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http://www.kidney-international.org & 2012 International Society of Nephrology
Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease Pablo A. Uren˜a Torres1 and Marc De Broe2 1
Nephrology Dialysis, Clinique du Landy, Saint Ouen, France and 2Department of Medicine, University of Antwerp, Antwerp, Belgium
Renal function impairment goes along with a disturbed calcium, phosphate, and vitamin D metabolism, resulting in secondary hyperparathyroidism (sHPT). These mineral metabolism disturbances are associated with soft tissue calcifications, particularly arteries, cardiac valves, and myocardium, ultimately associated with increased risk of mortality in patients with chronic kidney disease (CKD). sHPT may lead to cardiovascular calcifications by other mechanisms including an impaired effect of parathyroid hormone (PTH), and a decreased calcium-sensing receptor (CaR) expression on cardiovascular structures. PTH may play a direct role on vascular calcifications through activation of a receptor, the type-1 PTH/PTHrP receptor, normally attributed to PTH-related peptide (PTHrP). The CaR in vascular cells may also play a role on vascular mineralization as suggested by its extremely reduced expression in atherosclerotic calcified human arteries. Calcimimetic compounds increasing the CaR sensitivity to extracellular calcium efficiently reduce serum PTH, calcium, and phosphate in dialysis patients with sHPT. They upregulate the CaR in vascular cells and attenuate vascular mineralization in uremic states. In this article, the pathophysiological mechanisms associated with cardiovascular calcifications in case of sHPT, the impact of medical and surgical correction of sHPT, the biology of the CaR in vascular structures and its function in CKD state, and finally the role played by the CaR and its modulation by the calcimimetics on uremic-related cardiovascular calcifications are reviewed. Kidney International advance online publication, 21 March 2012; doi:10.1038/ki.2012.69 KEYWORDS: calcimimetics; calcium receptor; hyperparathyroidism; parathyroid hormone; renal osteodystrophy; vascular calcification
Correspondence: Pablo A. Uren˜a Torres, Service de Ne´phrologie et Dialyse. Clinique du Landy. 23, rue du Landy, 93400 Saint Ouen, France. E-mail:
[email protected] Received 9 October 2011; revised 10 December 2011; accepted 13 December 2011 Kidney International
More than a century after its identification, secondary hyperparathyroidism (sHPT) is still observed in the majority of patients with chronic kidney disease (CKD) stages 4–5, and in more than one-third of patients treated by dialysis. Renal function impairment goes along with a disturbed calcium, phosphate, and vitamin D metabolism, resulting in sHPT. These mineral metabolism disturbances are associated with soft tissue calcifications, particularly arteries, cardiac valves, and the myocardium, which are ultimately associated with increased risk of morbidity and mortality.1 Compared with age-matched subjects, CKD patients particularly present more atherosclerotic plaques and a more rapid calcification of these plaques and of the vascular media layer.2 Besides mineral alterations, sHPT may also lead to cardiovascular calcifications by other less known mechanisms, including an impaired action of parathyroid hormone (PTH) and a decreased expression of the calcium-sensing receptor (CaR) on cardiovascular structures. The conventional therapy of sHPT, generally used until the past 5–10 years, consisting of calcium salts and supra-physiological doses of vitamin D analogs, increases serum calcium and phosphate concentrations and the risk of cardiovascular mineralization. Similarly, radical treatment of sHPT, by subtotal or total surgical parathyroidectomy (PTX), results in a permanent and irreversible state of hypoparathyroidism, low bone remodeling, and exposition to a high risk of hyperphosphatemia, hypercalcemia, and cardiovascular calcifications.3 Thus, innovative therapies of sHPT such as calcium-free intestinal phosphate binders, lesser hypercalcemic vitamin D derivatives, and calcimimetics might control parathyroid gland hyperfunction, without significantly disturbing calcium phosphate metabolism, while preventing cardiovascular calcifications. In this article, we review the pathophysiological mechanisms associated with cardiovascular calcifications in case of sHPT, the impact of medical and surgical correction of sHPT on the progression of cardiovascular calcifications, the biology of the CaR in vascular structures, and its function in CKD state, and finally the role played by the CaR and its modulation by the calcimimetics on uremic-related cardiovascular calcifications. 1
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PAU Torres and M De Broe: Calcimimetics and cardiovascular calcifications
EPIDEMIOLOGY AND CONSEQUENCES OF CARDIOVASCULAR CALCIFICATIONS
Vascular and cardiac valve calcifications are more prevalent and severe in CKD patients compared with healthy subjects of the general population.4,5 Indeed, autopsy and clinical studies have found an increased intima layer thickness and areas of mineralization in coronary, renal, aorta, radial, and epigastric arteries in 490% of CKD patients compared with only 30% in age-matched control subjects. Similarly, media layer thickness and calcifications are also more frequently found in CKD patients than in control subjects, roughly 60% vs. 20%, respectively.2,6–9 Vascular calcifications also consistently share the same five classical risk factors associated with the presence and extent of these calcifications in the general population, including advanced age, diabetes, hyperlipidemia, inflammation, and tobacco use. In addition, dialysis treatment itself exponentially accelerates the process of vascular mineralization.2,8,10–12 Once cardiovascular calcifications are installed, their consequences can be overwhelming as suggested by their association with an increased risk of fatal outcomes in CKD patients, more than 50% of whom die from cardiovascular complications including myocardial infarction, heart failure, and sudden death.13 The consequences differ depending on the type of calcification, arterial intima or media, and in the heart, valvular or myocardial. Arterial intima calcification is mostly secondary to calcification of atherosclerotic plaques, which may increase the risk of arterial thrombosis, plaque instability, and myocardial infarction. Arterial media calcification leads to vessel stiffness, loss of vascular compliance, increased wave pulse velocity, left ventricular hypertrophy, diastolic dysfunction, coronary hypoperfusion, and finally heart failure.14 It is also responsible for the rather exceptionally observed calcifying uremic arteriopathy, which often leads to necrotizing lesions of distal extremities and an extremely high mortality rate. In the heart, myocardial calcification is a rare cause of severe heart failure. Calcification of cardiac valves is an important cause of both native and prosthetic and mitral and aortic valve dysfunction. CKD patients with cardiac valvular calcifications may also die, as do non-uremic patients, from myocardial infarction, heat failure, and sudden death.15 CALCIUM-SENSING RECEPTOR
The CaR is a 121-kDa protein with three main structural domains characteristic of G-protein-coupled receptors. It has a long extracellular N-terminal domain essential for the interaction with its principal agonist ionized calcium, seven hydrophobic membrane-spanning helices, which anchor it in the plasma membrane, and an intracellular C terminus, which has multiple regulatory protein kinase phosphorylation sites.16 The CaR is a low-affinity receptor, as millimolar concentrations of the agonists (3 mmol/l for calcium) are needed for its activation. It is also of limited selectivity as it can be activated by numerous divalent or trivalent cations in addition to calcium, and in order of potency, such as 2
La34Gd34Be24Ca24Ba24Sr24Mg2, and by other polycationic compounds such as neomycin, spermine, and numerous amino acids. It should be reminded that in clinical practice many of these cations would never reach the necessary plasma concentration to exert a calcimimetic effect except Gd3 and Mg2. The activation of the CaR by any one of the agonists leads to the stimulation of Gi protein, phospholipase C, inositide triphosphate cascade, the mobilization of intracellular calcium, and the activation of PKC. Its activation also inhibits the adenylcyclase signaling pathway and PKA. The CaR is expressed in organs principally regulating systemic calcium homeostasis, including kidney, intestine, bone, thyroid, and the parathyroid glands. However, it is also expressed in a variety of organs usually not thought to be involved in calcium metabolism, such as brain, skin, breast, testes, placenta, heart, and vessels. The consequence of the activation of the CaR and the cascade of intracellular signal pathways in parathyroid cells is the inhibition of PTH secretion, whereas in the thyroid C cells it increases calcitonin secretion, both effects leading to a reduction in serum calcium concentration. Its activation in the other three organs may also contribute to a further decrease in serum calcium; hence, in the kidney it increases urinary calcium excretion, in bone it decreases bone turnover, and in the intestine it decreases intestinal absorption of calcium. The same CaR is also present in the cardiovascular structures including aortic endothelial and smooth muscle cells where it may exert multiple and not yet fully elucidated physiological functions.17,18 COMPOUNDS MODULATING THE CALCIUM-SENSING RECEPTOR
The molecular characterization of the CaR also led to the discovery of several compounds capable of modulating its function.19 The first ones have been called ‘type I calcimimetics’ because they mimic the effects of extracellular calcium (eCa2 þ ). The second ones are called ‘type II calcimimetics’ because they change the structural conformation of the CaR and stereoselectively increase its sensitivity to 2þ . Thus, when tested in in vitro studies, type II eCa calcimimetics appear to lose their effects in the absence of 2þ ; they do not really mimic the effect of eCa2 þ . The eCa third ones have been called ‘calcilytics’ because they inhibit CaR function and stimulate PTH secretion. The mode of action of calcimimetics and calcilytics resides on their binding to distinct but overlapping regions of the extracellular loops of the transmembrane domain. Besides changing the structural conformation, calcimimetics can also enhance CaR function by increasing its expression; inversely, the calcilytics decrease parathyroid CaR expression. Several calcimimetics have already been made. The first-generation compounds, including NPS R-567, NPS S-567, NPS R-568, and NPS S-568, were retired from clinical development because of a low bioavailability (o1%). The second generation includes AMG-073 and Calindol. These compounds decrease the secretion of PTH in a dose-dependent Kidney International
PAU Torres and M De Broe: Calcimimetics and cardiovascular calcifications
manner, in cultured parathyroid cells and in healthy animals. They also diminish serum calcium concentration because of the decrease of PTH secretion, decreased bone turnover, stimulation of calcitonin secretion, and stimulation of the CaR in the kidney increasing calciuria. The third generation of calcimimetics, and peptides with CaR agonist properties, is already being developed, with two new compounds, the AC-265347, which shows higher potency than all previous calcimimetics,20 and the calcimimetic B, which has a more specific action on the parathyroid CaR and no stimulation of calcitonin secretion from thyroid C cells.21 CALCIMIMETICS AND CARDIOVASCULAR CALCIFICATIONS Direct effect of calcimimetics, in vitro and in vivo studies
A significant number of in vivo studies have suggested a direct action of the CaR in vascular mineralization. First, it should be reminded that the presence of a functional CaR in vascular structures was a controversial issue until the demonstration of its mRNA by real-time PCR, and its protein by immunostaining, in aortic VSMC and in aortic endothelial cells.17,18 These findings were confirmed and extended by the same methods in normal renal artery from a human kidney donor and in the epigastric artery from a recipient CKD patient.22–24 In addition to VSMC, the CaR was also detected in endothelial and perivascular cells.22–24 The receptor in VSMC is functional as shown by the increase in intracellular calcium and activation of the extracellular signal–regulated kinases (ERK1/2) signaling pathway after treatment with calcium or neomycin. Physiologically, the systemic activation of the CaR by pharmacological doses of type II calcimimetics increases vascular resistance in carotid, mesenteric, and hind limb arteries, leading to a significant elevation of arterial blood pressure in uremic and non-uremic animals.25 This effect is probably mediated by a reduction in the activity of NO synthase and hence local production of NO, also favored by the decrease in ionized calcium, as suggested by the findings that treatment with dose-dependently L-NAME blocked the calcimimetic effect.25 These findings have been contested by other observations showing that the calcimimetic cinacalcet HCl induced a dose-dependent vasodilation of pre-contracted aorta,17 and reduced arterial blood pressure in uremic rats and in spontaneously hypertensive rats.26,27 It should nevertheless be stressed that no clinical evidence for a significant effect of calcimimetics on blood pressure has been reported so far. The expression of the CaR is extremely reduced in atherosclerotic calcified human arteries, which has suggested that it could play a preventive role in vascular mineralization when expressed normally.22 This observation has been supported by the results of in vitro studies showing a marked reduction of the CaR expression in bovine VSMC when they are incubated in a mineralization medium containing a calcium concentration between 1.8 and 2.5 mmol/l, or with gadolinium.22 Similarly, overexpression of a dominantnegative CaR in the same cells augments mineral deposition. Kidney International
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Conversely, the incubation of these cells with the calcimimetic R-568 prevented calcium deposition, probably by stimulating the expression and sensitivity of the CaR. This effect may be comparable to the one observed in parathyroid cells where calcimimetics upregulate the CaR expression.28 Additional in vitro studies have also demonstrated that calcimimetics decrease calcification of human smooth muscle cells when cultured in high-phosphate medium; this inhibitory effect is abolished by the transfection in these cells of a silencing CaR RNA (SiRNA-CaR),29 suggesting that the direct activation of the CaR in vascular cells may slow down the calcification process. Calcimimetics may also prevent vascular calcifications by modulating the expression of several genes involved in bone mineralization. Indeed, in contrast to calcitriol, which downregulates the expression of the transcription factor MGP (matrix gla protein), an inhibitor of mineralization and upregulates the expression of the calcification-promoting sodium-phosphate cotransporter PiT-1, calcimimetics upregulate MGP and downregulate PiT1. Moreover, calcimimetics are able to decrease the vascular expression of bone morphogenic protein-2 and the osteoblastic transdifferentiation of VSMC.28 It should also be pointed out that calcimimetics upregulated the expression of CaR in vascular cells in uremic rats but not in control rats.28 The activation of the CaR by calcimimetics could also favor the regression of vascular calcifications through the stimulation of macrophages or phagocytic cells adjacent to calcified aortic lesions as found in an in vivo model of 5/6th nephrectomized rats.30 Several animal models have also tried to demonstrate the direct effect of calcimimetics on cardiovascular calcifications. In the first one, the administration of cinacalcet HCl at the oral dose of 10 mg/kg/day for 26 consecutive days prevented media aortic calcifications in 5/6th nephrectomized rats. However, when coadministered with calcitriol (0.1 s.c. mg/ day), cinacalcet HCl controlled the calcitriol-induced hypercalcemia and hyperphosphatemia but did not attenuate media vascular calcification.31 In the second one, calcimimetic NPS-R-568 alone reduced PTH and also prevented some calcitriol-induced vascular calcification.32 The third study showed that when uremic animals are fed with a highphosphate diet, accelerating the process of heart and vascular calcification, the heart and aorta contained significantly greater calcium deposition than control animals, and that the increase in aorta calcium content was associated with an increase in the expression of several osteogenic markers including osteocalcin, osteopontin, and Runx-2 genes. Both cinacalcet HCl and PTX prevented the calcifications in this model, suggesting that the calcification process was led by the excessively high PTH levels.33 A fourth study investigated the effect of NPS-R-568 on cardiovascular calcification in the ApoE/ mice, a hyperlipidic model of accelerated atherosclerosis rendered uremic by 5/6th nephrectomy.29 NPS-R568 efficiently reduced serum PTH, calcium, and phosphate levels, and delayed the progression of both atherosclerotic plaques and aortic calcification. The fifth observation, also in 3
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PAU Torres and M De Broe: Calcimimetics and cardiovascular calcifications
5/6th nephrectomized rats, showed that NPS-R-568 reduced vascular remodeling, intima-media thickness, and arterial calcification, whereas non-hypercalcemic doses of calcitriol induced calcium deposition in the aorta of uremic and nonuremic rats.28 Altogether, the results of these in vitro and in vivo studies point toward a direct implication of the CaR in the mechanisms of vascular function and mineralization. Indirect effects of calcimimetics via PTH, calcium, and phosphate PTH. Conflicting results exist with regard to the role
played by continuously elevated PTH concentration on cardiovascular calcifications (Figure 1). Physiologically, the activation of the PTH/PTHrP receptor (PTHR1)34 by either PTH or PTHrP decreases peripheral vascular resistances and arterial blood pressure, which might protect against vascular calcifications.35,36 Paradoxically, continuous high PTH is associated with arterial hypertension rather than with hypotension, which could be linked either to desensitization or downregulation of its own receptor in vascular cells, or to its renal effect on water and electrolyte balance. Indeed, PTH directly stimulates the renin–angiotensin–aldosterone system, as well as sympathetic activity and the secretion of cortisol, which can lead to sodium and water retention and ultimately to hypertension; these alterations may induce endothelial dysfunction and promote vascular calcifications.37,38 Moreover, PTH such as PTHrP may decrease calcification of cardiovascular cells, as PTHrP retards cartilage growth plate mineralization by inhibiting transcription factors such as Runx2/Cbfa1, Osterix, MSX2, and other pro-osteogenic proteins and the dedifferentiation of VSMC into osteoblastlike cells.39 PTHrP also prevents vascular calcification by blocking the induction of alkaline phosphatase activity in bovine VSMC through a PTHR1-dependent effect, which differs from its nuclear effect.40–44 Indeed, PTHrP and PTHR1 are highly expressed in human and rat atherosclerostic lesions, and, experimentally, endogenous whole PTHrP, conserving its NLS residues (nuclear/nucleolar localization sequence), stimulates VSMC proliferation, atheroma formation, and ossification. However, when PTHrP lacks its NLS sequence, Normal PTH
after experimental removal, it cannot get to the nucleus and instead inhibits proliferation and calcification, certainly through the activation of the cell surface receptor PTHR1. Thus, activation of the PTHR1 by PTH may have the same inhibitory effect on vascular calcification as the NLS-deleted PTHrP molecule. However, this protective effect may be compromised in CKD patients because of an altered receptor expression and function. In CKD, the PTHR1 is often deregulated by several mechanisms including PTHR1 downregulation,45 accumulation of inhibitory PTH fragments (PTH 7–84),46 and the excessive use of active vitamin D derivatives, which leads to a reduced PTHR1 expression.47 The downregulation of the PTHR1 might also explain why the administration of high doses of PTH in parathyroidectomized uremic animal cannot prevent the induction of aorta calcification even in the presence of normal circulating levels of calcium and phosphate.48 It is noteworthy that situations that are comparable to PTHR1 downregulation, such as in case of low serum PTH levels and low bone turnover, as in patients with iatrogenic or congenital hypoparathyroidism states, appear to increase the risk of cardiovascular calcifications. This has also been observed in hemodialysis patients in whom low serum PTH levels, resulting from extensive PTX, are associated with high arterial calcification scores (CAC).49,50 Nevertheless, in this situation of iatrogenic hypoparathyroidism, it cannot be ruled out that the preceding long-term exposure to excessive high PTH may have favored cardiovascular calcifications. The correction of an adynamic bone disease and calciphylaxis lesions by the administration of human recombinant PTH in a dialysis patient also suggests a protective effect of PTH on cardiovascular calcification.51 Therefore, it is tempting to speculate here that, in some situations, the high circulating levels of PTH may try to overcome the PTHR1 downregulation and protect against vascular calcifications. Calcium. Elevated calcium and phosphate concentrations undoubtedly contribute to the pathophysiology of cardiovascular calcifications in CKD patients (Figure 2).52,53 Serum Calcimimetics
High PTH
Parathyroid CaR Vascular PTH/PTHrP receptor (PTHR1) normally expressed
Vascular PTH/PTHrP receptor (PTHR1) down-regulated
Normal arterial pressure Runx2/Cbfa1 Osterix Msx2 Alkaline phosphatase
Arterial pressure Runx2/Cbfa1 Osterix Msx2 Alkaline phosphatase
Prevents cardiovascular calcifications
Promotes cardiovascular calcifications
Figure 1 | The role played by parathyroid hormone (PTH) on cardiovascular calcifications in chronic kidney disease. PTHrP, PTH-related peptide. 4
Vascular CaR
CaR PTH Calcium Phosphate
CaR MGP Run2/Cbfa1 BMP2
Prevent cardiovascular calcifications
Figure 2 | The role played by the vascular calcium-sensing receptor (CaR) and calcimimetics on cardiovascular calcifications in chronic kidney disease. MGP, matrix gla protein; PTH, parathyroid hormone. Kidney International
PAU Torres and M De Broe: Calcimimetics and cardiovascular calcifications
calcium concentration decreases by 6–10% during the treatment with calcimimetics, with the largest reduction occurring during the first 6 weeks after treatment initiation, and with the greatest reduction in patients with the highest serum calcium and PTH levels.19 The mechanism responsible for the calcium reduction under the calcimimetic therapy is not fully understood, but it is highly probable that the decrease in bone remodeling after lowering PTH by the calcimimetic may reduce the exchange of calcium between extracellular fluids and a miscible pool of calcium in bone. It is recognized that high calcium concentration leads to the phenotypic transformation of VSMC into osteoblast-like cells and mineralization.7 Moreover, high-calcium medium stimulates the expression of PiT1 in VSMC and increases the sensibility to these cells to mineralize in the presence of high phosphate levels.7,54 A high calcium concentration also promotes VSMC calcification by stimulating the expression of alkaline phosphatase and by decreasing the expression of MGP.7,54 Thus, it is plausible that by reducing serum calcium levels calcimimetics may protect against vascular mineralization. Phosphate. Calcimimetics significantly reduced serum phosphate levels certainly because of the decrease in bone remodeling and by allowing the use of lower doses of active vitamin D analogs, which potentially reduces intestinal phosphate absorption. A high phosphate concentration directly stimulates VSMC transformation in osteoblast-like cells through the activation of PiT1 and the stimulation of several transcription factors including Runx2/Cbfa1, osteopontin, Msx2, and Osterix. The phosphate-induced VSMC mineralization can be prevented by the inhibition of PiT1 and the phosphate uptake, either by foscarnet or PiT siRNA.1,7 Phosphate can also induce vascular calcification by promoting VSMC apoptosis and by facilitating the mineral nucleation of apoptotic bodies.55 It is noteworthy that the reduction of serum phosphate levels by the use of calcium-free intestinal phosphate binders significantly attenuates the progression of coronary artery CAC in dialysis patients as reported by several recent randomized clinical trials including Treat-To-Goal, RIND and DCOR.56,57 Therefore, by reducing serum phosphate levels, calcimimetics may attenuate the progression of cardiovascular calcification. Cinical data, the ADVANCE Study. The beneficial effect of reducing serum PTH levels either by surgical PTX or by medication in CKD patients with sHPT on vascular calcifications has not been definitely established. PTX may be associated with both reduction and progression of cardiovascular calcifications in these patients.58–61 Native and active vitamin D analogs efficiently reduce serum PTH levels; however, there is no scientific evidence demonstrating any effect on the progression of cardiovascular calcifications. There are several publications illustrating the healing of calciphylaxis, painful cutaneous purpuric lesions that lead to tissue calcification and ischemic necrosis, in CKD patients with sHPT and treated with calcimimetics.62–64 The ADVANCE Study is the first and unique randomized clinical trial that has assessed the effect of a calcimimetic Kidney International
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combined with low doses of active vitamin D (o6 mg, equivalent of paricalcitol/week), compared with flexible doses of active vitamin D, on the progression of cardiovascular calcifications in 320 adult hemodialysis patients with sHPT.65 All patients with hyperphosphatemia exclusively received calcium-based phosphate-binding agents in order to reduce potential confounding effects. Patients were stratified according to their Agatston coronary artery calcification (CAC) score: 30–399 (low to intermediate cardiovascular risk), 400–999 (moderate to high cardiovascular risk), and X1000 (extremely high cardiovascular risk). The primary end point was the percentage change in Agatston CAC score from baseline to week 52.65 What were the results obtained in this trial? Biochemical parameters of bone and mineral metabolism, including serum PTH, calcium, and phosphate, were better controlled in the cinacalcet group than in the control group.66 At the end of the study, 235 patients were available for efficacy analysis, 115 patients in the cinacalcet group and 120 patients in the control group. The median percentage increase in Agatston CAC score from baseline to week 52 was 24% in the cinacalcet group compared with 31% in the control group (31–24 ¼ 7%, P ¼ 0.073). Although this difference was not statistically significant at the coronary arteries, the difference between the two groups was statistically significant at the aortic valve CAC (Po0.014), but not at the mitral valve. The beneficial effect of the calcimimetic on the progression of aortic valve calcification might be of clinical relevance knowing the deadly association between aortic valve stenosis and poor survival rate in dialysis patients.15,67,68 Interestingly, when comparing the two groups with the volumetric score of calcification, the increase in volume CAC score was 22% in the cinacalcet group and 30% in the control group (30–22 ¼ 8%, P ¼ 0.009). The percentage of patients showing an increase of 415% in the Agatston CAC score was 37% in the cinacalcet group versus 58% in the control group for patients with a baseline score 41000.66 Moreover, a post-hoc subgroup analysis showed that when the dose of vitamin D was p6 mg/week (paricalcitol equivalent) in the group receiving cinacalcet, the progression of cardiovascular calcification was slower than that in the group receiving flexible doses of vitamin D sterols; the increase in Agatston CAC score was 17% in the cinacalcet group and 31% in the control group (31–17 ¼ 14%, P ¼ 0.017; ANZSN Abstract, article submitted). What is the importance of this trial to clinical practice? The ADVANCE Study provides some useful information for our daily clinical practice. The first one would be the demonstration of the discrepancy between actual global recommendations and what we have seen in this trial. KDIGO does not give precise recommendation regarding the evaluation or assessment of cardiovascular calcifications in dialysis patients, methods, frequency, etc. Nevertheless, the results of this study show that more than 50% of permanent adult dialysis patients with serum PTH value 4300 pg/ml actually have asymptomatic coronary calcification with a 5
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CAC score 430. Owing to the association between coronary calcifications and deleterious cardiac outcomes, we should pay more attention to this issue and explore these patients earlier. The second point is the clear demonstration of a significant association between high serum PTH level and CAC score. For each increase of 100 pg/ml in serum PTH, there is a significant increase in the risk of CAC score after adjusting for all the confounding variables. This suggests that it would be worth keeping serum PTH values probably below 300 pg/ml in order to decrease the risk of cardiovascular calcification and not over 500 pg/ml as recently recommended by KDIGO. The third point is that we can medically and efficiently control sHPT without surgery in the majority of the patients and attenuate the progression of coronary, aortic, and valvular calcifications in dialysis patients. The ADVANCE Study had numerous limitations including its short follow-up of only 52 weeks, a length of time insufficient to detect substantial changes in vascular remodeling. In addition, the differences between groups were probably less important because of the presence of active vitamin D therapy in both groups, which resulted in a moderate reduction of serum PTH levels in the control group. The restriction placed on subjects’ use of calciumbased phosphate binders helped to reduce the effects of cointerventions; however, this restriction also limited the ability to generalize the study’s results, as non-calcium-based phosphate binders were commonly prescribed either alone or in combination with calcium salts. Consequently, the independent effect of cinacalcet on the progression of vascular and cardiac valve calcification in patients treated with sevelamer, lanthanum carbonate, and/or other noncalcium-based phosphate binders remains to be determined. Because the doses of vitamin D sterols differed substantially between treatment groups, the slower progression of CAC among subjects treated with cinacalcet plus low-dose vitamin D sterols cannot be attributed solely to the use of cinacalcet. CONCLUSION AND PERSPECTIVE
Cardiovascular calcifications in CKD patients display similar risk factors as for the general population, with the exception that they are more frequent, diffuse, severe, and rapidly progressive particularly in dialysis patients. In addition, they also added another major risk factor in CKD patients, sHPT and its disturbed calcium phosphate metabolism. The control of sHPT by calcimimetics and the simultaneous reduction of serum calcium and phosphate, as well as the calcimimeticinduced CaR upregulation in vascular cells, may attenuate the progression of vascular calcification in CKD patients. The results of the ADVANCE clinical trial generate the basis for future interventional trials in this highly exposed CKD population where the prevention and attenuation of cardiovascular calcifications might certainly need more than a single treatment focused on PTH and mineral metabolism. The results from the ongoing EVOLVE Study (Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events)69 will help determine whether the treatment by 6
calcimimetic can reduce the exceptionally high rates of mortality and cardiovascular events among patients with sHPT on hemodialysis. DISCLOSURE
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