific uraemic arteriolopathy (calciphylaxis) in haemodialysis patients [121, 122]

    Disrupts vitamin K dependent gamma-carboxylation (activation) of

  • MGP
  • osteocalcin, a pro-osteoblastic bone protein that is associated with increased bone mineral density
Vitamin K2

    Deficient in dialysis patients [95]. Influenced by warfarin as above

  • Supplementation reduced VC in animals [123]
  • Low dietary intake associated with severe aortic valve calcification [124].
  • MGP/osteocalcin concentrations improve on supplementation in dialysis patients [95]
  • As detailed above, mediated via MGP and osteocalcin
Pyrophosphate
  • Deficiency in animals and humans leads to massive calcification [125].
  • Lower concentrations seen in haemodialysis patients, associated with VC in ESRF [78]
  • Supplementation inhibited VC in recent animal model [81]
  • Directly blocks hydroxyapatite formation within VSMC.
  • May inhibit nanocrystal formation [24]
Bone morphogenetic protein-7 (BMP-7)

    Part of a tumour growth factor beta cytokine family, crucial in development, active in adult life with broadly pro-osteoblastic properties. Down-regulated in renal failure

  • Supplementation prevents VC in animal CKD model [126]
  • Promotes bone formation and skeletal deposition of phosphate [37], ameliorating adynamic bone disease / low bone turnover
  • Maintains VSMC differentiation and inhibits transformation to an osteoblastic phenotype [127]
Osteoprotegerin (OPG)

    Part of the tumour necrosis factor (TNF) superfamily – decoy receptor for receptor activator of nuclear factor kappa B ligand (RANKL) – expressed in endothelial cells, VSMCs and osteoblasts, broadly anti-inflammatory, inhibits osteoclast differentiation

  • Deficiencies in animal models result in medial VC [128, 129]
  • Conversely it is positively associated with CAC and cardiovascular events in haemodialysis patients [130]
  • Exact pathways of OPG interaction with calcification in the vasculature are unknown, positive association implies OPG may be involved in a compensatory mechanism
  • RANKL initiates osteoblastic transformation of VSMCs [131]
  • Inhibits osteoclast formation and activation in bone, preventing resorption
  • Inhibits pro-apoptotic pathway in VSMCs, reducing the potential for apoptotic initiation of VC [131]
Fetuin-A

    An extracellular calcium-regulatory protein which inhibits VC

  • Knockout mice develop extensive VC [132]
  • CKD patients with lower serum fetuin-A have increased CV mortality [132]
  • Low fetuin-A in dialysis patients is associated with VC, calcific uraemic arteriolopathy and CV mortality [133]
  • Inhibits de novo Ca-PO4 precipitation [134]
  • Inhibits calcification within VSMCs preventing vesicular-mediated precipitation of Ca-PO4 [135]
Osteopontin (OPN)

    An extracellular phosphoprotein

  • Absent in normal arteries, detectable within the media of calcified vessels in CKD patients [24]
  • Osteopontin and MGP co-knockout mice develop accelerated calcification vs. MGP knockout mice
  • Inhibits hydroxyapatite crystal growth
  • Promotes osteoclastic function

Potential therapeutic interventions to prevent, arrest or reverse vascular calcification

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

Primary prevention

The strong relationship between progressive renal dysfunction and the increased prevalence, severity and progression of VC, means that primary prevention of kidney disease and renal functional loss over time would have a big impact on VC. It would most likely profoundly improve CV survival but, as mentioned, it remains a considerable challenge [41].

Currently the treatment of hypertension and the use of statins are the key interventions in those with CKD, limiting disease progression and reducing cardiovascular events [42-44]. Several large hypertension trials in patients with normal renal function have shown that treatment improves of measures arterial stiffness, such as pulse wave velocity [45, 46]. However surprisingly few equivalent studies exist in patients with CKD. Despite this, supportive evidence of efficacy exists from several studies in animal models, where treatment of hypertension reduces vascular calcification [47, 48], and by one recent randomized trial showing that dual RAAS blockade in CKD patients is associated with improved arterial stiffness [49]. In addition optimal treatment of diabetes can slow GFR decline [50], and may help to prevent vessel calcification associated with diabetes. The use of RAAS blockers for albuminuria in diabetes, or proteinuria in non-diabetic disease, is the cornerstone of nephro-protection, and may itself have a beneficial impact on VC [51].

However, given the ageing population and the epidemics of obesity and type II diabetes, there are likely to be many more, not fewer, calcified patients with CKD in the future.

Secondary prevention

The role of CKD mineral bone disease

There are CV risks associated with plasma phosphate concentrations in the middle to upper tertiles of the normal range [52]. In both CKD patients and the general population higher plasma phosphate concentrations are associated with the development and progression of CAC, and the development of LVH [52].

Of intense interest presently is whether the vascular toxicity associated with plasma phosphate concentrations is a direct consequence of phosphate acting on VSMCs in the arterial media [53], or a direct effect of the concurrent elevation of fibroblast growth factor-23 (FGF-23) elevation. It is plausible that both plasma phosphate and FGF-23 can be directly detrimental to blood vessel function and structure [52, 54].

This being the case, the focus of prevention shifts to attempts to temper the rise of plasma phosphate with worsening degrees of CKD (i.e. CKD 4–5), and also to attempt to normalize already elevated plasma phosphate concentrations in dialysis patients.

Phosphate control – dietary and oral phosphate binders

The mainstay of phosphate control presently is dietary phosphate restriction to about 800–1000 mg phosphate day−1, trying in particular to avoid sources of inorganic phosphate, such as food preservatives and flavourings seen in ‘fast-food’ meals and soft drinks [55]. These diets can lead to reductions in plasma phosphate and urinary fractional excretion of phosphate but are notoriously hard to persevere with and recidivism is typical [55].

In addition to dietary manipulations there is extensive usage of a range of oral phosphate binding medications [56], which to variable degrees bind phosphate in the gut using calcium, magnesium, aluminium, lanthanum or resin-based salts or compounds. This is a complex area, expertly reviewed recently [56]. There are several studies which support the notion that limitation of excess exogenous calcium, much of it from the calcium-containing oral phosphate binders, can induce relative metabolic and cellular low bone turnover, and thus lead to promotion of ectopic calcium and phosphate deposition in the soft tissues, most prominently in the vasculature. This tendency is worsened by the excessive use of vitamin D compounds, which significantly increase calcium and phosphate absorption from the GI tract [56]. Long term avoidance of a positive calcium and phosphate balance requires closer attention to diet, drugs and dialysis techniques than most patients typically receive currently.

Phosphate control – mode and timing of renal replacement therapy

In patients on dialysis treatment programmes, the standard 3–4 h dialysis treatment schedules thrice weekly are inefficient at removing plasma phosphate, because of its extensive hydration shell, and the fact that phosphate in the body is mainly intracellular in its location. As plasma phosphate falls through dialysis removal, more intracellular phosphate exits cells to compensate [57].

It is clear that using more sophisticated (haemofiltration, haemodiafiltration) dialysis, or standard dialysis but for 8 h, 6 nights a week, can lead to excellent plasma phosphate control, and to less progression of CAC [57]. However this effect is confounded as better dialysis also corrects a range of other electrolyte, metabolic and hormonal abnormalities associated with CKD, including blood pressure. Sadly this ‘gold standard’ approach to renal replacement therapy remains the lucky choice for a small minority of contemporary dialysis patients in most countries [58].

Choice of vitamin D analogue

In several animals models it has been shown that the choice of synthetic or semi-synthetic vitamin D receptor activator (VDRA) can influence the development of VC. Paricalcitol has been shown in several reports to be less associated with VC in this setting [59]. This may contribute to the survival advantage reported by cross-sectional surveys and registries for patients on paricalcitol as opposed to other VDRAs [60], although this remains controversial in the absence of any randomized controlled trial. No differences in VC or survival have ever been shown in man in a suitably sized randomized controlled trial, and many authoritative opinions remain sceptical [61].

Parathyroidectomy and cinacalcet

For progressive, biochemically-severe, and often symptomatic secondary hyperparathyroidism, a surgical parathyroidectomy is the treatment of choice. This is particularly true when the usual treatment with vitamin D compounds is ineffective at reducing parathyroid hormone (PTH) concentrations or leads to significant hypercalcaemia or hyperphosphataemia. It has been clearly shown that the high PTH, high calcium, high phosphate milieu associated with advanced secondary hyperparathyroidism is also associated with rapid loss of mineral from bone and reciprocal increases in vessel calcium content. Surgical parathyroidectomy has been shown to arrest VC progression and can lead to dramatic amelioration of calcium deposits in skin, joints and small arteries [62].

Cinacelcet is the first licensed calcium-sensing receptor (CaSR) allosteric activator. Its use has dramatic effects in reducing plasma PTH and calcium concentrations, and a smaller effect in dialysis patients in reducing plasma phosphate concentrations [63]. In animal models these classes of compounds are strikingly successful at preventing or reversing VC. This prompted the ADVANCE trial [64] in which 165 dialysis patients in each of two arms were studied to see the impact of cinacalcet on progressive coronary artery, aortic and valvular calcification. The overall results were very close to positive (around P = 0.05) for vessels and valves, and it has been argued that this should be seen as a positive intervention [64, 65]. Recently, the EVOLVE study has reported and this has failed to demonstrate a salutary effect of the use of cinacalcet to reduce PTH concentrations on overall and CV survival rates [66].

Renal transplantation

The definitive treatment for renal failure is renal transplantation. It has now been shown very clearly that transplantation does slow down, but does not abolish, established coronary and aortic calcifications in CKD patients. There are however no animal models which have examined calcified animals with advanced CKD who then undergo transplantation. While it is logical to think that the post-transplantation correction of plasma calcium, phosphate, PTH and FGF-23 concentrations would reduce the propensity for VC, there are no animal or clinical data to support this. In the clinical domain Seyahi et al. undertook the largest and longest study of post-renal transplantation CAC behaviour, demonstrating that CAC progressed after transplantation [67]. Schankel et al. examined 82 asymptomatic patients and concluded that CAC progression was seen in a quarter of their cohort who was followed-up for just under 2 years [68]. Mazzaferro et al. examined 41 renal transplant recipients and a control group composed of 30 dialysis patients. The patients were followed-up for nearly 2 years and progression was observed in 12.2% of the renal transplant recipients [69]. They concluded that renal transplantation slows, but does not halt, CAC progression, and that improvement of CAC is a very rare event. Finally, Bargnoux et al. examined CAC progression in 76 patients who were followed-up for 1 year; CAC progressed in 26.3% of their patients and interestingly regressed in 14.5% [70]. Several other factors have been shown in one or more studies to predict post-transplant CAC changes, including lipid concentrations, BP control, osteoprotegerin and phosphate concentrations, and bisphosphonate use.

Manipulating the complex biology of vascular calcification

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

Sodium thiosulfate

Sodium thiosulfate has recently been suggested as a major improvement in the treatment of the rare but devastating condition calcific uraemic arteriolopathy (calciphylaxis) [71, 72]. In this condition the calcification of arterioles and subsequent intimal proliferation leads to luminal obliteration and necrotic skin lesions, with patients commonly dying of sepsis.

Sodium thiosulfate's proposed mechanism is that it greatly enhances the solubility of calcium in deposits and thereby makes it available for haemodialysis clearance. It may also have an antioxidant effect, with enhanced glutathione generation, nitric oxide and endothelial cell mechanisms. Additionally its metabolite, hydrogen sulphide, might have vasodilatory effects [73]. Sodium thiosulfate is cleared renally and by dialysis, so doses need to be infused after each dialysis (25–50 g intravenously over 1 h). Side effects are limited to a small increase in anion gap because of circulating thiosulfate, as well as reports of anorexia, nausea and vomiting after more rapid high dose infusions.

There is one small study of the use of a prolonged course of sodium thiosulfate targeting CAC in dialysis patients from Korea [74]. Although the findings seemed to support benefit of this intervention, we feel this is urgently in need of being repeated over a longer time period in a bigger more clinically heterogeneous patient cohort. We would not currently recommend its use in this setting outside clinical trials.

Bone morphogenetic protein-7 (animal models)

In a most elegant series of experiments, Hruska's group from St Louis, Missouri, USA showed in two independent and separate studies that renal injury and subsequent CKD directly inhibited skeletal anabolism, and that stimulation of bone formation decreased serum phosphate [37]. Where the serum calcium, phosphate, PTH and calcitriol were maintained normal after renal ablation in mice, and even mild renal injury equivalent to stage 3 CKD, decreased bone formation rates were seen. In low density lipoprotein receptor null (LDLR-/-) mice fed high fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidaemia and insulin resistance), the mice have extensive VC, both the intimal and medial. This VC was made worse by CKD and ameliorated by bone morphogenetic protein-7 (BMP-7). These mice also had hyperphosphataemia which responded to BMP-7 treatment. Subsequent examination of their skeletons revealed significant reductions in bone formation rates were associated with high fat feeding, and that the addition of CKD resulted in the low bone turnover or adynamic bone disorder (ABD), while VC was made worse. The effect of CKD in decreasing skeletal anabolism (decreased bone formation rates and reduced number of bone modelling units) occurred despite secondary hyperparathyroidism. The mechanism by which BMP-7 treatment corrected low bone turnover and hyperphosphatemia was thought to be by stimulation of skeletal phosphate deposition, reducing plasma phosphate and thereby removing a major stimulus to VC. This may happen in man [75].

Pyrophosphate

Tissue pyrophosphate release is regulated by three factors. First, the rate-limiting enzyme ‘ecto-nucleotide pyrophosphatase phospho-diesterase-1’ (ENPP-1), second, the transmembrane transporter ‘ANK’ encoded by the ‘progressive ankylosis’ locus and third, the membrane-bound enzyme ‘tissue non-specific alkaline phosphatase’ (TNAP). Activity of ENPP-1 determines the production rate of pyrophosphates, and intact ANK secures extracellular availability by specifically transporting pyrophosphates out of the cells. However, TNAP degrades secreted pyrophosphates into single phosphate ions and, thus, an increased enzyme activity would cause local hyperphosphataemia. Both genetic ANK and ENPP-1 deficiencies in mice cause phenotypes of dystrophic calcification. In humans, a loss of function mutation of ENPP-1 has been identified as causing a severe disorder termed idiopathic infantile arterial calcification (IIAC) leading to severe vascular calcification in newborns and small children [76, 77].

A recent report by O'Neill et al. concerned the measurement of plasma pyrophosphate concentrations in 115 individuals in CKD stages 4–5 and correlated these concentrations with the degree and change in large artery calcification [78]. This was quantitatively detected at the superficial femoral artery by CT, obtained at baseline and after 1 year. An inverse association was found between baseline calcification score and pyrophosphate concentrations. Also, an inverse, though non-significant association between calcification progression and pyrophosphate concentrations was reported [78]. This paper is of significant relevance because observations like these may pave the way to novel therapeutic pathways and strategies. Taken together, will pyrophosphate measurements have any potential at all to become a relevant risk biomarker for CKD patients in the future? At the moment, there is no definite answer to any of these questions, but this is a potentially exciting interventional pathway [79-81].

Bisphosphonates

Experimental data from animal models and patients on chronic haemodialysis suggest that nitrogen-containing bisphosphonates (NCBPs; e.g. ibandronate, alendronate, risedronate and zoledronate) may limit vascular and valvular calcification [82-84]. Bisphosphonates are primarily used in the management of osteoporosis, binding to hydroxyapatite, preventing osteoclast-mediated bone resorption. NCBPs inhibit farnesylpyrophosphate synthase, an enzyme in the mevalonate pathway further down than HMG-CoA reductase, the site of statin action. Consequently, several pharmacologic effects are common to both NCBPs and statins. NCBPs decrease serum LDL-cholesterol concentrations by approximately 5%, raise HDL-cholesterol by 10–18% [85, 86] and reduce inflammation by inhibiting the secretion of several inflammatory cytokines [87]. However, NCBP inhibition of vascular and valvular calcification may be secondary to prevention of bone resorption and the subsequent release of calcium phosphate from bone. Recent data suggesting that NCBPs and other osteoporosis therapies may slow the progression of aortic stenosis support this hypothesis [88].

There is some suggestion that NCBPs may modulate cardiovascular calcification, including from the recent MESA study. Here NCBPs were associated with decreased prevalence of cardiovascular calcification in older women, but more prevalent cardiovascular calcification in younger subjects [89].

However, it must be stated very strongly that there are substantial potential risks of bone and other toxicities using NCBPs in CKD which renders this a complex, confusing and challenging area [90]. Most of these compounds are substantially renally-excreted, and thus tend to accumulate significantly in plasma and bone, with prolonged and often excessive skeletal actions. Diagnosis and treatment of osteoporosis, and any impact on associated tendencies to VC, remain challenging and under-researched. Whether the novel anti-resorptive monoclonal antibody denosumab [91], which has no renal excretion or sequelae, or the even newer anti-sclerostin antibodies, can also influence VC is not yet known.

Vitamin K2 antagonists and warfarin avoidance

It has been suggested that the use of vitamin K antagonists (VKA) in CKD 4–5 and dialysis is associated with tissue calcification (see Table 1). Experimental data suggest that VKA may decrease the activity of matrix-g-carboxyglutamic acid (GLA) protein (MGP), a strong inhibitor of soft tissue calcification [92, 93]. Rennenberg et al. [94] showed that the long term use of VKA is associated with enhanced extra-coronary VC also in patients with normal or near-normal kidney function (eGFR > 60 ml min−1). Weijs et al. [92] performed a study in which a prospective coronary calcium scan was undertaken in 157 AF patients without significant cardiovascular disease, including 71 (45%) patients who were chronic VKA users. No significant differences in clinical characteristics were found between patients on VKA treatment and non-anticoagulated patients. However, median CAC scores differed significantly between the groups (0 vs. 29 respectively, P < 0.001). Mean CAC scores also increased with the duration of VKA use. Multivariable logistic regression analysis revealed that age and VKA treatment were significantly related to increased CAC score.

A large multicentre trial is due to start in which the use of vitamin K1 supplementation to suppress CKD related over-production of under-carboxylated and under-hydroxylated MGP [95] will be examined. It was originally hoped that vitamin K2 (menaquinone) could be used in this trial but for regulatory reasons in Germany vitamin K1 (phylloquinone) will be used (Georg Schlieper, personal communication). It is hoped that the progression of existing CAC in dialysis patients can thus be reduced.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

CVD is the chief cause of morbidity and mortality in CKD. VC is common in CKD, worsens with time, presence of diabetes, smoking status and duration of dialysis, and is associated with abnormal bone and mineral metabolism parameters, especially plasma phosphate. It is strongly linked with reduced patient survival. There is as yet, however, no consensus on screening for its presence, nor about interventions to retard progression, let alone promote reversal. Many bone-specific or related factors seem associated with its development and progression (see Table 1). It is clear from the most dramatic interventions that normalize phosphate, namely intensive dialysis and renal transplantation, that this cannot regress existing large vessel calcification. This is likely to be because the process of reversal will need to be an active cellular one, involving resorption of calcified lesions in the vessel wall and probably requiring a complex series of pharmacological interventions with agents not yet available. Promoting this process in the vessels, while avoiding simultaneous skeleton demineralization remains a formidable challenge, and is not achievable with the tools currently at our disposal. Thus current clinical practice should focus on prevention and retardation of progression. Interventions such as pyrophosphate, BMP-7, vitamin K2 and CaSR allosteric activators seem to us to be the most attractive and likely avenues to explore with further well designed randomized controlled trials.

Competing Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work. DG has received speaking and advisory honoraria from Amgen, Fresenius, Genzyme and Shire and JS has received speaking and advisory honoraria from MSD, Abbott and Astra-Zeneca. Dr Spaak is coordinator of the Karolinska Cardiorenal Theme Centre, which has received grants from Amgen and Abbott.

Dr Leonard gratefully acknowledges financial support provided by the National Institute of Health Research (NIHR).

References

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  2. Abstract
  3. Introduction
  4. Cardiovascular disease in chronic kidney disease
  5. The cardio-renal concept
  6. Calcification in cardiovascular disease and chronic kidney disease
  7. Reciprocity between calcium in the skeleton, vessels and valves
  8. Potential therapeutic interventions to prevent, arrest or reverse vascular calcification
  9. Manipulating the complex biology of vascular calcification
  10. Conclusions
  11. Competing Interests
  12. References
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