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, DOI: 10.1517/14740338.2014.937423
To link to this article: http://dx.doi.org/10.1517/14740338.2014.937423

Published online: 05 Jul 2014.

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Date: 28 September 2016, At: 22:18

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
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
= 0.3 mM

300

[Ca2+]o = 1.8 mM

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

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

1
2
3
Ca mg/dl d IV h

-2

-1

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)

1145

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

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Affiliation

Simonetta Genovesi1 & 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: simonetta.genovesi@unimib.it
2
Ospedale San Carlo Borromeo, Nephrology and
Dialysis Unit, Milano, Italy

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Expert Opin. Drug Saf. (2014) 13(9)