Vascular calcification in chronic kidney disease: an update.

Nephrol Dial Transplant (2016) 31: 31–39 doi: 10.1093/ndt/gfv111 Advance Access publication 26 April 2015

Vascular calcification in chronic kidney disease: an update Georg Schlieper1, Leon Schurgers2, Vincent Brandenburg3, Chris Reutelingsperger2 and Jürgen Floege1 1

Department of Nephrology, RWTH University of Aachen, Aachen, Germany, 2Department of Biochemistry, Faculty of Medicine, Health and Life

Science, Maastricht, The Netherlands and 3Department of Cardiology, RWTH University of Aachen, Aachen, Germany

Correspondence and offprint requests to: Jürgen Floege; E-mail: juergen.fl[email protected]

Keywords: cardiovascular diseases, MGP, phenotype switch, vitamin K, VSMC

INTRODUCTION Cardiovascular mortality increases progressively with advancing chronic kidney disease (CKD) and loss of renal function. In dialysis patients, it is the most frequent cause of death and indeed most patients beginning renal replacement therapy have abnormal cardiovascular function and dimensions. Traditional risk factors such as hypercholesterolaemia or arterial hypertension fail to adequately explain these observations, pointing to an added role of non-traditional risk factors such as uraemia, disordered mineral-bone disease, premature senescence of cardiovascular tissues, inflammatory and oxidative stress and others [1]. Here, we review the latest insights on cardiovascular calcifications in CKD, which become highly © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

C L I N I C A L M A N I F E S TAT I O N S A N D CONSEQUENCES Two types of vascular calcification can be differentiated, both of which affect the majority of patients with long-standing CKD and particularly patients on dialysis: arterial media calcification (calcific arteriosclerosis or Mönckeberg’s sclerosis) and accelerated calcification of intimal plaque (calcific atherosclerosis) [2]. Calcific atherosclerosis may be the last step in classical atherosclerosis whereas medial calcification is mainly non-inflammatory and associated with duration of haemodialysis, calcium–phosphate disorders, diabetes and ageing [5]. Cardiac calcifications (i.e. myocardial or valvular calcifications) are not covered here and predominantly affect the aortic valve leaflets. A fourth, rare form of vascular calcification is calcific uraemic arteriolopathy (calciphylaxis), which we have reviewed recently [6]. This disorder is of potential outstanding interest since it is considered a time-lapse example of more common calcification disorders potentially allowing for an easier identification of pathomechanisms contributing to calcification in general. 31

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Cardiovascular calcification is both a risk factor and contributor to morbidity and mortality. Patients with chronic kidney disease (and/or diabetes) exhibit accelerated calcification of the intima, media, heart valves and likely the myocardium as well as the rare condition of calcific uraemic arteriolopathy (calciphylaxis). Pathomechanistically, an imbalance of promoters (e.g. calcium and phosphate) and inhibitors (e.g. fetuin-A and matrix Gla protein) is central in the development of calcification. Next to biochemical and proteinacous alterations, cellular processes are also involved in the pathogenesis. Vascular smooth muscle cells undergo osteochondrogenesis, excrete vesicles and show signs of senescence. Therapeutically, measures to prevent the initiation of calcification by correcting the imbalance of promoters and inhibitors appear to be essential. In contrast to prevention, therapeutic regression of cardiovascular calcification in humans has been rarely reported. Measures to enhance secondary prevention in patients with established cardiovascular calcifications are currently being tested in clinical trials.

prevalent as CKD progresses and which are potent predictors of cardiovascular mortality in CKD patients [2]. It has been argued that cardiovascular calcification in CKD is merely a consequence of vascular inflammation and as such does not constitute a relevant treatment target [3]. However, inflammation is not a major feature of degenerative calcification, for example of the vascular media. In addition, measures that experimentally reduce CKD-associated vascular calcification and do not necessarily involve effects on inflammatory processes, translate into better survival [4]. However, we acknowledge that there is currently a paucity of data to confirm this in patients with CKD and of course the problem exists that therapeutic measures that affect calcification in patients usually have a broad array of actions and consequences. Thus, it may not be possible to conclusively answer this question in patients.

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A B S T R AC T

P AT H O M E C H A N I S M S Calcification promoters An imbalance of calcification promoters and inhibitors (Table 1) in CKD paves the way for the development of extraosseous calcifications [10]. Of note, these factors may act differently on different parts of the arterial tree [11, 12]. Altered mineral homeostasis. The main constituents of vascular calcifications are calcium and phosphate mainly in the form of hydroxylapatite [13]. Elevated serum levels of both calcium and phosphate are risk factors for increased mortality in CKD patients [14] and promote mineralization of vascular smooth muscle cells (VSMCs) (Figures 1 and 2). Experimental studies have shown that increasing phosphate concentrations (entering the cell via the sodium-dependent phosphate cotransporter PiT-1) can induce human arterial VSMCs to

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Table 1. Promotors and inhibitors of cardiovascular calcifications Promotors

Inhibitors

BMP-2, 4 and 6 Osteocalcin Bone sialoprotein Alkaline phosphatase Calcium and phosphate ions Oxidative stress Inflammatory cytokines (IL-6, IL1, TNF) Diabetes (high glucose, AGE) Modified lipids, cholesterol Coumarin derivatives Matrix vesicles/exosomes apoptosis/apoptotic bodies MMP2, 3 and 7 Runx2 Sox9 Osterix/Sp7

Matrix Gla protein Osteopontin Osteoprotegerin Fetuin-A Klotho Pyrophosphate Carbonic anhydrase BMP-7 Vitamin K Magnesium Sodium thiosulfate

F I G U R E 1 : Microcalcifications of a uraemic artery visualized by

TEM. Microcalcifications show various morphologies with a lamellar core-shell structure in many particles which suggest that apoptotic bodies or matrix vesicles may serve as calcification nidus.

transdifferentiate towards an osteoblastic phenotype (see below). In contrast to bone morphogenetic protein (BMP)-7, other BMPs such as BMP-2 appear to promote calcification [15]. As ageing is an important confounder when investigating human arteries and pathomechanisms of calcification, arteries of uraemic children are important models to gain insight into the process of calcification. Indeed, in studies on arteries of children with CKD, phosphate could induce progression of calcification and osteogenic transdifferentiation, and calcium could potentiate these effects [16]. Disturbed calcium and phosphate metabolism in uraemia is often accompanied by dysregulation of PTH and FGF23. High PTH levels implicate rapid bone turnover with associated calcium and phosphorus release into the circulation (and likely the vasculature) whereas suppressed PTH can produce adynamic/low-

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Irrespective of the affected vascular bed, the presence, amount and also progression of vascular calcification as detected by various non-invasive means helps identify patients at particular risk compared to those without or with low-grade calcification. There is an ongoing scientific debate about the true killer in CKD—calcification versus arterial stiffening [3, 7]—however, vascular calcification is without doubt associated with a dismal cardiovascular outcome in patients with CKD. There are no fixed boundaries between stiffening arterial disease and calcifying arterial disease in CKD. In fact, these closely related vascular pathologies both go along with reduced arterial elasticity, high pulse pressure and augmented pulse-wave velocity. The resultant cardiomyocyte hypertrophy contributes to the negative sequel of left-ventricular dysfunction and hypertrophy (LVH), which are among the most significant driving forces of cardiovascular risk in CKD patients [8]. Uraemic valvular disease, particularly as calcific aortic stenosis, further contributes to an increased afterload and therefore represents a highly prevalent trigger or aggravating factor for LVH. Uraemia-associated LVH is characterized by cardiomyocyte disarray and interstitial fibrosis [9] thought to induce systolic and/or diastolic heart failure as well as various arrhythmias all of which likely predispose CKD patients to sudden cardiac death. In daily practice, assessment of cardiovascular calcifications in CKD patients cannot be recommended as routine diagnostics on a regular basis and should be reserved for particular situations (e.g. ultrasound of the iliac arteries for transplant listing, echocardiography to detect calcific aortic valve stenosis or when patients want to know their individual cardiovascular risk). In addition, we feel that in many patients a diagnostic workup for calcifications has little clinical consequence. Thus, in old dialysis patients with a relatively short life expectancy, the detection of cardiovascular calcifications usually does not alter their treatment. Vice versa in younger dialysis patients, in particular those waiting for a kidney transplant, every measure should be undertaken to prevent the development of calcification rather than wait for them to become detectable and to act only then.

F I G U R E 2 : Vascular smooth muscle cell (VSMC): contractile and synthetic phenotype. In healthy arteries most VSMCs have a contractile phenotype (A). Certain stress signals may alter gene expression thereby modulating the VSMC phenotype from a contractile to a synthetic phenotype. The synthetic phenotype (B) is more susceptible to calcification.

Altered vascular enzyme activity. Alkaline phosphatase indirectly facilitates hydroxyapatite formation by reducing levels of pyrophosphate, a calcification inhibitor (see below) [29]. Within this context, loss of CD73 activity, an enzyme that generates adenosine and anorganic phosphate from AMP, resulted in an increase in alkaline phosphatase activity and thereby seems to induce calcification [30]. Recently, another phosphatase called PHOSPHO1 has been shown to be involved in

Mechanisms of cardiovascular calcification in CKD

Other calcification promoters. An involvement of lipids and/or oxidation in vascular calcification has been shown in experimental studies. In VSMCs, lipids such as palmitic acid can induce mineralization through Acyl-CoA synthetases and NFKB [32], and oxidized low-density lipoprotein promoted osteoblast differentiation by up-regulating osterix expression dependent on Msx2 [33]. Several other factors such as microRNAs may also promote vascular calcification [34]. Overexpression of the adipokine c1q/tumour necrosis factor-related protein-3 promoted phosphate-induced VSMC calcification [35]. Drugs and diseases such as diabetes are known to be associated with cardiovascular calcifications. For example, warfarin is known to induce cardiovascular calcifications by inhibiting the vitamin K cycle thereby leading to less active MGP, and inflammation leads to reduced fetuin-A levels (see below). Recently, endothelial microparticles have been shown to mediate inflammation-induced vascular calcification [36] pointing to an interaction between different vascular cells and layers, thereby opening a more complex and fascinating research field. Calcification inhibitors Even in healthy subjects, body fluids are supersaturated with regard to calcium and phosphate. Spontaneous pathological precipitation of calcium–phosphate crystals, however, does not occur. This is due to the tight control of calcium precipitation by multiple calcification inhibitors, which either work alone or in concert. Below, we will address the major actors involved in calcification inhibition. Fetuin-A. Fetuin-A (AHSG; 2-Heremans-Schmid glycoprotein) is a hepatic plasma protein belonging to subgroup 3 of the cystatin superfamily, which also includes fetuin-B, histidine-rich glycoprotein, and kininogen [37]. Fetuin-A circulates in plasma at high concentrations, ranging from 0.5 to 1.0 g/L in humans [38]. Fetuin-A-deficient mice on a DBA/2 background clearly established the role of fetuin-A as a systemic inhibitor of ectopic calcification [39]. Lack of fetuin-A

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Altered vascular extracellular matrix. Extracellular matrix molecules such as collagen type 1, bone sialoprotein, fibronectin and decorin have been shown to be involved in the process of biomineralization in the vasculature. Genetic diseases such as pseudoxanthoma elasticum (PXE) or Marfan’s syndrome are characterized by a clinical phenotype that is similar to that of arterial remodelling which is linked to calcification [22, 23]. Arterial remodelling is defined as structural and functional changes of the vascular wall that occur in response to disease, injury or ageing. Vascular remodelling results in VSMC phenotypic switching (see below), thereby promoting calcification. Matrix metalloproteinases (MMP) that degrade components of the ECM can modulate artery calcification [24]. Cathepsin S deficiency, which normally exhibits elastolytic activity, abolishes vascular calcification in renal disease [25]. Indeed, calcification often occurs along elastin fibres, and elastin degradation can enhance calcification [26]. Recently, elastin haploinsufficiency has been shown to impede the progression of arterial calcification in matrix Gla protein (MGP)-deficient mice [27]. Elastin degradation occurs in experimental CKD [28]; however, elastin degradation could not be detected in human uraemic arteries [13].

vascular calcification as inhibition of PHOSPHO1-inhibited calcification [31].


turnover bone disease [17], which is often associated with the presence of cardiovascular calcifications. Klotho serves as a coreceptor for FGF23, and Klotho deficiency has been implicated in the development of arterial calcification and the resistance to protective vascular effects of FGF23 [18]. FGF23 itself does not seem to induce vascular calcification [19]. VSMCs express lower levels of the calcium-sensing receptor in calcified arteries, and such reduced levels thereby could contribute to calcification [20]. Of interest, calcimimetics prevented experimental medial calcification [21].

Matrix Gla protein. MGP is a vitamin K-dependent protein. It is widely expressed and accumulates in cartilage and calcified tissues. The function of MGP became clear in MGP-deficient mice, which die within 2 months after birth as a consequence of massive haemorrhages due to blood vessel rupture caused by arterial calcification [45]. The necessity for vitamin K as a cofactor to activate MGP was shown by chemical inhibition of MGP function [46] and by mutagenesis of the glutamate residues [47]. The precise function of MGP has not been unravelled yet, but likely includes inhibition of calcium crystal growth, blocking BMP-2 and BMP-4 function and shielding the nidus for calcification [48]. Like fetuin-A, MGP accumulates in extracellular vesicles thereby forming a break on unwanted calcium–phosphate precipitation [49]. Osteoprotegerin. OPG acts as a soluble (decoy)-receptor for RANKL. OPG is widely expressed, but particularly highly expressed in VSMCs and endothelial cells of arteries. Its function is to prevent binding of RANKL to RANK [50], thereby inhibiting osteoclast function and subsequent bone resorption. Mice with OPG deficiency have both increased osteoporosis and vascular calcification [51]. Clinically, high circulating levels of OPG are associated with atherosclerosis or risk factors of atherosclerotic disease indicating a compensatory increase [52]. Pyrophosphate, ectonucleotide pyrophosphatase phosphodiesterase. ENPP1 is a gene, which encodes a pyrophosphategenerating enzyme that regulates extracellular phosphate. The ENPP1 gene has been linked to ectopic calcification through a mouse model known as the ‘tiptoe walking mouse’ [53]. Normal levels of extracellular pyrophosphate are sufficient to prevent vascular calcification [54]. In haemodialysis patients, plasma levels of pyrophosphate are decreased and correlate inversely with vascular calcification. Osteopontin. OPN is an extracellular phosphoprotein that has many phosphoserines that are negatively charged [55]. This negative charge gives OPN its strong affinity for hydroxyapatite. OPN is present in mineralized tissues such as bones and teeth. OPN-deficient mice suffer from accelerated vascular calcification [56]. OPN regulates mineralization by inhibiting calcium crystal growth and by promoting osteoclast function. In healthy arteries, OPN is not present, however, in calcified plaques it is highly upregulated [57].

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Altered phenotype and responses of vascular smooth muscle cells Osteochondrogenesis. VSMCs are key in suppressing mineralization of vascular tissue. They are armed with an array of proteins that inhibit calcification such as BMP-7 [58], osteopontin [57] and MGP [48]. In addition, they can take up from the circulation the potent inhibitor fetuin-A [42]. Paradoxically, VSMCs also have the ability to promote mineralization for example by producing extracellular vesicles (EVs) that act as nucleation sites for calcification in a manner similar to matrix vesicles in bone formation [16]. Why pro-calcification mechanisms are executed by VSMCs is still poorly understood. It may simply be an undesired bystander effect of the innate capacity of VSMCs to adapt to a changing environment by switching phenotype in combination with a pathological environment, such as that present in CKD. VSMCs can reversely switch phenotype from a contractile to a synthetic (migratory/proliferative) [59] and osteochondrogenic phenotype [60]. Inflammation [61], oxidative stress [62] and ageing (see below) can cause upregulation of osteochondrogenic transcription factors in VSMCs including Msx2, Runx2, Sox9 and osterix. These transcription factors mediate switching into osteochondrogenic phenotypes with upregulated expression of bone and chondrocyte proteins such as osteopontin, osteocalcin and alkaline phosphatase and downregulated expression of VSMC contractile proteins such as SM22-α and SM α-actin [63]. Uraemia can aggravate this process, e.g. with de novo expression of osteocalcin and downregulation of alpha smooth muscle actin [64]. Mice deficient for smooth muscle cell- specific Runx2 are largely protected from vascular calcification [65]. The contractile phenotype is a predominantly quiescent and anticalcifying phenotype whereas synthetic and osteochondrogenic phenotypes are associated with an increased propensity to promote calcification [66] (L. Schurgers, unpublished observations). Osteochondrogenic markers have been observed during vascular calcification in animal models [60] and in calcifying arteries of CKD patients [67] underscoring the theory that VSMCs switching into the osteochondrogenic phenotype precedes vascular calcification. Vascular ageing and senescence. Phenotypic switching of VSMCs has also been observed during normal vascular ageing with associated cellular senescence [68]. Investigating the VSMC phenotype associated with diseases and cellular senescence at the molecular level led to a hypothesis that vascular calcification in diseases such as CKD can be regarded as the result of premature ageing of VSMCs [69]. Prelamin A, an unprocessed product of the LMNA gene, is considered a driving factor in ageing of VSMCs. In vitro, prelamin A expression by VSMCs caused DNA damage, upregulation of Runx2, osteochondrogenic differentiation and calcfication [70]. In vivo prelamin A has been detected in VSMC nuclei in calcified arteries of aged individuals [71] and young CKD patients [70] indicating accelerated ageing in the latter. This interesting perspective will offer novel potential strategies and targets to prevent and combat vascular calcification. Extracellular vesicles and mineralization. Extracellular vesicles are considered major players in promoting VSMC-mediated

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contributes to vascular damage in the case of preexisting damage [40]. In haemodialysis patients, low fetuin-A levels were shown to be associated with inflammation and connected vascular calcification to mortality in patients [38]. Calciprotein particles (CPP) were identified as a trigger for ectopic calcification with a major role for fetuin-A in the formation and removal of these particles [41]. Locally, in the vasculature, small extracellular vesicular structures derived from VSMCs accumulate fetuin-A to prevent calcification [42]. Recently, fetuin-A was shown to alter the cytotoxicity of calcifying particles on human VSMCs [43]. Besides these direct effects on calcifying particles, fetuin-A can bind directly to BMP-2, BMP-4 and BMP-6 thereby blocking osteochondrogenic activity [44].

CLINICAL THERAPEUTIC CONSEQUENCES Calcium and phosphate balance Advanced CKD predisposes to calcium retention if dietary sources exceed 800 mg/day [78]. Dialysate composition is another important consideration in the calcium mass balance. Dialysate calcium concentrations of 1.25 mmol/L are usually associated with a near neutral balance, whereas higher concentrations promote calcium loading during haemodialysis [79]. Particularly in patients on calcium-containing phosphate binders, the consensus is reached to go even lower with dialysate calcium [80]. Another important consideration is serum

Table 2. Randomized clinical trials in dialysis patients assessing the effect of different phosphate binders on the progress of cardiovascular calcification Reference

Population

Comparators

Study duration (months)

Key finding

Chertow et al. [86]

200 prevalent HD patients 129 incident HD patients 109 incident HD patients 203 prevalent HD patients 183 prevalent HD patients 45 prevalent HD patients 52 prevalent HD patients

(A) Calcium acetate or carbonate (B) Sevelamer chloride (A) Calcium acetate or carbonate (B) Sevelamer chloride (A) Calcium acetate or carbonate (B) Sevelamer chloride (A) Calcium acetate plus statin (B) Sevelamer plus statin (A) Calcium carbonate (B) Sevelamer chloride (A) Calcium carbonate (B) Lanthanum carbonate (A) Calcium carbonate (B) Lanthanum carbonate

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Faster progress of CAC and aorta calcium score with calcium compared with sevelamer Faster progress of CAC scores with calcium-containing phosphate binders only with preexisting calcification at baseline Faster progress of CAC scores with calcium-containing phosphate binders in a diabetic subgroup (n = 64) No significant difference in calcification progress between the groups Faster progress of CAC scores with calcium-containing phosphate binders Less aortic calcification progress with lanthanum carbonate

Block et al. [87] Gallasi et al. [88] Qunibi et al. [89] Kakuta et al. [90] Toussaint et al. [91] Ohtake et al. [92]

18 18 12 12 18 6

Faster progress of CAC scores with calcium carbonate versus lanthanum carbonate

CAC, coronary artery calcification; HD, haemodialysis.


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phosphate, since cardiovascular calcification is markedly accelerated in patients with a positive intradialytic calcium mass balance and insufficient control of phosphate (E. Ok, personal communication). Fine-tuning of the dialysate calcium should also include circulating iPTH. Thus, dialysate calcium concentrations of 1.25 mmol/L or lower stimulate PTH release, whereas 1.375 mmol/L led to stable PTH levels [81]. The former would be desirable in cases of low baseline PTH, i.e. below the 2-fold upper normal range of the assay, which is usually associated with adynamic bone disease and thus relative inability of the bone to incorporate calcium and phosphate. Importantly, however, there are presently no large outcome studies demonstrating that a very low dialysate calcium is safe and improves clinical outcome. Most centres therefore do not decrease dialysate calcium below 1.25 mmol/L unless patients are overtly hypercalcaemic. Currently, there is a discussion on the optimal dialysate calcium [82, 83] with recent calculations favouring a calcium of 1.25 mmol/L or lower [80] or using an individualized approach [84]. However, the hard evidence for a lower calcium dialysate is questioned [85]. Phosphate retention is another consequence of advanced CKD, in particular if dietary intake is high. Measurements of urinary phosphate excretion in particular fractional excretion may provide information on the dietary intake, at least in stable patients, and may be used to guide dietary counselling. In addition to diet, phosphate binders are usually required in advanced CKD. Several studies have investigated whether the choice of phosphate binders, in particular calcium-containing or calcium-free, affects the progression of cardiovascular calcification in dialysis patients (Table 2). Collectively, these studies show consistently a slower progress if calcium-containing phosphate binders are avoided [86–90]. Smaller pilot studies described similar observations for the comparison of lanthanum carbonate with calcium carbonate [91, 92]. In nondialysis-dependent CKD patients (CKD stages 3–4), an Italian study noted the slowest progression of cardiovascular calcifications in patients given a phosphate-restricted diet plus sevelamer when compared with diet alone or diet and calcium acetate [93]. This notion was challenged by another study in 148 CKD stage 3–4 patients, which concluded that phosphate


calcification in vitro [49] and in vivo [72]. Extracellular vesicles are membrane-encapsulated vesicles that provide nucleation sites for formation of seed calcium crystals that, fuelled by various mechanisms [73], can grow further [42, 49]. They can be produced by living cells (micro- and matrix vesicles, exosomes) and dying cells (apoptotic bodies) [74] and are present in calcified arteries of CKD patients [13]. VSMCs can generate extracellular vesicles in vitro that differ in composition and calcifying properties depending on VSMC environmental factors such as Ca2+ and phosphate, and phenotype [49, 75]. VSMCs normally produce extracellular vesicles that contain inhibitors of calcification such as carboxylated MGP and fetuin-A. Elevated Ca2+ and phosphate, inflammatory cytokines and reactive oxygen species can cause phenotypic switching and a shift of production towards extracellular vesicles lacking those inhibitors and exposing pro-calcifying phosphatidylserine and annexins [49]. In addition to actively participating in vascular calcification while alive, VSMCs can produce pro-calcifying extracellular vesicles during their demise through apoptosis and secondary necrosis. Apoptotic bodies, which are membrane-encapsulated cell fragments resulting from apoptosis, resemble matrix vesicles and show pro-calcifying properties [76]. Chronic VSMC apoptosis in an animal model causes calcification of atherosclerotic plaques of young animals [77]. ZVAD, an inhibitor of apoptosis, strongly inhibited calcification of CKD vessels in an ex vivo model [16].

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Vitamin D derivatives We are not aware of large randomized controlled trials in advanced CKD patients that have investigated the effects of active vitamin D derivatives on calcification progress. Clearly, historical experience suggests that large doses of calcitriol or other active vitamin D compounds can accelerate vascular calcification. Another area of uncertainty is native vitamin D. Here, a recent small randomized trial in haemodialysis patients compared placebo or cholecalciferol (25 000 IU) therapy every 2 weeks [96]. After a 12-month period, calcification scores had progressed similarly in both study arms. Calcimimetics The only large randomized study to assess the effects of cinacalcet on cardiovascular calcification progress was the ADVANCE trial [97]. In this trial, 360 haemodialysis patients were randomized to cinacalcet plus low-dose calcitriol or vitamin D analogue, or flexible vitamin D therapy. The primary end point, i.e. the percentage change in coronary artery calcification scores from baseline to Week 52 did not differ significantly between the two arms but the study noted a consistent trend in favour of the combined regimen at all sites investigated. Furthermore, the study may have been confounded by the excessive use of vitamin D analogue in the combination arm [98]. Case reports additionally describe resolution of extraosseous calcifications following the institution of cinacalcet in patients with extremely high PTH levels [99]. Vitamin K and vitamin K antagonists So far, the effects of vitamin K supplementation on cardiovascular calcification has not been tested in CKD patients. However, we have reported that uncarboxylated MGP is markedly reduced in dialysis patients upon administration of up to 360 µg vitamin K2 per day [100]. These data lay the foundation for the randomized VitaVasK trial in which haemodialysis patients are given 5 mg of vitamin K1 thrice weekly while calcification progress is monitored over 18 months [101]. Vice

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versa, based on the experimental observations with MGP (see above), the approximately 10-fold increased risk of calciphylaxis and the uncertain cost-benefit ratio, we have advocated against a liberal use of vitamin-K antagonists in dialysis patients [102]. Other approaches Other than a very small pilot study, which noted no progression of calcification with a magnesium-containing phosphate binder [103], no data are available to substantiate the hypothesis that magnesium interferes with calcification in CKD. Similarly, pilot data suggest an arrest of calcification in dialysis patients given intravenous sodium thiosulfate after each dialysis for 5 months, but the long-term effects of this approach on bone remain uncertain [104]. Finally, in 50 patients with CKD stages 3–4, alendronate did not decrease the progression of vascular calcification compared with placebo over 18 months [105]. A number of small studies suggested a halt or slow down of calcification progression (e.g. [106]), but a larger study still reported progression of vascular calcification in transplant patients [107]. PTH was not an independent predictor for progression in that study [107]. In our view, a combination of the above-mentioned therapies (individualized to each patient) and not a single option might be the best therapeutic approach to prevent the development and progression of cardiovascular calcifications. The treatment of calcific uraemic arteriolopathy remains a challenge, and so far treatment consists of a largely empiric, multimodal approach (including optimization of mineral metabolism, administration of sodium thiosulfate, gentle debridement, etc.) [108]. The CKD-MBD working group of the ERA-EDTA has initiated a call for action by defining calcific uraemic arteriolopathy as one of the outstanding research targets for the upcoming years. CONCLUSIONS Taken together, a plethora of different factors contribute to the development of cardiovascular calcifications in CKD. Different pathologies (atherosclerotic calcification, media sclerosis and valvular calcification) may have overlapping yet distinct mechanisms. VSMCs are actively involved in the process of media calcification. Therapy aims at correcting the imbalance of promoters and inducers to prevent the initiation and progression of cardiovascular calcifications. AC K N O W L E D G E M E N T S We apologize to all authors whose important contributions we could not cite due to space restrictions.

C O N F L I C T O F I N T E R E S T S TAT E M E N T G.S. has received speaker and consultancy honoraria from Amgen und Sanofi and J.F. has received speaker and consultancy honoraria from Amgen, Fresenius, Sanofi, Shire and Vifor.

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binders in such patients actually promote rather than retard the progression of vascular calcification compared to placebo [94]. The authors speculated that subsequent to binding phosphate in the intestinal lumen, luminal wall phosphate transport is upregulated and thus more rather than less phosphate was absorbed. In our view, it is more likely, however, that the authors created an artefact by pooling patients randomized to calcium acetate, lanthanum carbonate or sevelamer carbonate into one ‘phosphate binder’ group. Indeed, inspection of the supplemental data, with all the limitations of small group sizes, suggests that only the group receiving calcium acetate but not the other groups exhibited progressive cardiovascular calcification. Thus, in our view, there is a very consistent data base that in patients with advanced CKD or on dialysis and with a reasonable life expectancy, calcium-containing phosphate binders should be avoided. Concerning outcome data, most studies failed to detect a survival advantage for calciumfree phosphate binders (most likely due to insufficient power of the single studies); however, a meta-analysis reported a 22% risk reduction with calcium-free phosphate binders [95].

REFERENCES

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1. Schlieper G, Hess K, Floege J et al. The vulnerable patient with chronic kidney disease. Nephrol Dial Transplant 2015; doi: 10.1093/ndt/gfv041 2. Ketteler M, Schlieper G, Floege J. Calcification and cardiovascular health: new insights into an old phenomenon. Hypertension 2006; 47: 1027–1034 3. Zoccali C, London G. Con: Vascular calcification is a surrogate marker, but not the cause of ongoing vascular disease, and it is not a treatment target in chronic kidney disease. Nephrol Dial Transplant 2015; 30: 352–357 4. Finch JL, Lee DH, Liapis H et al. Phosphate restriction significantly reduces mortality in uremic rats with established vascular calcification. Kidney Int 2013; 84: 1145–1153 5. Lanzer P, Boehm M, Sorribas V et al. Medial vascular calcification revisited: review and perspectives. Eur Heart J 2014; 35: 1515–1525 6. Brandenburg VM, Sinha S, Specht P et al. Calcific uraemic arteriolopathy: a rare disease with a potentially high impact on chronic kidney diseasemineral and bone disorder. Pediatr Nephrol 2014; 29: 2289–2298 7. Bover J, Evenepoel P, Urena-Torres P et al. Pro: cardiovascular calcifications are clinically relevant. Nephrol Dial Transplant 2015; 30: 345–351 8. London G, Covic A, Goldsmith D et al. Arterial aging and arterial disease: interplay between central hemodynamics, cardiac work, and organ flow-implications for CKD and cardiovascular disease. Kidney Int Suppl (2011) 2011; 1: 10–12 9. Tyralla K, Amann K. Cardiovascular changes in renal failure. Blood Purif 2002; 20: 462–465 10. Ketteler M, Rothe H, Kruger T et al. Mechanisms and treatment of extraosseous calcification in chronic kidney disease. Nat Rev Nephrol 2011; 7: 509–516 11. O’Neill WC, Adams AL. Breast arterial calcification in chronic kidney disease: absence of smooth muscle apoptosis and osteogenic transdifferentiation. Kidney Int 2014; 85: 668–676 12. Schlieper G. Vascular calcification in chronic kidney disease: not all arteries are created equal. Kidney Int 2014; 85: 501–503 13. Schlieper G, Aretz A, Verberckmoes SC et al. Ultrastructural analysis of vascular calcifications in uremia. J Am Soc Nephrol 2010; 21: 689–696 14. Floege J, Kim J, Ireland E et al. Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol Dial Transplant 2011; 26: 1948–1955 15. Derwall M, Malhotra R, Lai CS et al. Inhibition of bone morphogenetic protein signaling reduces vascular calcification and atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 613–622 16. Shroff RC, McNair R, Skepper JN et al. Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J Am Soc Nephrol 2010; 21: 103–112 17. Qi Q, Monier-Faugere MC, Geng Z et al. Predictive value of serum parathyroid hormone levels for bone turnover in patients on chronic maintenance dialysis. Am J Kidney Dis 1995; 26: 622–631 18. Lim K, Lu TS, Molostvov G et al. Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation 2012; 125: 2243–2255 19. Scialla JJ, Lau WL, Reilly MP et al. Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int 2013; 83: 1159–1168 20. Alam MU, Kirton JP, Wilkinson FL et al. Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells. Cardiovasc Res 2009; 81: 260–268 21. Henley C, Davis J, Miller G et al. The calcimimetic AMG 641 abrogates parathyroid hyperplasia, bone and vascular calcification abnormalities in uremic rats. Eur J Pharmacol 2009; 616: 306–313 22. Uitto J, Li Q, Jiang Q. Pseudoxanthoma elasticum: molecular genetics and putative pathomechanisms. J Invest Dermatol 2010; 130: 661–670 23. Pereira L, Lee SY, Gayraud B et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci USA 1999; 96: 3819–3823 24. Basalyga DM, Simionescu DT, Xiong W et al. Elastin degradation and calcification in an abdominal aorta injury model: role of matrix metalloproteinases. Circulation 2004; 110: 3480–3487

25. Aikawa E, Aikawa M, Libby P et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 2009; 119: 1785–1794 26. Hosaka N, Mizobuchi M, Ogata H et al. Elastin degradation accelerates phosphate-induced mineralization of vascular smooth muscle cells. Calcif Tissue Int 2009; 85: 523–529 27. Khavandgar Z, Roman H, Li J et al. Elastin haploinsufficiency impedes the progression of arterial calcification in MGP-deficient mice. J Bone Miner Res 2014; 29: 327–337 28. Pai A, Leaf EM, El-Abbadi M et al. Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease. Am J Pathol 2011; 178: 764–773 29. Lomashvili KA, Cobbs S, Hennigar RA et al. Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin. J Am Soc Nephrol 2004; 15: 1392–1401 30. St Hilaire C, Ziegler SG, Markello TC et al. NT5E mutations and arterial calcifications. N Engl J Med 2011; 364: 432–442 31. Kiffer-Moreira T, Yadav MC, Zhu D et al. Pharmacological inhibition of PHOSPHO1 suppresses vascular smooth muscle cell calcification. J Bone Miner Res 2013; 28: 81–91 32. Kageyama A, Matsui H, Ohta M et al. Palmitic acid induces osteoblastic differentiation in vascular smooth muscle cells through ACSL3 and NF-kappaB, novel targets of eicosapentaenoic acid. PLoS One 2013; 8: e68197 33. Taylor J, Butcher M, Zeadin M et al. Oxidized low-density lipoprotein promotes osteoblast differentiation in primary cultures of vascular smooth muscle cells by up-regulating Osterix expression in an Msx2-dependent manner. J Cell Biochem 2011; 112: 581–588 34. Massy ZA, Drueke TB. Vascular calcification. Curr Opin Nephrol Hypertens 2013; 22: 405–412 35. Zhou Y, Wang JY, Feng H et al. Overexpression of c1q/tumor necrosis factor-related protein-3 promotes phosphate-induced vascular smooth muscle cell calcification both in vivo and in vitro. Arterioscler Thromb Vasc Biol 2014; 34: 1002–1010 36. Buendia P, Montes de Oca A, Madueno JA et al. Endothelial microparticles mediate inflammation-induced vascular calcification. FASEB J 2015; 9: 73–181 37. Lee C, Bongcam-Rudloff E, Sollner C et al. Type 3 cystatins; fetuins, kininogen and histidine-rich glycoprotein. Front Biosci (Landmark Ed) 2009; 14: 2911–2922 38. Ketteler M, Bongartz P, Westenfeld R et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 2003; 361: 827–833 39. Schäfer C, Heiss A, Schwarz A et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest 2003; 112: 357–366 40. Westenfeld R, Schafer C, Kruger T et al. Fetuin-A protects against atherosclerotic calcification in CKD. J Am Soc Nephrol 2009; 20: 1264–1274 41. Herrmann M, Schafer C, Heiss A et al. Clearance of fetuin-A--containing calciprotein particles is mediated by scavenger receptor-A. Circ Res 2012; 111: 575–584 42. Reynolds JL, Skepper JN, McNair R et al. Multifunctional roles for serum protein fetuin-A in inhibition of human vascular smooth muscle cell calcification. J Am Soc Nephrol 2005; 16: 2920–2930 43. Dautova Y, Kozlova D, Skepper JN et al. Fetuin-A and albumin alter cytotoxic effects of calcium phosphate nanoparticles on human vascular smooth muscle cells. PLoS ONE 2014; 9: e97565 44. Demetriou M, Binkert C, Sukhu B et al. Fetuin/alpha2-HS glycoprotein is a transforming growth factor-beta type II receptor mimic and cytokine antagonist. J Biol Chem 1996; 271: 12755–12761 45. Luo G, Ducy P, McKee MD et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 386: 78–81 46. Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998; 18: 1400–1407 47. Murshed M, Schinke T, McKee MD et al. Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J Cell Biol 2004; 165: 625–630

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FULL REVIEW

72. Shroff R, Long DA, Shanahan C. Mechanistic insights into vascular calcification in CKD. J Am Soc Nephrol 2013; 24: 179–189 73. New SE, Aikawa E. Role of extracellular vesicles in de novo mineralization: an additional novel mechanism of cardiovascular calcification. Arterioscler Thromb Vasc Biol 2013; 33: 1753–1758 74. Gyorgy B, Szabo TG, Pasztoi M et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 2011; 68: 2667–2688 75. Reynolds JL, Joannides AJ, Skepper JN et al. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 2004; 15: 2857–2867 76. Proudfoot D, Skepper JN, Hegyi L et al. Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res 2000; 87: 1055–1062 77. Clarke MC, Littlewood TD, Figg N et al. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ Res 2008; 102: 1529–1538 78. Spiegel DM, Brady K. Calcium balance in normal individuals and in patients with chronic kidney disease on low- and high-calcium diets. Kidney Int 2012; 81: 1116–1122 79. Bosticardo G, Malberti F, Basile C et al. Optimizing the dialysate calcium concentration in bicarbonate haemodialysis. Nephrol Dial Transplant 2012; 27: 2489–2496 80. Gotch FA, Kotanko P, Thijssen S et al. The KDIGO guideline for dialysate calcium will result in an increased incidence of calcium accumulation in hemodialysis patients. Kidney Int 2010; 78: 343–350 81. Basile C, Libutti P, Di Turo AL et al. Effect of dialysate calcium concentrations on parathyroid hormone and calcium balance during a single dialysis session using bicarbonate hemodialysis: a crossover clinical trial. Am J Kidney Dis 2012; 59: 92–101 82. Gotch FA. Pro/Con debate: the calculation on calcium balance in dialysis lowers the dialysate calcium concentrations ( pro part). Nephrol Dial Transplant 2009; 24: 2994–2996 83. Drueke TB, Touam M. Calcium balance in haemodialysis--do not lower the dialysate calcium concentration too much (con part). Nephrol Dial Transplant 2009; 24: 2990–2993 84. Messa P. The ups and downs of dialysate calcium concentration in haemodialysis patients. Nephrol Dial Transplant 2013; 28: 3–7 85. Moe SM, Drueke TB. The KDIGO guideline on dialysate calcium and patient outcomes: need for hard evidence. Kidney Int 2011; 79: 478, author reply 478–479. 86. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002; 62: 245–252 87. Block GA, Spiegel DM, Ehrlich J et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 2005; 68: 1815–1824 88. Galassi A, Spiegel DM, Bellasi A et al. Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders. Nephrol Dial Transplant 2006; 21: 3215–3222 89. Qunibi W, Moustafa M, Muenz LR et al. A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study. Am J Kidney Dis 2008; 51: 952–965 90. Kakuta T, Tanaka R, Hyodo T et al. Effect of sevelamer and calcium-based phosphate binders on coronary artery calcification and accumulation of circulating advanced glycation end products in hemodialysis patients. Am J Kidney Dis 2011; 57: 422–431 91. Toussaint ND, Lau KK, Polkinghorne KR et al. Attenuation of aortic calcification with lanthanum carbonate versus calcium-based phosphate binders in haemodialysis: A pilot randomized controlled trial. Nephrology (Carlton) 2011; 16: 290–298 92. Ohtake T, Kobayashi S, Oka M et al. Lanthanum carbonate delays progression of coronary artery calcification compared with calcium-based phosphate binders in patients on hemodialysis: a pilot study. J Cardiovasc Pharmacol Ther 2013; 18: 439–446

G. Schlieper et al.


48. Schurgers LJ, Uitto J, Reutelingsperger CP. Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends Mol Med 2013; 19: 217–226 49. Kapustin AN, Davies JD, Reynolds JL et al. Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ Res 2011; 109: e1–12 50. Hofbauer LC, Schoppet M. Osteoprotegerin: a link between osteoporosis and arterial calcification? Lancet 2001; 358: 257–259 51. Bucay N, Sarosi I, Dunstan CR et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260–1268 52. Kazama JJ, Shigematsu T, Yano K et al. Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure. Am J Kidney Dis 2002; 39: 525–532 53. Okawa A, Nakamura I, Goto S et al. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet 1998; 19: 271–273 54. Lomashvili KA, Narisawa S, Millan JL et al. Vascular calcification is dependent on plasma levels of pyrophosphate. Kidney Int 2014; 85: 1351–1356 55. Scatena M, Liaw L, Giachelli CM. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol 2007; 27: 2302–2309 56. Speer MY, McKee MD, Guldberg RE et al. Inactivation of the osteopontin gene enhances vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an inducible inhibitor of vascular calcification in vivo. J Exp Med 2002; 196: 1047–1055 57. Giachelli CM, Speer MY, Li X et al. Regulation of vascular calcification: roles of phosphate and osteopontin. Circ Res 2005; 96: 717–722 58. Montezano AC, Zimmerman D, Yusuf H et al. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension 2010; 56: 453–462 59. Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 2004; 84: 767–801 60. Speer MY, Yang HY, Brabb T et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res 2009; 104: 733–741 61. Bostrom KI, Rajamannan NM, Towler DA. The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ Res 2011; 109: 564–577 62. Byon CH, Javed A, Dai Q et al. Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. J Biol Chem 2008; 283: 15319–15327 63. Steitz SA, Speer MY, Curinga G et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res 2001; 89: 1147–1154 64. Gauthier-Bastien A, Ung RV, Lariviere R et al. Vascular remodeling and media calcification increases arterial stiffness in chronic kidney disease. Clin Exp Hypertens 2014; 36: 173–180 65. Sun Y, Byon CH, Yuan K et al. Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res 2012; 111: 543–552 66. Iyemere VP, Proudfoot D, Weissberg PL et al. Vascular smooth muscle cell phenotypic plasticity and the regulation of vascular calcification. J Intern Med 2006; 260: 192–210 67. Tyson KL, Reynolds JL, McNair R et al. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol 2003; 23: 489–494 68. Monk BA, George SJ. The effect of ageing on vascular smooth muscle cell behaviour – A mini-review. Gerontology 2015; 61: 416–426 69. Shanahan CM. Mechanisms of vascular calcification in CKD-evidence for premature ageing? Nat Rev Nephrol 2013; 9: 661–670 70. Liu Y, Drozdov I, Shroff R et al. Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescenceassociated secretory phenotype in vascular smooth muscle cells. Circ Res 2013; 112: e99–109 71. Ragnauth CD, Warren DT, Liu Y et al. Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging. Circulation 2010; 121: 2200–2210

101. Krueger T, Schlieper G, Schurgers L et al. Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol. Nephrol Dial Transplant 2014; 29: 1633–1638 102. Kruger T, Floege J. Vitamin K antagonists: beyond bleeding. Semin Dial 2014; 27: 37–41 103. Spiegel DM, Farmer B. Long-term effects of magnesium carbonate on coronary artery calcification and bone mineral density in hemodialysis patients: a pilot study. Hemodial Int 2009; 13: 453–459 104. Mathews SJ, de Las Fuentes L, Podaralla P et al. Effects of sodium thiosulfate on vascular calcification in end-stage renal disease: a pilot study of feasibility, safety and efficacy. Am J Nephrol 2011; 33: 131–138 105. Toussaint ND, Lau KK, Strauss BJ et al. Effect of alendronate on vascular calcification in CKD stages 3 and 4: a pilot randomized controlled trial. Am J Kidney Dis 2010; 56: 57–68 106. Moe SM, O’Neill KD, Reslerova M et al. Natural history of vascular calcification in dialysis and transplant patients. Nephrol Dial Transplant 2004; 19: 2387–2393 107. Marechal C, Coche E, Goffin E et al. Progression of coronary artery calcification and thoracic aorta calcification in kidney transplant recipients. Am J Kidney Dis 2012; 59: 258–269 108. Schlieper G, Brandenburg V, Ketteler M et al. Sodium thiosulfate in the treatment of calcific uremic arteriolopathy. Nat Rev Nephrol 2009; 5: 539–543 Received for publication: 16.1.2015; Accepted in revised form: 17.3.2015

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Nephrol Dial Transplant (2016) 31: 39–45 doi: 10.1093/ndt/gfu243 Advance Access publication 16 July 2014

Salt and nephrolithiasis Andrea Ticinesi1,2, Antonio Nouvenne2, Naim M. Maalouf3, Loris Borghi1,2 and Tiziana Meschi1,2 1

Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy, 2Internal Medicine and Critical Subacute Care Unit,

Parma University Hospital, Parma, Italy and 3Charles and Jane Pak Center for Mineral Metabolism and Clinical Research and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Correspondence and offprint requests to: Andrea Ticinesi; E-mail: [email protected]

A B S T R AC T Dietary sodium chloride intake is nowadays globally known as one of the major threats for cardiovascular health. However, there is also important evidence that it may influence idiopathic calcium nephrolithiasis onset and recurrence. Higher salt intake has been associated with hypercalciuria and hypocitraturia, which are major risk factors for calcium stone formation. Dietary salt restriction can be an effective means for secondary prevention of nephrolithiasis as well. Thus in this paper, we review the complex relationship between salt and nephrolithiasis, pointing out the difference between dietary sodium and salt intake and the best methods to assess them, highlighting the main findings of © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.


93. Russo D, Bellasi A, Pota A et al. Effects of phosphorus-restricted diet and phosphate-binding therapy on outcomes in patients with chronic kidney disease. J Nephrol 2015; 28: 73–80 94. Block GA, Wheeler DC, Persky MS et al. Effects of Phosphate Binders in Moderate CKD. J Am Soc Nephrol 2012; 23: 1407–1415 95. Jamal SA, Vandermeer B, Raggi P et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 2013; 382: 1268–1277 96. Delanaye P, Weekers L, Warling X et al. Cholecalciferol in haemodialysis patients: a randomized, double-blind, proof-of-concept and safety study. Nephrol Dial Transplant 2013; 28: 1779–1786 97. Raggi P, Chertow GM, Torres PU et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant 2011; 26: 1327–1339 98. Urena-Torres PA, Floege J, Hawley CM et al. Protocol adherence and the progression of cardiovascular calcification in the ADVANCE study. Nephrol Dial Transplant 2013; 28: 146–152 99. Aladren Regidor MJ. Cinacalcet reduces vascular and soft tissue calcification in secondary hyperparathyroidism (SHPT) in hemodialysis patients. Clin Nephrol 2009; 71: 207–213 100. Westenfeld R, Krueger T, Schlieper G et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis 2012; 59: 186–195

epidemiologic, laboratory and intervention studies and focusing on open issues such as the role of dietary salt in secondary causes of nephrolithiasis. Keywords: hypercalciuria, nephrolithiasis, salt, urinary calcium, urinary sodium

INTRODUCTION Excessive salt intake has been focused on in the last few years as one of the main elements that influence health status. In particular, salt is linked to hypertension and cardiovascular disease, and therefore many professional organizations have 39

Skin autofluorescence associates with vascular calcification in chronic kidney disease.

"Angiography without contrast": Severe vascular calcification in chronic kidney disease.

Role of kidney biomarkers of chronic kidney disease: An update.

Dipeptidyl peptidase-4 inhibitor gemigliptin protects against vascular calcification in an experimental chronic kidney disease and vascular smooth muscle cells.

An update on coronary artery disease and chronic kidney disease.

[Chronic kidney disease--update 2014].

Arterial stiffness in chronic kidney disease: an update.

Role of different imaging modalities of vascular calcification in predicting outcomes in chronic kidney disease.

Update on inflammation in chronic kidney disease.

Vascular calcification in chronic kidney disease: role of disordered mineral metabolism.

Arterial stiffness, vascular calcification and bone metabolism in chronic kidney disease.

Lowering vascular calcification burden in chronic kidney disease: Is it possible?

Intermedin1-53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of α-Klotho.

The role of klotho on vascular calcification and endothelial function in chronic kidney disease.

Effects of unfractionated heparin on renal osteodystrophy and vascular calcification in chronic kidney disease rats.

Magnesium and outcomes in patients with chronic kidney disease: focus on vascular calcification, atherosclerosis and survival.

Klotho connects intermedin1-53 to suppression of vascular calcification in chronic kidney disease.

Vascular calcification: When should we interfere in chronic kidney disease patients and how?

Inflammatory cytokines and reactive oxygen species as mediators of chronic kidney disease-related vascular calcification.

Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease.

Kidney Disease: Improving Global Outcomes--an update.

The Addition of Vascular Calcification Scores to Traditional Risk Factors Improves Cardiovascular Risk Assessment in Patients with Chronic Kidney Disease.

Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease.

Vascular calcification in end-stage renal disease.