Expert Opinion on Drug Safety
ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20
Cardiovascular complications of calcium supplementation in chronic kidney disease: are there arrhythmic risks? Simonetta Genovesi & Maurizio Gallieni To cite this article: Simonetta Genovesi & Maurizio Gallieni (2014) Cardiovascular complications of calcium supplementation in chronic kidney disease: are there arrhythmic risks?, Expert Opinion on Drug Safety, 13:9, 1143-1148 To link to this article: http://dx.doi.org/10.1517/14740338.2014.937423
Published online: 05 Jul 2014.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieds20 Download by: [109.161.194.168]
Date: 22 September 2015, At: 00:52
Editorial
1.
Calcium metabolism
2.
Calcium overload and atrial fibrillation
3.
Calcium overload,
Cardiovascular complications of calcium supplementation in chronic kidney disease: are there arrhythmic risks? Simonetta Genovesi† & Maurizio Gallieni †
hypercalcemia and ventricular
University of Milano-Bicocca and Nephrology Unit, San Gerardo Hospital, Department of Health Sciences, Monza, Italy
arrhythmias
Downloaded by [109.161.194.168] at 00:52 22 September 2015
4.
Expert opinion
Calcium supplements may induce hypercalcaemia in patients with chronic kidney disease (CKD) or patients on hemodialysis. Even in the absence of overt hypercalcaemia, calcium supplementation may be associated with a positive calcium balance and intracellular calcium overload. There is an increased risk of complex supraventricular, ventricular arrhythmias or the risk of suffering a cardiac arrest in the presence of hypercalcaemia and calcium overload in subjects with impaired or absent renal function. A maximum intake of 1000 mg elemental calcium, combining supplements and dietary calcium, together with a 1.5 mmol/l level in the dialysate, may be a safer (opinion based) recommendation in CKD patients. This is especially the case if the patient already shows signs of extra-skeletal calcification or if they present cardiac comorbidities. Lower calcium levels in the dialysis fluid might reduce the positive calcium balance but can increase intradialytic plasma calcium changes and therefore increase the risk of arrhythmias. Keywords: atrial fibrillation, calcium, cardiac arrest, chronic kidney disease Expert Opin. Drug Saf. (2014) 13(9):1143-1148
An interesting review published in this journal [1] pointed out the possible clinical risks associated with oral calcium supplementation and calcium-based phosphate binders in subjects with impaired renal function. Calcium supplements may induce hypercalcemia in patients with chronic kidney disease (CKD) or on hemodialysis (HD), but even in the absence of overt hypercalcemia, they may be associated with a positive calcium balance and intracellular calcium overload [2]. A recent meta-analysis showed a significant reduction of all-cause mortality in patients treated with noncalcium-containing binders compared with those taking calciumcontaining phosphate binders [3]. When addressing potential cardiovascular damages due to calcium overload, vascular and heart valves calcifications are mainly considered. We want to highlight the possible risk of arrhythmia associated with calcium overload and hypercalcemia in subjects with impaired or absent renal function. 1.
Calcium metabolism
Calcium metabolism is regulated by complex interaction factors, including a hormonal network acting on parathyroid glands, kidneys, bone and the intestine. The main hormones involved are 1,25-dihydroxycholecalciferol, parathyroid hormone (PTH) and calcitonin, maintaining constant plasma calcium levels and preventing calcium spiking even after the ingestion of substantial amounts of calcium. The osteocyte-produced hormone fibroblast growth factor 23 is also a determinant 10.1517/14740338.2014.937423 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
1143
S. Genovesi & M. Gallieni
A.
V (mv)
20 0
[Ca2+]o = 0.9 mM
-20
[Ca2+]o = 1.2 mM
-40
[Ca2+]o = 1.8 mM
-60 -80 0
100
200
B.
300
400
500
t (ms)
ERP (ms)
400 350
[Ca2+]o = 0.9 mM Δ = 0.3 mM
300
[Ca2+]o = 1.8 mM
Downloaded by [109.161.194.168] at 00:52 22 September 2015
250 30
50
70
90
110
130
150
Pacing rate (bpm)
Figure 1. A. Effects of different Ca2+ concentrations on atrial action potential simulation. B. Atrial effective refractory period (ERP) dependence on Ca2+ concentration at different pacing rates. Modified with permission from [8].
of mineral homeostasis, regulating phosphate and vitamin D metabolism, as well as PTH synthesis and secretion. Calcium has a specific receptor (calcium sensing receptor), regulating PTH secretion, but also expressed in other organs involved with calcium homeostasis, such as kidney, thyroid C-cells, bone and intestine. Calcium regulates also numerous physiological events as a second messenger and triggers pathological events such as cell injury and death. Intracellular calcium levels are much lower than serum levels, and the effects of calcium overload on intracellular calcium-related functions remain largely unknown. 2.
Calcium overload and atrial fibrillation
Patients with CKD and end-stage renal disease (ESRD) show an increased incidence and prevalence of atrial fibrillation (AF) [4] and, similarly to the general population, AF reduces survival in renal failure patients [5]. The onset, relapse and perpetuation of the arrhythmia may be facilitated by electrophysiological alterations (electrical remodeling) and/or anatomical changes of the atrium (structural remodeling). The reduced conduction velocity of the electrical stimulus across the atrium and the shortening of the effective refractory period (ERP) of the atrial cell establish the electrophysiological conditions allowing the start and maintenance of the arrhythmia [6]. Calcium plays an important role in AF pathophysiology. Experimental studies have shown that electrical remodeling is essentially caused by intracellular calcium overload. The presence of a cytosolic Ca2+-overload induces a downregulation of the Ca2+ inward current (ICa2+) and this in turn causes a change in the action potential, which loses its plateau. As a result, a reduction of atrial refractoriness 1144
and an impaired adaptation of ERP to changes in heart rate can be observed [7]. Bioengineering studies, performed with the help of computational models, showed that, correspondingly with the increase in ionic calcium levels, the ERP of atrial cells shortens progressively [8,9], creating a favorable situation for the onset of AF. A sensitivity analysis of the ERP dependence on extracellular ionic concentrations showed that Ca2+ increments from 0.9 to 1.8 mmol cause progressively ERP decreases, at different frequency pacing (Figure 1, [8]). Furthermore, ERP length decreases in four different human atrial tissues models (crista terminalis, right atrial appendage, atrioventricular ring and common atrial myocardium) when Ca2+ concentrations increase [9]. A positive calcium balance and the consequent risk of hypercalcemia could thus facilitate the onset of AF in patients with CKD, a population frequently presenting an anatomical background characterized by atrial dilatation and fibrosis, which already represents a pro-arrhythmic substrate. Moreover, it has been shown that the HD session can be a trigger for the onset of AF episodes [10,11]. There are no studies demonstrating a direct relationship between calcium-based drugs and AF. The only information pointing in that direction is a notification made at the American Heart Association meeting of 2011 [12]. In an observational study of 132,000 subjects, the investigators found that patients with 25(OH)-vitamin D serum levels greater than 100 ng/ml were at a 2.5 times greater risk of developing AF. Further studies should validate this observation; moreover, it should be emphasized that a 25(OH)-vitamin D level of 100 ng/ml is hard to achieve. There is strong evidence that AF patients have an increased thromboembolic risk, which requires oral anticoagulation.
Expert Opin. Drug Saf. (2014) 13(9)
Cardiovascular complications of calcium supplementation in chronic kidney disease
100
100 r = 0.55 p < 0.001
80
Downloaded by [109.161.194.168] at 00:52 22 September 2015
60 QTc msec d IV h
QTc msec d IV h
60 40 20 0
40 20 0
-20
-20
-40
-40
-60 -2
r = 0.62 p < 0.001
80
-60 -1
0
1 2 3 Ca mg/dl d IV h
4
5
-2
-1
0
1
2
3
4
5
6
Ca++ mmol/L d IV h
Figure 2. Scatter plot of intradialytic plasma calcium and Ca2+ gradient versus QTc modifications (end-dialysis values minus predialysis values). Modified with permission from [20]. QTc: QT interval correct by heart rate.
Warfarin treatment in CKD and ESRD is debated because a reduction of the thromboembolic risk is not certain, while an increased risk of bleeding has been showed [13]. Warfarin therapy can also favor vascular calcification, via the block of several vitamin K-dependent proteins, in particular, Matrix Gla Protein, by inhibiting the vitamin K cycle [14]. Vascular calcifications might be more common in CKD patients who simultaneously take warfarin and calcium salts, and particular caution should be used in these subjects.
Calcium overload, hypercalcemia and ventricular arrhythmias
3.
In CKD subjects, a high percentage of the causes of death is cardiovascular in nature and about 25% of HD patients die from sudden death [15]. Hemodialysis patients present with several factors predisposing for the onset of life-threatening cardiac arrhythmias. Both factors characterizing uremic cardiomyopathy and factors related to the HD session, in particular alterations in ventricular repolarization, are involved. It is known that in the general population and in different patient groups a prolonged QT interval (electrocardiographic measure of the duration of ventricular repolarization) may cause life-threatening arrhythmias and sudden death [16]. Prevalence of QT interval prolongation in ESRD patients is elevated [17,18]. The causes of this finding are uncertain; however, a correlation between QT interval duration and aortic calcifications has been demonstrated [19]. Moreover, an association between QT interval prolongation and mortality in ESRD patients has been reported [17,18]. Intradialytic QT interval modifications are a complex phenomenon, mainly dependent on the interactions of changing plasma calcium and potassium levels. QT interval increases
when plasma calcium and/or potassium decrease. Plasma potassium levels always decrease during HD and its reduction is the main factor involved in the intradialytic prolongation of ventricular repolarization, but changes in plasma calcium level play an important role as well. Serum calcium might change depending on calcium dialysate concentration and its relationship with predialysis plasma values. Reductions in potassium level being equal, the QT interval increases, remains stable or decreases according to the way in which plasma calcium concentration changes during the HD procedure. Furthermore, higher pre-post HD plasma calcium gradients induce greater QT interval prolongation (Figure 2, [20]). This observation was confirmed using a computational model, which simulated the changes of the ventricular action potential occurring during the HD session [21]. The widest variations between pre- and post-HD calcium levels occur in those patients who present higher plasma calcium values at the start of the session, exposing these subjects to dangerous QT interval prolongations during the HD procedure and in the following hours. Intradialytic changes in plasma pH also could play a role: high bicarbonate concentration in the dialysis fluid determines an increase of QT interval duration, probably because plasma alkalinization reduces ionized calcium levels [22]. Cardiac arrest during HD is a rare event with extremely poor outcome. The dialysate electrolyte concentration plays an important role in determining the occurrence of intradialytic cardiac arrest. Low potassium (< 2 mmol/l), but also low calcium concentrations are associated with a higher incidence of intradialytic cardiac arrest [23,24]. A recent study revealed that low calcium dialysate (< 1.25 mmol/l) was associated with a twofold increased risk of intradialytic sudden death. Higher corrected serum calcium and increasing serum-
Expert Opin. Drug Saf. (2014) 13(9)
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S. Genovesi & M. Gallieni
dialysate calcium gradient were also associated with increased risk of sudden cardiac arrest [24]. It is conceivable that higher predialytic serum calcium levels may induce nephrologists to lower the calcium concentration in the dialysate. Considering that the pre-post HD serum calcium gradient is one of the main determining factors of intradialytic QT interval changes, we can hypothesize that an excessive prolongation of the ventricular repolarization may cause malignant ventricular arrhythmias, inducing ventricular fibrillation and cardiac arrest during the HD session. In HD patients, the effect of sevelamer versus calcium carbonate on cardiovascular death due to cardiac arrhythmias was investigated. Sevelamer-treated patients exhibited a reduction in risk of death due to cardiac arrhythmias compared with calcium carbonate-treated patients. Plasma calcium levels were similar at baseline but significantly higher after 24 months in calcium carbonate-treated patients [25]. An increased incidence of sudden death has been shown after the first HD session of the week [15]. It is possible that the long interdialytic interval carries an increased risk of arrhythmia because of higher plasma/dialysate potassium gradient, especially in patients with higher predialysis plasma calcium levels, who might have a negative intradialytic calcium balance. Severi et al. [26] recently demonstrated that hemodiafiltration with calcium profiling prevents important intradialytic QT interval increments. In conclusion, potential hypercalcemia due to uncontrolled administration of oral calcium supplements or calcium-based phosphate binders may create a highly negative scenario for the risk of intradialytic cardiac arrest and sudden death in HD patients. Data from literature demonstrate a potential arrhythmic risk of pre-HD hypercalcemia and suggest paying special attention in monitoring calcium levels in patients taking these drugs. 4.
Expert opinion
Controversial findings have suggested that calcium supplements are associated with an increased risk of severe cardiac adverse events [27] that may be amplified in the CKD and HD population, where urinary excretion of calcium is impaired and calcium salts as phosphate binders and/or high calcium concentrations in the dialysate could contribute in determining a positive calcium balance. Vascular calcifications represent a plausible link between calcium and phosphate overload and the increased mortality associated with CKD mineral and bone disorders [28], but even intracellular derangements of calcium metabolism and calcifications of the heart conduction system might be a clinical issue and conduction defects due to conduction system calcification might be under-reported or unrecognized causes of cardiac morbidity [29].
1146
AF and ventricular arrhythmias are clinically relevant events that contribute to the morbidity and mortality of CKD patients. Prevention of arrhythmias is important because treatment of AF with warfarin may determine bleeding and other complications, including vascular calcification, while ventricular arrhythmias management may be challenging. A positive calcium balance, especially when hypercalcemia develops, represents an avoidable condition favoring arrhythmias. A relevant goal in the field of cardiovascular complications and deaths in the CKD and HD population is to ascertain the role of calcium overload in determining unfavorable outcomes. Calcium balance in CKD is complex, and important variables include bone turnover, dialysis frequency, dialysate calcium concentration, calcium in diet and calciumcontaining phosphate binder. A precise assessment of calcium balance is difficult to achieve for the complex regulation of calcium transport in the intestine, in the kidney and ultimately in ESRD patients who may have calcium levels ranging from hypocalcemia to hypercalcemia. The consequences of extracellular versus intracellular calcium overload are also an unresolved issue. Dialysis technology allowing the nephrologist to modulate the intradialytic calcium balance would be extremely useful [26] as we could decide to determine a negative, neutral or positive calcium balance during HD session depending on the clinical status and needs of the patient. Currently, most European patients are maintained in a likely neutral or slightly positive intradialytic calcium balance by using a relatively high-calcium concentration (1.5 mmol/l) in the dialysate. The high cost of calcium-free phosphate binders induces many nephrologists to keep using calciumbased binders. Guidelines on the safe amount of calcium binders are mostly opinion based, indicating a maximum dose of 2000 mg of elemental calcium, including calcium in the diet, but for patients with 1.25 mmol/l concentrations in the dialysis fluid. Incidentally, we cannot assume that all oral calcium medications are the same [30], and timing of the oral dose (with or without food) might influence intestinal calcium absorption. Keeping a safer approach, we believe that a maximum dose of 1000 mg elemental calcium is a more prudent, opinion-based recommendation in CKD patients, especially if they already show signs of extraskeletal calcification or if they present cardiac comorbidities.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Expert Opin. Drug Saf. (2014) 13(9)
Cardiovascular complications of calcium supplementation in chronic kidney disease
Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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3.
..
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Taksande SR, Worcester EM. Calcium supplementation in chronic kidney disease. Expert Opin Drug Saf 2014;13(9):1175-85 Gallieni M, Cozzolino M. Calcium and phosphate: serum levels versus body balance. Kidney Int 2008;74:246-7 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;1268-77 The article is a comprehensive review of the literature. Zimmerman D, Sood MM, Rigatto C, et al. Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis. Nephrol Dial Transplant 2012;27:3816-22 Genovesi S, Vincenti A, Rossi E, et al. Atrial fibrillation and morbidity and mortality in a cohort of long-term hemodialysis patients. Am J Kidney Dis 2008;51:255-62 Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol 2008;1:62-73 Nattel S, Dobrev D. The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. Eur Heart J 2012;33:1870-7 The article provides important information about the relationship between calcium and atrial fibrillation (AF).
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development of atrial fibrillation in dialysis patients. Heart 2014;100:685-90 The article provides clinical evidence regarding intradialytic AF. Vincenti A, Passini E, Fabbrini P, et al. Recurrent intradialytic paroxysmal atrial fibrillation: hypotheses on onset mechanisms based on clinical data and computational analysis. Europace 2014;16:396-404 The article provides hypotheses on the mechanisms of intradialytic AF onset. Smith MB, May HT, Blair TL, et al. Vitamin D Excess is significantly associated with risk of atrial fibrillation. Circulation 2011;124:A14699 Ng KP, Edwards NC, Lip GY, et al. Atrial fibrillation in CKD: balancing the risks and benefits of anticoagulation. Am J Kidney Dis 2013;62:615-32
14.
Schurgers LJ. Vitamin K: key vitamin in controlling vascular calcification in chronic kidney disease. Kidney Int 2013;83:782-4
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Genovesi S, Valsecchi MG, Rossi E, et al. Sudden death and associated factors in a historical cohort of chronic haemodialysis patients. Nephrol Dial Transplant 2009;24:2529-36
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17.
Zhang Y, Post WS, Blasco-Colmenares E, et al. Electrocardiographic QT interval and mortality: a meta-analysis. Epidemiology 2011;5:660-70 Hage FG, de Mattos AM, Khamash H, et al. QT prolongation is an independent predictor of mortality in end-stage renal disease. Clin Cardiol 2010;44:361-6
18.
Genovesi S, Rossi E, Nava M, et al. A case series of chronic haemodialysis patients: mortality, sudden death, and QT interval. Europace 2013;15:1025-33
8.
Severi S, Pogliani D, Fantini G, et al. Alterations of atrial electrophysiology induced by electrolyte variations: combined computational and P-wave analysis. Europace 2010;12:842-9
19.
Claes KJ, Heye S, Nuyens D, et al. Impact of vascular calcification on corrected QT interval at the time of renal transplantation. Am J Nephrol 2012;24-30
9.
Krueger MW, Severi S, Rhode K, et al. Alterations of atrial electrophysiology related to hemodialysis session:insights from a multiscale computer model. J Electrocardiol 2011;44:176-83
20.
10.
Buiten MS, de Bie MK, Rotmans BA, et al. The dialysis procedure as a trigger for atrial fibrillation: new insights in the
Genovesi S, Dossi C, Vigano` MR, et al. Electrolyte concentration during haemodialysis and QT interval prolongation in uraemic patients. Europace 2008;10:771-7 The article provides important information about changes in
..
Expert Opin. Drug Saf. (2014) 13(9)
ventricular repolarization hemodialysis related. 21.
Severi S, Grandi E, Pes C, et al. Calcium and potassium changes during haemodialysis alter ventricular repolarization duration: in vivo and in silico analysis. Nephrol Dial Transplant 2008;23:1378-86
22.
Di Iorio B, Torraca S, Piscopo C, et al. Dialysate bath and QTc interval in patients on chronic maintenance hemodialysis: pilot study of single dialysis effects. J Nephrol 2012;25:653-60
23.
Pun PH, Lehrich RW, Honeycutt EF, et al. Modifiable risk factors associated with sudden cardiac arrest within hemodialysis clinics. Kidney Int 2011;79:218-27
24.
Pun PH, Horton JR, Middleton JP. Dialysate calcium concentration and the risk of sudden cardiac arrest in hemodialysis patients. Clin J Am Soc Nephrol 2013;8:797-803 The article provides important clinical data on the relationship between calcium and intradialytic cardiac arrest.
.
25.
..
Di Iorio B, Molony D, Bell C, et al. Sevelamer versus calcium carbonate in incident hemodialysis patients: results of an open-label 24-month randomized clinical trial. Am J Kidney Dis 2013;62:771-8 The article provides important clinical data on arrhythmic risk in patients taking calcium-based phosphate binders.
26.
Severi S, Bolasco P, Badiali F, et al. Calcium profiling in hemodiafiltration: a new way to reduce the calcium overload risk without compromising cardiovascular stability. Int J Artif Organs 2014;37:206-14
27.
Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c3691
28.
Brancaccio D, Bellasi A, Cozzolino M, et al. Arterial accelerated aging in dialysis patients: the clinical impact of vascular calcification. Curr Vasc Pharmacol 2009;7:374-80
29.
Isotalo PA, Halil A, Green M, et al. Metastatic calcification of the cardiac conduction system with heart block:
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an under-reported entity in chronic renal failure patients. J Forensic Sci 2000;45:1335-8 30.
Hansen C, Werner E, Erbes HJ, et al. Intestinal calcium absorption from different calcium preparations: influence of anion and solubility. Osteoporos Int 1996;6:386-93
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Affiliation
Simonetta Genovesi†1 & Maurizio Gallieni2 † Author for correspondence 1 University of Milano-Bicocca and Nephrology Unit, San Gerardo Hospital, Department of Health Sciences, Via Cadore 48, 20900, Monza, MB, Italy Tel: +39 039 2332426; Fax: +390392332376; E-mail: [email protected] 2 Ospedale San Carlo Borromeo, Nephrology and Dialysis Unit, Milano, Italy
1148
Expert Opin. Drug Saf. (2014) 13(9)
ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20
Cardiovascular complications of calcium supplementation in chronic kidney disease: are there arrhythmic risks? Simonetta Genovesi & Maurizio Gallieni To cite this article: Simonetta Genovesi & Maurizio Gallieni (2014) Cardiovascular complications of calcium supplementation in chronic kidney disease: are there arrhythmic risks?, Expert Opinion on Drug Safety, 13:9, 1143-1148 To link to this article: http://dx.doi.org/10.1517/14740338.2014.937423
Published online: 05 Jul 2014.
Submit your article to this journal
Article views: 276
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieds20 Download by: [109.161.194.168]
Date: 22 September 2015, At: 00:52
Editorial
1.
Calcium metabolism
2.
Calcium overload and atrial fibrillation
3.
Calcium overload,
Cardiovascular complications of calcium supplementation in chronic kidney disease: are there arrhythmic risks? Simonetta Genovesi† & Maurizio Gallieni †
hypercalcemia and ventricular
University of Milano-Bicocca and Nephrology Unit, San Gerardo Hospital, Department of Health Sciences, Monza, Italy
arrhythmias
Downloaded by [109.161.194.168] at 00:52 22 September 2015
4.
Expert opinion
Calcium supplements may induce hypercalcaemia in patients with chronic kidney disease (CKD) or patients on hemodialysis. Even in the absence of overt hypercalcaemia, calcium supplementation may be associated with a positive calcium balance and intracellular calcium overload. There is an increased risk of complex supraventricular, ventricular arrhythmias or the risk of suffering a cardiac arrest in the presence of hypercalcaemia and calcium overload in subjects with impaired or absent renal function. A maximum intake of 1000 mg elemental calcium, combining supplements and dietary calcium, together with a 1.5 mmol/l level in the dialysate, may be a safer (opinion based) recommendation in CKD patients. This is especially the case if the patient already shows signs of extra-skeletal calcification or if they present cardiac comorbidities. Lower calcium levels in the dialysis fluid might reduce the positive calcium balance but can increase intradialytic plasma calcium changes and therefore increase the risk of arrhythmias. Keywords: atrial fibrillation, calcium, cardiac arrest, chronic kidney disease Expert Opin. Drug Saf. (2014) 13(9):1143-1148
An interesting review published in this journal [1] pointed out the possible clinical risks associated with oral calcium supplementation and calcium-based phosphate binders in subjects with impaired renal function. Calcium supplements may induce hypercalcemia in patients with chronic kidney disease (CKD) or on hemodialysis (HD), but even in the absence of overt hypercalcemia, they may be associated with a positive calcium balance and intracellular calcium overload [2]. A recent meta-analysis showed a significant reduction of all-cause mortality in patients treated with noncalcium-containing binders compared with those taking calciumcontaining phosphate binders [3]. When addressing potential cardiovascular damages due to calcium overload, vascular and heart valves calcifications are mainly considered. We want to highlight the possible risk of arrhythmia associated with calcium overload and hypercalcemia in subjects with impaired or absent renal function. 1.
Calcium metabolism
Calcium metabolism is regulated by complex interaction factors, including a hormonal network acting on parathyroid glands, kidneys, bone and the intestine. The main hormones involved are 1,25-dihydroxycholecalciferol, parathyroid hormone (PTH) and calcitonin, maintaining constant plasma calcium levels and preventing calcium spiking even after the ingestion of substantial amounts of calcium. The osteocyte-produced hormone fibroblast growth factor 23 is also a determinant 10.1517/14740338.2014.937423 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
1143
S. Genovesi & M. Gallieni
A.
V (mv)
20 0
[Ca2+]o = 0.9 mM
-20
[Ca2+]o = 1.2 mM
-40
[Ca2+]o = 1.8 mM
-60 -80 0
100
200
B.
300
400
500
t (ms)
ERP (ms)
400 350
[Ca2+]o = 0.9 mM Δ = 0.3 mM
300
[Ca2+]o = 1.8 mM
Downloaded by [109.161.194.168] at 00:52 22 September 2015
250 30
50
70
90
110
130
150
Pacing rate (bpm)
Figure 1. A. Effects of different Ca2+ concentrations on atrial action potential simulation. B. Atrial effective refractory period (ERP) dependence on Ca2+ concentration at different pacing rates. Modified with permission from [8].
of mineral homeostasis, regulating phosphate and vitamin D metabolism, as well as PTH synthesis and secretion. Calcium has a specific receptor (calcium sensing receptor), regulating PTH secretion, but also expressed in other organs involved with calcium homeostasis, such as kidney, thyroid C-cells, bone and intestine. Calcium regulates also numerous physiological events as a second messenger and triggers pathological events such as cell injury and death. Intracellular calcium levels are much lower than serum levels, and the effects of calcium overload on intracellular calcium-related functions remain largely unknown. 2.
Calcium overload and atrial fibrillation
Patients with CKD and end-stage renal disease (ESRD) show an increased incidence and prevalence of atrial fibrillation (AF) [4] and, similarly to the general population, AF reduces survival in renal failure patients [5]. The onset, relapse and perpetuation of the arrhythmia may be facilitated by electrophysiological alterations (electrical remodeling) and/or anatomical changes of the atrium (structural remodeling). The reduced conduction velocity of the electrical stimulus across the atrium and the shortening of the effective refractory period (ERP) of the atrial cell establish the electrophysiological conditions allowing the start and maintenance of the arrhythmia [6]. Calcium plays an important role in AF pathophysiology. Experimental studies have shown that electrical remodeling is essentially caused by intracellular calcium overload. The presence of a cytosolic Ca2+-overload induces a downregulation of the Ca2+ inward current (ICa2+) and this in turn causes a change in the action potential, which loses its plateau. As a result, a reduction of atrial refractoriness 1144
and an impaired adaptation of ERP to changes in heart rate can be observed [7]. Bioengineering studies, performed with the help of computational models, showed that, correspondingly with the increase in ionic calcium levels, the ERP of atrial cells shortens progressively [8,9], creating a favorable situation for the onset of AF. A sensitivity analysis of the ERP dependence on extracellular ionic concentrations showed that Ca2+ increments from 0.9 to 1.8 mmol cause progressively ERP decreases, at different frequency pacing (Figure 1, [8]). Furthermore, ERP length decreases in four different human atrial tissues models (crista terminalis, right atrial appendage, atrioventricular ring and common atrial myocardium) when Ca2+ concentrations increase [9]. A positive calcium balance and the consequent risk of hypercalcemia could thus facilitate the onset of AF in patients with CKD, a population frequently presenting an anatomical background characterized by atrial dilatation and fibrosis, which already represents a pro-arrhythmic substrate. Moreover, it has been shown that the HD session can be a trigger for the onset of AF episodes [10,11]. There are no studies demonstrating a direct relationship between calcium-based drugs and AF. The only information pointing in that direction is a notification made at the American Heart Association meeting of 2011 [12]. In an observational study of 132,000 subjects, the investigators found that patients with 25(OH)-vitamin D serum levels greater than 100 ng/ml were at a 2.5 times greater risk of developing AF. Further studies should validate this observation; moreover, it should be emphasized that a 25(OH)-vitamin D level of 100 ng/ml is hard to achieve. There is strong evidence that AF patients have an increased thromboembolic risk, which requires oral anticoagulation.
Expert Opin. Drug Saf. (2014) 13(9)
Cardiovascular complications of calcium supplementation in chronic kidney disease
100
100 r = 0.55 p < 0.001
80
Downloaded by [109.161.194.168] at 00:52 22 September 2015
60 QTc msec d IV h
QTc msec d IV h
60 40 20 0
40 20 0
-20
-20
-40
-40
-60 -2
r = 0.62 p < 0.001
80
-60 -1
0
1 2 3 Ca mg/dl d IV h
4
5
-2
-1
0
1
2
3
4
5
6
Ca++ mmol/L d IV h
Figure 2. Scatter plot of intradialytic plasma calcium and Ca2+ gradient versus QTc modifications (end-dialysis values minus predialysis values). Modified with permission from [20]. QTc: QT interval correct by heart rate.
Warfarin treatment in CKD and ESRD is debated because a reduction of the thromboembolic risk is not certain, while an increased risk of bleeding has been showed [13]. Warfarin therapy can also favor vascular calcification, via the block of several vitamin K-dependent proteins, in particular, Matrix Gla Protein, by inhibiting the vitamin K cycle [14]. Vascular calcifications might be more common in CKD patients who simultaneously take warfarin and calcium salts, and particular caution should be used in these subjects.
Calcium overload, hypercalcemia and ventricular arrhythmias
3.
In CKD subjects, a high percentage of the causes of death is cardiovascular in nature and about 25% of HD patients die from sudden death [15]. Hemodialysis patients present with several factors predisposing for the onset of life-threatening cardiac arrhythmias. Both factors characterizing uremic cardiomyopathy and factors related to the HD session, in particular alterations in ventricular repolarization, are involved. It is known that in the general population and in different patient groups a prolonged QT interval (electrocardiographic measure of the duration of ventricular repolarization) may cause life-threatening arrhythmias and sudden death [16]. Prevalence of QT interval prolongation in ESRD patients is elevated [17,18]. The causes of this finding are uncertain; however, a correlation between QT interval duration and aortic calcifications has been demonstrated [19]. Moreover, an association between QT interval prolongation and mortality in ESRD patients has been reported [17,18]. Intradialytic QT interval modifications are a complex phenomenon, mainly dependent on the interactions of changing plasma calcium and potassium levels. QT interval increases
when plasma calcium and/or potassium decrease. Plasma potassium levels always decrease during HD and its reduction is the main factor involved in the intradialytic prolongation of ventricular repolarization, but changes in plasma calcium level play an important role as well. Serum calcium might change depending on calcium dialysate concentration and its relationship with predialysis plasma values. Reductions in potassium level being equal, the QT interval increases, remains stable or decreases according to the way in which plasma calcium concentration changes during the HD procedure. Furthermore, higher pre-post HD plasma calcium gradients induce greater QT interval prolongation (Figure 2, [20]). This observation was confirmed using a computational model, which simulated the changes of the ventricular action potential occurring during the HD session [21]. The widest variations between pre- and post-HD calcium levels occur in those patients who present higher plasma calcium values at the start of the session, exposing these subjects to dangerous QT interval prolongations during the HD procedure and in the following hours. Intradialytic changes in plasma pH also could play a role: high bicarbonate concentration in the dialysis fluid determines an increase of QT interval duration, probably because plasma alkalinization reduces ionized calcium levels [22]. Cardiac arrest during HD is a rare event with extremely poor outcome. The dialysate electrolyte concentration plays an important role in determining the occurrence of intradialytic cardiac arrest. Low potassium (< 2 mmol/l), but also low calcium concentrations are associated with a higher incidence of intradialytic cardiac arrest [23,24]. A recent study revealed that low calcium dialysate (< 1.25 mmol/l) was associated with a twofold increased risk of intradialytic sudden death. Higher corrected serum calcium and increasing serum-
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dialysate calcium gradient were also associated with increased risk of sudden cardiac arrest [24]. It is conceivable that higher predialytic serum calcium levels may induce nephrologists to lower the calcium concentration in the dialysate. Considering that the pre-post HD serum calcium gradient is one of the main determining factors of intradialytic QT interval changes, we can hypothesize that an excessive prolongation of the ventricular repolarization may cause malignant ventricular arrhythmias, inducing ventricular fibrillation and cardiac arrest during the HD session. In HD patients, the effect of sevelamer versus calcium carbonate on cardiovascular death due to cardiac arrhythmias was investigated. Sevelamer-treated patients exhibited a reduction in risk of death due to cardiac arrhythmias compared with calcium carbonate-treated patients. Plasma calcium levels were similar at baseline but significantly higher after 24 months in calcium carbonate-treated patients [25]. An increased incidence of sudden death has been shown after the first HD session of the week [15]. It is possible that the long interdialytic interval carries an increased risk of arrhythmia because of higher plasma/dialysate potassium gradient, especially in patients with higher predialysis plasma calcium levels, who might have a negative intradialytic calcium balance. Severi et al. [26] recently demonstrated that hemodiafiltration with calcium profiling prevents important intradialytic QT interval increments. In conclusion, potential hypercalcemia due to uncontrolled administration of oral calcium supplements or calcium-based phosphate binders may create a highly negative scenario for the risk of intradialytic cardiac arrest and sudden death in HD patients. Data from literature demonstrate a potential arrhythmic risk of pre-HD hypercalcemia and suggest paying special attention in monitoring calcium levels in patients taking these drugs. 4.
Expert opinion
Controversial findings have suggested that calcium supplements are associated with an increased risk of severe cardiac adverse events [27] that may be amplified in the CKD and HD population, where urinary excretion of calcium is impaired and calcium salts as phosphate binders and/or high calcium concentrations in the dialysate could contribute in determining a positive calcium balance. Vascular calcifications represent a plausible link between calcium and phosphate overload and the increased mortality associated with CKD mineral and bone disorders [28], but even intracellular derangements of calcium metabolism and calcifications of the heart conduction system might be a clinical issue and conduction defects due to conduction system calcification might be under-reported or unrecognized causes of cardiac morbidity [29].
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AF and ventricular arrhythmias are clinically relevant events that contribute to the morbidity and mortality of CKD patients. Prevention of arrhythmias is important because treatment of AF with warfarin may determine bleeding and other complications, including vascular calcification, while ventricular arrhythmias management may be challenging. A positive calcium balance, especially when hypercalcemia develops, represents an avoidable condition favoring arrhythmias. A relevant goal in the field of cardiovascular complications and deaths in the CKD and HD population is to ascertain the role of calcium overload in determining unfavorable outcomes. Calcium balance in CKD is complex, and important variables include bone turnover, dialysis frequency, dialysate calcium concentration, calcium in diet and calciumcontaining phosphate binder. A precise assessment of calcium balance is difficult to achieve for the complex regulation of calcium transport in the intestine, in the kidney and ultimately in ESRD patients who may have calcium levels ranging from hypocalcemia to hypercalcemia. The consequences of extracellular versus intracellular calcium overload are also an unresolved issue. Dialysis technology allowing the nephrologist to modulate the intradialytic calcium balance would be extremely useful [26] as we could decide to determine a negative, neutral or positive calcium balance during HD session depending on the clinical status and needs of the patient. Currently, most European patients are maintained in a likely neutral or slightly positive intradialytic calcium balance by using a relatively high-calcium concentration (1.5 mmol/l) in the dialysate. The high cost of calcium-free phosphate binders induces many nephrologists to keep using calciumbased binders. Guidelines on the safe amount of calcium binders are mostly opinion based, indicating a maximum dose of 2000 mg of elemental calcium, including calcium in the diet, but for patients with 1.25 mmol/l concentrations in the dialysis fluid. Incidentally, we cannot assume that all oral calcium medications are the same [30], and timing of the oral dose (with or without food) might influence intestinal calcium absorption. Keeping a safer approach, we believe that a maximum dose of 1000 mg elemental calcium is a more prudent, opinion-based recommendation in CKD patients, especially if they already show signs of extraskeletal calcification or if they present cardiac comorbidities.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Expert Opin. Drug Saf. (2014) 13(9)
Cardiovascular complications of calcium supplementation in chronic kidney disease
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Affiliation
Simonetta Genovesi†1 & Maurizio Gallieni2 † Author for correspondence 1 University of Milano-Bicocca and Nephrology Unit, San Gerardo Hospital, Department of Health Sciences, Via Cadore 48, 20900, Monza, MB, Italy Tel: +39 039 2332426; Fax: +390392332376; E-mail: [email protected] 2 Ospedale San Carlo Borromeo, Nephrology and Dialysis Unit, Milano, Italy
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