Sudden cardiac death in chronic kidney disease: epidemiology and prevention

Sudden cardiac death in chronic kidney
disease: epidemiology and prevention
M. Khaled Shamseddin and Patrick S. Parfrey
Abstract | Annual cardiovascular mortality in patients with chronic kidney disease (CKD) is much higher than
in the general population. The rate of sudden cardiac death increases as the stage of CKD increases and
could be responsible for 60% of cardiac deaths in patients undergoing dialysis. In hemodialysis units treating
patients with CKD, cardiac arrest occurs at a rate of seven arrests per 100,000 hemodialysis sessions.
Important risk factors for sudden cardiac death in patients with CKD include hospitalization within the past
30 days, a drop of 30 mmHg in systolic blood pressure during hemodialysis, duration of life on hemodialysis,
time since the previous dialysis session, and the presence of concomitant diabetes mellitus. As a result of
the adverse cardiomyopathic and vasculopathic milieu in CKD, the occurrence of arrhythmias, conduction
abnormalities, and sudden cardiac death could be exacerbated by electrolyte shifts, divalent ion abnormalities,
diabetes, sympathetic overactivity, in addition to inflammation and perhaps iron deposition. Impaired
baroreflex effectiveness and sensitivity, as well as obstructive sleep apnea, might also contribute to the risk
of sudden death in CKD. The likelihood of survival following cardiac arrest is very low in dialysis patients.
Primary and secondary prevention of cardiac arrest could reduce cardiovascular mortality in patients with CKD.
Cardioverter-defibrillator implantation decreases the risk of sudden death in patients with CKD. The decision to
implant a cardioverter-defibrillator should be influenced by the patient’s age and stage of CKD.
Shamseddin, M. K. & Parfrey, P. S. Nat. Rev. Nephrol. 7, 145–154 (2011); published online 1 February 2011; doi:10.1038/nrneph.2010.191
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learning objectives
Upon completion of this activity, participants should be able to:
1 Distinguish risk factors for sudden cardiac death among
patients with end-stage renal disease.
2 Evaluate the pathophysiology that promotes sudden cardiac
death among patients with chronic kidney disease.
3 Analyze factors related to dialysis which might promote
higher rates of sudden cardiac death.
4 Apply research to prevent sudden cardiac death among
patients receiving dialysis.
Competing interests
The authors, the locum journal Chief Editor R. Ireland and the
CME questions author C. P. Vega declare no competing interests.
Patients with end-stage renal disease (esrD) are
exposed to substantial hemodynamic stress and metabolic perturbations, which predispose them to cardiomyopathy, atherosclerosis, and arteriosclerosis. 1–3
Consequently, annual cardiovascular mortality among
patients with esrD is much higher than in the general
population.1,2 sudden cardiac death might be responsible for 60% of these cardiac deaths in patients undergoing dialysis.4 in those who also have diabetes mellitus,
sudden cardiac death has been reported to be the most
frequent cause cardiovascular death.4
even in the intermediate stages of chronic kidney
disease (CKD; stages 3–4), cardiovascular mortality is
higher than in individuals without CKD.5–7 results from
the Heart outcomes and Prevention evaluation (HoPe)
study 5,6 indicated that mild renal insufficiency (defined
as a serum creatinine level 125–200 μmol/l [n = 980] or
glomerular filtration rate (GFr) ≤65 ml/min [n = 3,394])
in patients with cardiovascular disease was associated
with a 40% increase in the risk of cardiac death when
compared with those who had cardiovascular disease and
normal kidney function.5,6 likewise, in the Hypertension
optimal treatment (Hot) study,7 the risk of cardiovascular mortality was analyzed in 18,790 patients with
hypertension who had a baseline serum creatinine level
≤265 μmol/l. no clinical evidence of atherosclerotic vascular disease was present in the majority of these patients
(90%). a threefold increase in adjusted relative risk of
nature reviews | nephrology
Division of Nephrology,
Memorial University of
Newfoundland, Patient
Research Centre,
Health Science Centre
(M. K. Shamseddin),
Patient Research
Centre, Health Science
Centre, 300 Prince
Phillip Drive, St John’s,
NL A1B 3V6, Canada
(p. S. parfrey).
Correspondence to:
P. S. Parfrey
[email protected]
volume 7 | marCH 2011 | 145
© 2011 Macmillan Publishers Limited. All rights reserved
25 –
■ Chronic kidney disease (CKD) is a risk factor for sudden cardiac death; the rate
of sudden cardiac death increases as the stage of CKD increases
■ In hemodialysis units, cardiac arrest occurs at a rate of seven per 100,000
hemodialysis sessions
■ Survival following cardiac arrest is very poor
■ Adverse cardiomyopathic and vasculopathic milieu in CKD predispose to
conduction abnormalities and arrhythmic events
■ Multiple risk factors and mechanisms can contribute to the risk of sudden
death in CKD; primary and secondary prevention could reduce cardiovascular
mortality in patients with CKD
■ Patients with CKD at risk of sudden cardiac death can be identified and the
decision to implant a cardioverter-defibrillator should be influenced by age and
stage of CKD
cardiovascular mortality was observed in those with
mild CKD defined as a baseline serum creatinine level
>130 μmol/l (CKD stages 3–4).7
the population of individuals with CKD is expanding, the incidence of cardiovascular disease is high, the
risk of cardiac death in these patients is high, and survival
of CKD patients after cardiac arrest is poor. this review
describes the incidence of sudden cardiac death in dialysis and nondialysis CKD patients. we discuss the risk
factors and mechanisms associated with sudden cardiac
death and examine some therapeutic approaches.
Incidence of sudden cardiac death in CKD
the proportion of deaths designated as ‘sudden’ is similar
in both patients with CKD and the general population.8 in
a British community-based study by thomas and colleagues, approximately 70% of deaths were the result
of cardiac disease, and roughly half of those cardiovascular deaths were sudden.8 among diabetic hemodialysis patients, the 4D study,9 in 178 German dialysis
centers, showed that 26% of adjudicated cardiac deaths
were sudden, while coronary artery disease, heart
failure, and other cardiac etiologies were the cause of 9%,
6%, and 3% of the adjudicated deaths, respectively.
a study of 4,120 deaths in the usa during the 2-year
follow-up of 12,833 prevalent hemodialysis patients
showed that the greatest percentage of all deaths (27%)
were caused by sudden cardiac arrest, while other cardiovascular conditions (including coronary artery disease,
vascular heart disease, cardiomyopathy, arrhythmia,
pericarditis and cardiac tamponade, and pulmonary
edema) accounted for 20% of all deaths.10
a high rate of sudden cardiac death in 5,830 dialysis
patients who underwent coronary artery bypass (CaBG)
surgery in the us was reported by Herzog et al.11 allcause and arrhythmia-related mortality were 290 and
76 deaths per 1,000 patient years, respectively.11 Deaths
from sudden cardiac arrest or arrhythmia accounted
for approximately 25% of all-cause deaths.11 the rate
of sudden cardiac death was also examined in 19,440
us patients with CKD who had undergone cardiac
catheterization at a single institution. 12 522 sudden
cardiac deaths occurred; in 25% of cases, the patients had
Sudden cardiac death rate per 1,000 patient-years
Key points
20 –
15 –
10 –
eGFR ≥60
eGFR 15–59
eGFR <15
Figure 1 | Sudden cardiac death rate according to stage of
chronic kidney disease. Rates of sudden cardiac death
stratified by baseline eGFR. Rates are shown as events per
1,000 patient-years and are as follows: eGFR ≥60 ml/min,
3.8 (95% CI 0–8); eGFR 15–59 ml/min, 7.3 (95% CI 2–13);
eGFR <15 not on dialysis, 12.6 (95% CI 5–20); dialysis,
24.2 (95% CI 14–34). Permission obtained from Nature
Publishing Group © Pun, P. H. et al. Kidney Int. 76, 652–658
(2009). Abbreviation: eGFR, estimated glomerular
filtration rate.
an estimated (eGFr) <60ml/min/1.73 m2.12 the sudden
cardiac death rate increased with increasing severity of CKD (Figure 1). the hazard ratio (Hr) for each
10 ml/min/1.73 m2 decline in eGFr was 1.11 (95% Ci
1.06–1.17, P <0.001).12
among patients undergoing dialysis, the frequency
of sudden cardiac death increases both with the duration of time that the patient has been undergoing dialysis and with the duration of time since their previous
dialysis session, and is highest among individuals with
dia betes. 13,14 Furthermore, the ratio of observed to
expected deaths was higher than expected in the first
12 h after initiation of the hemodialysis session, and
increased as the time from start of the dialysis session
exceeded 36 h.14 the number of observed deaths was
three times higher than expected in the period 60–72 h
after the start of the dialysis session (Figure 2). other
risk factors for sudden death included hospitalization
within the past 30 days and a decrease of 30 mmHg in
systolic blood pressure (sBP) during hemodialysis.14
Patients with esrD and diabetes have a higher risk of
sudden death than nondiabetic esrD patients, with an
incidence of 20% within the first 2 years after dialysis
is initiated.15
Incidence of cardiac arrest in CKD
Cardiac arrest is defined as an abrupt cessation of cardiac
function from which the patient may or may not recover.
in a case–control study, Karnik et al. reported that in
patients with esrD undergoing dialysis, 400 cardiac
arrests occurred in a total of 5,744,708 hemodialysis
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3.0 –
Causes of cardiovascular disease in chronic kidney disease
Ratio observed:expected deaths
2.5 –
2.0 –
Left ventricular
pressure overload
Left ventricular
volume overload
1.5 –
1.0 –
Maladaptive left
ventricular hypertrophy,
myocyte death
0.5 –
Heart failure
Critical stenosis
of large vessels
of conduit vessels
Ischemic heart disease,
peripheral vascular disease,
cardiovascular disease
Heart failure,
ischemic heart
0.0 –
Cardiac arrest
Time from start of dialysis (h)
Figure 2 | Ratio of actual to expected number of
occurrences of sudden death for each 12 h interval from
the start of hemodialysis. Permission obtained from
Nature Publishing Group © Bleyer, A. J. et al. Kidney Int. 69,
2268–2273 (2006).
Figure 3 | The pathophysiology of diseases that predispose patients with chronic
kidney disease to cardiac arrest. Cardiomyopathy due to left ventricular pressure
and volume overload and vasculopathy due to atherosclerosis and arteriosclerosis
are two major mechanisms that predispose patients with chronic kidney disease to
cardiovascular disease.
sessions; equivalent to a rate of seven arrests per 100,000
hemodialysis sessions. 13 in another cohort study of
295,913 incident dialysis patients surviving at least 1 year
on dialysis, the rate of cardiac arrest was 93 events per
1,000 patient-years at year 1, and 164 events per 1,000
patient-years at year 4.4 among patients with diabetes
who were undergoing dialysis, the rate of cardiac arrest
at year 1 was 110 events per 1,000 patient-years, rising to
208 events per 1,000 patient-years at year 4.4
the survival rates following cardiac arrest reported
by Herzog et al.4 were 32% at 30 days and 17% at 1 year
after dialysis, respectively, dropping to 13% at year 1
in patients with diabetes.4 on the other hand, 60% of
patients with esrD who experienced a cardiac arrest in
the dialysis unit died within 48 h of cardiac arrest; 13%
of these deaths occurred while in dialysis units.13 Finally,
the annual mortality among patients who survive cardiac
arrest has been reported to reach 87%.15
in predialysis patients, left ventricular hypertrophy
(lvH) increases as GFr falls. 16 in fact, the clinical
manifestation of cardiomyopathy—heart failure—occurs
as frequently as atherosclerotic events in patients with
CKD.2 lvH is present in almost 75% of patients starting
dialysis.16 Progressive left ventricular dilation and lvH
continues after dialysis is initiated17,18 and is associated
with the subsequent development of heart failure. 19
Progressive hypertrophy is partly explained by hypertension, but not by a wide array of potential risk factors,
including moderate anemia.20
lvH could predispose individuals to sudden death
through prolongation of corrected Qt (Qtc) interval
or by increasing arrhythmogenesis. the Qtc interval is
substantially longer in hemodialysis patients than in
those who have near-normal kidney function, and is
associated with several manifestations of uremic cardiomyopathy including increased left ventricular mass index
and end diastolic volume, and reduced left ventricular
ejection fraction.19,21 in addition, more premature ventricular complexes (PvCs) occur during hemodialysis
in patients with lvH compared with those without left
ventricular hypertrophy.22
risk factors and mechanisms
in patients with CKD, cardiomyopathy occurs frequently because of left ventricular pressure and volume
overload. Both atherosclerotic and arteriosclerotic
vascular disease also occur frequently (Figure 3). this
adverse cardiomyopathic and vasculopathic milieu
predisposes indivi duals with CKD to arrhythmias,
conduction abnormalities, and sudden cardiac death,
which is likely to be exacerbated by electrolyte shifts,
divalent ion abnormalities, diabetes, and sympathetic
overactivity, in addition to inflammation and possibly
iron deposition (Figure 4). impaired baroreflex effectiveness and sensitivity, as well as obstructive sleep
apnea might also contribute to the risk of sudden death.
each of these risk factors is discussed in greater detail
below (Box 1).
Ischemic heart disease
in the general population, coronary heart disease is an
important cause of sudden death. in patients undergoing
hemodialysis, coronary artery disease probably causes
arrhythmogenesis as severe coronary stenosis is associated with the induction and lengthy persistence of ventricular arrhythmias during and after hemodialysis.23,24
Furthermore, the number of PvCs during and after
hemodialysis is higher in patients with than in those
without ischemic heart disease.22,24
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Cardiomyopathy, ischemic heart disease
Box 1 | Risk factors for sudden death in dialysis patients
■ Cardiomyopathy
■ Left ventricular hypertrophy
■ Fibrosis
Electrolyte shifts
Sympathetic overactivity
Divalent ion abnormalities
Baroreflex effectiveness
Iron overload
Obstructive sleep apnea
■ Microvascular disease
■ Ischemic heart disease
■ Ventricular arrhythmias
■ QTc dispersion
■ QTc variability index
■ Electrolyte shifts
■ Divalent ion abnormalities
Arrhythmias, QTc prolongation
Cardiac arrest
Figure 4 | The pathophysiology of sudden cardiac death in
patients with chronic kidney disease. Risk factors such as
cardiomyopathy and diabetes provoke QT interval
abnormalities and dysarrhythmia, which results in cardiac
arrest in patients with chronic kidney disease.
novel markers of coronary ischemia can identify
patients who are at high risk of sudden cardiac death.
ischemia modified albumin (ima) is a novel biomarker
of acute ischemia that has high sensitivity and moderate
specificity.25,26 in 114 patients with esrD, an ima level
of ≥95 Ku/l predicted all-cause mortality with a sensitivity and specificity of 76% and 74%, respectively,27
while an elevated cardiac troponin level of ≥0.06 μg/l
predicted mortality with a sensitivity of 75% and a specificity of 72%.27 Cardiac mortality risk was increased
sevenfold in patients with combined elevated ima
and cardiac troponin levels (odds ratio [or] 7.12, 95%
Ci 4.14–10.12, P = 0.005).27
severely impaired myocardial fatty acid metabolism—
occurring as a result of recurrent myocardial ischemia—
can also identify patients on hemodialysis who are at high
risk of sudden cardiac death.28 in a prospective study with
3.6 ± 1.0 years of follow-up, 318 asymptomatic hemodialysis patients with no clinical history of myocardial
infarction and/or coronary revascularization underwent
single-photon emission computed tomography (sPeCt)
using the iodinated fatty acid analog iodine-123 (i123)β-methyliodophenyl-pentadecanoic acid (BmiPP) and
thallium (tl) chloride.28 uptake on sPeCt images was
graded in 17 segments on a 5-point scale (0 normal, 4
absent) and assessed as summed BmiPP or tl cores.28
50 patients died from cardiac events; 11 from sudden
cardiac death, 22 from acute myo cardial infarction,
and 17 from congestive heart failure.28 a BmiPP score
≥12 was associated with cardiac death (Hr 22; 95% Ci
8.5–56.1; P <0.0001).28 Furthermore, cardiac death-free
survival at 3 years was 61% and 98% in patients with
BmiPP scores of ≥12 and <12, respectively.28
QTc, QT dispersion, and variability index
the Qt interval on the electrocardiogram (eCG) is a
measure of the duration of ventricular depolarization
■ Vascular calcification
■ Sympathetic overactivity
■ Baroreflex effectiveness
■ Baroreflex sensitivity
■ Obstructive sleep apnea
■ Diabetes mellitus
Abbreviation: QTc, corrected QT.
and repolarization.29 torsade de pointes is a polymorphic
ventricular tachycardia that occurs in the setting of prolonged Qt interval.29 CKD and esrD can be associated with prolonged Qt interval, Qtc, and torsade
de pointes; these conditions can be a cause of sudden
cardiac death.21
Prolonged Qtc in patients with CKD and esrD
usually results from inhomogeneity of both myocardial
depolarization and repolarization that occurs secondary to lvH19 and intercardiomyocytic fibrosis.21,30 in
68 nondiabetic patients with esrD who were undergoing hemodialysis with a normal maximal eCG stress
test and no evidence of lvH on eCG,31 hemodialysis
increased Qtc intervals from 421 ± 26 ms before hemodialysis to 434 ± 29 ms after hemodialysis (P = 0.005).
abnormally prolonged Qtc intervals (>440 ms) after
hemodialysis were recorded 1.5–2.3 times more often
than in the high-risk euroDiaB iDDm population.31
in addition, patients with greater increases in Qtc
intervals after hemodialysis had higher baseline plasma
calcium levels (r = 0.47, P <0.001); and lower calcium
levels after hemodialysis (r = 0.33, P <0.05).31 these data
suggest that abnormalities in calcium hemostasis may
induce prolongation of Qtc, and may predispose to
sudden death.
Qt dispersion—defined as the difference between the
maximal and minimal Qt intervals on a standard eCG
(Qtmax – Qtmin)—is also associated with increased
risk of ventricular arrhythmias and mortality in patients
with congestive heart failure and in the general population.32 a small study showed that elevated Qt dispersion
in patients on dialysis (20 hemodialysis patients and 20
patients with continuous ambulatory peritoneal dialysis
[CaPD]) was significantly higher than in with healthy
controls (P <0.05).33 the difference in Qt dispersion rates
between patients undergoing hemodiaysis and those on
CaPD was not statistically significant.33 in a retrospective
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cohort study of 147 adult patients undergoing dialysis,34
Qtc interval dispersion (Qtcd) that occurred for longer
than 74 ms was an independent predictor of all-cause
mortality (relative risk [rr] 1.53, 95% Ci 1.19–1.98,
P = 0.0001), cardiovascular mortality (rr 1.57, 95% Ci
1.05–2.36, P = 0.028), and arrhythmia-related mortality
(rr 1.58, 95% Ci 0.98–2.54, P = 0.061).34
Qt variability index (Qtvi)—computerized and calculated as the logarithm of the ratio between the variances
of the normalized Qt and rr intervals—can provide an
estimation of the temporal variability in the myocardial
repolarization process35 and predict the subsequent risk
of sudden cardiac death or ventricular arrhythmia in
patients who present for electrophysiological investigation.36 Johnsson et al. reported that Qtvi was increased
by 47% in 153 patients with advanced CKD (43 individuals with stage 4 CKD, 67 patients undergoing hemodialysis, and 43 patients on CaPD) during a 30 min rest
period compared with 39 age-matched healthy controls.35
the Qtvi was similar in patients with stage 4 CKD and
in those on dialysis, whereas it was higher in patients
with diabetes compared with nondiabetic patients with
renal failure.35 Furthermore, in a multiple linear regression analysis, a history of diabetes or coronary artery
disease were the only independent predictors of Qtvi
in patients with advanced CKD.35 the elevated Qtvi in
patients with advanced CKD was the result of both
reduced rr interval variance (secondary to reduced autonomic control of heart rate) and increased Qt-interval
variance.35,37 in another study by atiga and colleagues,
the Qtvi was higher in patients presenting with sudden
cardiac death than in patients who presented with other
manifestations of heart disease.36 in a logistic multiple
regression, Qtvi identified patients who died suddenly
(or = 12.5, P = 0.004).36 Qtvi ≥0.1 was significantly
associated with a higher risk of arrhythmias.36
Finally, it should be noted that several drugs (such
as typical and atypical antipsychotics, sotalol, and antiarrhythmics) could prolong cardiac repolarization (Qt
interval) and trigger torsades de pointes, and could
increase the risk of sudden cardiac death in patients
with CKD.29,38
inflammation has been found to be associated with
sudden cardiac death independently of traditional cardiovascular risk factors.39 after adjusting for demographic
characteristics, comorbidities, and laboratory factors, the
highest tertiles of the inflammatory markers C-reactive
protein (CrP) and interleukin 6 (il-6) were associated with a doubled risk of sudden cardiac death compared with the lowest tertiles, while a decrease in serum
albumin level was associated with a 1.35-fold increased
risk of sudden cardiac death in the highest tertile compared with the lowest tertile.39 inflammation could trigger
sudden cardiac death through premature atherosclerosis
and cytokine-induced plaque instability or by a direct
effect on the myocardium and the electrical conduction
system.39 as renal function deteriorates, levels of toxins
and proinflammatory cytokines increase.40 in patients
Proinflammatory cytokines
(e.g. IL-6)
Asymmetric dimethylarginine
Atherosclerosis and
Proinflammatory cytokines
(e.g. IL-6)
Platelet-activating factor
Modulation of ion channel function
Aggravation of sympathetic tone
Myocardial fibrosis
Cardiac death
Figure 5 | Pathophysiology of inflammation and cardiac
death. Chronic inflammation in patients with end-stage
renal disease provokes vasculopathy, myocardial fibrosis,
sympathetic hyperactivity and ion channel malfunction,
which results in a high risk of cardiac death. Abbreviations:
CRP, C-reactive protein; IL-6, interleukin 6.
with CKD, elevated levels of inflammatory mediators
induce the production of reactive oxygen species that
accelerate vascular atherosclerosis and arterial calcification. 41 the accumulation of asymmetric dimethylarginine inhibits nitric oxide synthesis in endothelial cells
inducing endothelial dysfunction, vasoconstriction, and
atherosclerosis.40 High levels of the inflammatory marker
homocysteine is associated with atherothrombotic events
and incident cardiovascular mortality in patients undergoing hemodialysis.42 in patients with esrD, elevated
levels of calcification promoters (such as osteopontin)
and reduced levels of calcification inhibitors (such as
Fetuin-a), in addition to abnormal calcium–phosphate
metabolism, hyperparathyroidism, and oxidant stresses
promote myo cardial fibrosis and metastatic vascular
calcification,41 which results in diminished coronary flow
during diastole.41
CrP and cytokines (such as il-6 and platelet-activating
factor) have been associated with arrhythmias through
the modulation of ion channel function39,43,44 and the
aggravation of sympathetic tone.39 myocardial fibrosis, which has been associated with the inflammatory
process, could affect ventricular conduction causing
a delay in repolarization that could lead to ventricular arrhythmias.39,45,46 all of these mechanisms could
contribute to sudden cardiac death (Figure 5).
Electrolyte shifts
the rapid change in the extracellular concentration of
electrolytes during a dialysis session leads to a secondary
shift of electrolytes between the intracellular and extracellular milieu, which depends on the electrochemical
gradient. as a result, cellular membrane polarization
and stability may be affected. 13,41 Data from patients
treated at Fresenius medical Care north americaaffiliated centers13,47 showed that dialysis with a potassium dialyzate concentration of 0 mmol/l or 1 mmol/l
was a significant risk factor for cardiac arrest.13 this prescription had been used in 17.1% of cases who experienced a cardiac arrest compared with 8.8% of controls
nature reviews | nephrology
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(P <0.0001).13 Cardiac arrests were more frequent during
dialysis sessions carried out on a monday compared
with a wednesday (P = 0.001) and Friday (P = 0.004).13
although the mechanism for this observation was not
studied it may be due to increased potassium concentrations or increased blood volume. Furthermore, in
patients undergoing hemodialysis, complex arrhythmias
were observed more frequently during and after hemodialysis in those with a decreasing potassium profile
compared with individuals whose potassium levels
were kept constant (2.5 mmol/l).48 Calcium homeostasis
and hypocalcemia after hemo dialysis correlated with
prolonged corrected Qtc interval and sudden cardiac
death as reported above.31 Finally, in a small study (31
patients undergoing hemodialysis), although serum
magnesium level decreased after hemodialysis from
0.95 ± 0.04 mmol/l to 0.890 ± 0.09 mmol/l (P = 0.052),
hypomagnesmia was not correlated with corrected
Qtc dispersion.49
Abnormalities in divalent ion metabolism
Hyperphosphatemia usually develops as kidney function deteriorates and is a common problem among
patients with esrD. 50 in the usa, 40% of patients
undergoing hemodialysis has hyperphosphatemia,
defined as a serum phosphate (Po4) level >2.1 mmol/l
(6.5 mg/dl).50 Hyperphosphatemia provokes secondary hyperparathyroidism, smooth muscle proliferation,
vascular calcification, and coronary atherosclerosis. 51
Hyperphosphatemia-induced myocardial calcification could alter microcirculatory hemodynamics, raise
extravascular resistance and threaten myocardial perfusion. 52 Hyperphosphatemia was associated with a
mortality risk 27% higher than that of patients with
Po 4 levels 0.8–2.1 mmol/l. 50 Furthermore, elevated
Ca × Po4 product (>5.8 mmol2/l2) was also associated
with increased risk of death (rr = 1.34, P <0.01). 50
whether this increased mortality risk is associated with
an increased risk of sudden death is unknown.
in a study of 12,833 patients undergoing hemodilaysis,
a 0.3 mmol/l incremental increase in serum Po4 level was
associated with a 9% increase in the risk of death related
to coronary artery disease (P <0.0005) and a 6% increase
in the risk of sudden cardiac death (P <0.01).10 Deaths
related to coronary artery disease (rr 1.06, P <0.05)
and sudden cardiac death (rr 1.07 per 0.81 mmol2/l2,
P <0.005) correlated with elevated levels of Ca × Po4
product in a linear manner.10 sudden cardiac deaths
were also related to log parathyroid hormone in a nonlinear fashion (u-shaped relationship), but were strongly
associated with serum parathyroid hormone >52.1 ng/l
(rr = 1.25, P <0.05).10
Divalent ion abnormalities predispose to vascular calcification of conduit vessels. in addition, these
abnormalities can contribute to cardiac valve calcification and the adverse consequences of arterio sclerosis.
among 140 patients with esrD who underwent
echocardiography and coronary angiography, 56 (40%)
experienced mitral annular calcification, which was
associ ated with a significant increase in all-cause
mortality (P = 0.04).53 mitral annular calcification was
also independently associated with substantial coronary
artery disease, defined as luminal stenosis >70% by visual
estimation in at least one coronary artery (or 12, 95% Ci
3.25–26.12, P = 0.001).53 whether this increased risk of
death is associated with increased risk of sudden death
is unknown, although it is likely.
Iron overload
the role of iron in the pathogenesis of cardiovascular
disease in patients with esrD is not well defined; iron
overload has, however, been associated with elevated
rates of hospitalization and mortality in patients
with esrD. 54 iron can promote the production of
reactive oxygen species and free radicals resulting
in intercardiomyocytic fibrosis. 55 in a study of 102
nondiabetic patients undergoing peritoneal dialysis who were matched with 102 healthy patients with
a serum creatinine level <133 μmol/l (1.5 mg/dl), the
mean Qtc dispersion among the patients was significantly longer than in control participants (69.8 ± 40.0
versus 55.2 ± 33.6 ms, P <0.01).56 High iron saturation
>35.2% was an independent factor for Qtc dispersion
longer than 74 ms (sensitivity 71.4%, specificity 55.3%,
r = 0.432, P <0.001).56 iron overload in esrD possibly
increases the risk of sudden cardiac death because of
these conduction abnormalities.
Sympathetic overactivity
sympathetic overactivity is an early event in the pathophysiology of acute and chronic kidney injury of various
etiologies.57,58 renal norephephrine release is enhanced
by 30% in the cortex of subtotally neph rectomized
rats. 57,59 augmented sympathetic drive is seen even
during hemodialysis sessions, suggesting that this event
is volume independent.57,59 such events usually subside
following bilateral nephrectomy.57,59 sympathetic overactivity is usually secondary to an afferent signal of
sensory renal nerves activating the sympathetic nervous
system, resulting in enhanced sympathetic and norepinephrine release.57 the later response could aggravate
hypertension, ventricular hypertrophy, and heart failure
and result in increased risk of sudden cardiac death.57
another suggested novel mechanism for sympathetic
overactivity 60 relates to the reduced amount of renalase (a flavin adenine dinucleotide-dependent amine
oxidase) secreted by injured kidneys. renalase metabolizes catecholamines and, in patients with esrD, this
enzyme is markedly reduced resulting in augmented
sympathetic drive.60
Obstructive sleep apnea
obstructive sleep apnea, demonstrated by episodes
of nocturnal arterial oxygen desaturation, has been
reported to affect 21–47% of patients undergoing dialysis
compared with 2–4% of the general population.9,61 in the
4D study, 40% of people who died as a result of sudden
cardiac arrest were found dead in bed in the morning.9
the investigators postulated that this outcome might be
related to obstructive sleep apnea.9
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Baroreflex effectiveness and sensitivity
impaired arterial baroreflex function is associated with
an increased risk of ventricular arrhythmia and sudden
cardiac death.62 in healthy individuals, an appropriate
baroreflex response is usually obtained in 25% of all sBP
ramps during the day and in 15% during the night.63
the ability of the arterial baroreflex to preserve shortterm blood pressure homeostasis—defined as arterial
baroreflex sensitivity—has been identified as a prognostic marker of cardiovascular mortality in patients
with myocardial infarction.64 the baroreflex effectiveness
index (Bei) is defined as the ratio between the number
of sBP ramps, followed by baroreflex-mediated changes
in heart rate, and the total number of sBP ramps during
the recording period.65
in 216 patients with hypertension and stage 4 or 5
CKD, the baroreflex sensitivity was reduced by 51% and
the Bei by 49% compared with age-matched healthy
controls (n = 43).62 although the treatment modality
for renal failure had no effect on baroreflex sensitivity
or effectiveness, patients with CKD and diabetes had a
greater reduction in both baroreflex sensitivity and effectiveness than patients with CKD who did not have diabetes.62 During the 41-month follow-up period 69 of the
patients with hypertension died.65 sudden cardiac death
occurred in 15 of these patients (22% of all deaths).65
reduced Bei was an independent predictor of all-cause
mortality, while reduced baroreflex sensitivity was an
independent predictor of sudden cardiac death.65
Drug therapy
in a single, randomized controlled trial, use of the
β-blocker carvedilol reduced morbidity, and all-cause
and cardiovascular mortality in patients with esrD
and dilated cardiomyopathy who were undergoing
dialysis.66 Patients were randomly assigned to carvedilol
(n = 58, open-label) or placebo (n = 56) on top of standard
treatment for heart failure and were followed-up over
2 years.66 all-cause mortality was 51.7% in the treatment
group versus 73.2% in the placebo group (P <0.01), and
cardiovascular mortality was significantly reduced in
the carvedilol group.66 in a large, retrospective study of
43,200 patients undergoing hemodialysis, 729 patients
experienced a cardiac arrest.67 β-Blockers were prescribed
more frequently among those who survived than among
those who died from a sudden cardiac arrest (53% versus
40%, or 0.59, 95% Ci 0.43–0.80, P = 0.0007).67 among
those who survived, β-blockers were associated with a
significantly lower risk of death at 24 h and 6 months
after cardiac arrest.67 in addition, a positive correlation
was observed between increasing β-blocker dose and
survival.67 selection bias in the treatment group could,
however, potentiate the positive effect of β-blockers on
survival, as patients with very poor cardiac function,
low blood pressure, and/or intradialytic hypotension
might not be prescribed these drugs.67 in the absence of
large multicenter, randomized controlled trials to evaluate the benefits of β-blockers in patients with CKD, the
indications for these agents derived from patients without
renal disease should be applied to those with CKD.
Renin–angiotensin system blockers
suppression of the renin–angiotensin–aldosterone
system could be an effective approach to reduce cardiovascular risk in patients on dialysis. However, few studies
on the effect of angiotensin-converting-enzyme (aCe)
inhibitors and angiotensin ii receptor blockers (arBs) on
cardiovascular and sudden death have been conducted in
patients undergoing dialysis. in a small randomized controlled trial of 80 patients undergoing hemodialysis, who
had no clinical evidence of cardiac disease, use of the
angiotensin ii type-1 receptor blocker candesartan was
associated with a reduced incidence of cardiovascular
events and mortality compared with placebo (46.3%
versus 53.8%).68 the use of aCe inhibitors and arBs was
associated with a significantly reduced risk of sudden
cardiac death after 6 months of treatment (adjusted or
0.51, 95% Ci 0.28–0.95, P = 0.03) in survivors of a cardiac
arrest.67 a positive correlation was observed between the
dose of aCe inhibitor and/or arB and survival.67
Furthermore, the investigators of the renaal trial
have reported that use of the arB losartan is associated
with reduced incidence of first hospitalization for congestive heart failure in patients with nondialysis-requiring
CKD.69 Conversely, the FosiDial study,70 a placebocontrolled randomized trial of prevalent hemodialysis
patients with established lvH, did not show a substantial adjusted effect of the aCe inhibitor fosinopril on the
primary end point—combined fatal and nonfatal first
cardiovascular events—in the intention to treat analysis (rr 0.93, 95% Ci 0.68–1.26, P = 0.35) or in the per
protocol analysis (adjusted rr 0.79, 95% Ci 0.59–1.10,
P = 0.099). However, this study was underpowered for
the primary event rate.70 Furthermore, patients assigned
to the treatment group had a higher baseline risk (such
as lvH, coronary artery disease, diabetes, and duration on hemodialysis) than the control group.70 Cohort
studies have not shown a notable association between
the use of aCe inhibitors and cardiovascular outcomes
or death,71–73 but these trials are limited by selection bias
inherent in the study design. in light of above mentioned
limitations and in the absence of large, double-blinded
randomized controlled trials in patients undergoing
dialysis, the use of aCe inhibitors, arBs, or both should
follow indications derived from trials in patients without
renal disease.
increased availability of angiotensin ii in the tissues
of incident hemodialysis patients with genotype D of the
aCe gene has been associated with an increased risk of
cardiovascular death.74 if this association is confirmed,
this genotype may be a useful marker for identifying
CKD patients at increased risk of cardiovascular death.
Dialysis dose
Higher dialysis dose may control volume overload,
improve the uremic milieu, diminish levels of inflammatory markers and reduce lvH and lv dilation, thereby
reducing the risk of sudden cardiac death.
nature reviews | nephrology
volume 7 | marCH 2011 | 151
© 2011 Macmillan Publishers Limited. All rights reserved
in the Hemodialysis (Hemo) study,75 1,846 patients
undergoing three times weekly hemodialysis sessions
were randomly assigned to low (standardized Kt/v
1.25) versus high (standardized Kt/v 1.65) dialysis doses,
and low versus high flux membrane; no major benefit
of either intervention on mortality was observed. the
rrs of all-cause mortality in the high versus low-dose
group and high versus low flux membrane group were
1.11 (95% Ci 0.89–1.37, P = 0.30) and 1.04 (95% Ci
0.84–126, P = 0.30), respectively.75 However, daily hemodialysis could potentially reduce cardiovascular events
or mortality. although no randomized trials with hard
clinical end points have been undertaken, Culleton et al.
have demonstrated improvement in lv mass index in
those randomly allocated to daily dialysis compared to
conventional dialysis.76
in conclusion, currently there are insufficient data
to make any recommendations about increasing dialysis dose to reduce the risk of sudden cardiac death in
patients with esrD.
Automated external defibrillators
a total of 110 cardiac arrests in two hemodialysis facilities in King County, seattle, us were identified by Davis
et al. over 14 years; 65% of these events occurred during
hemodialysis sessions and were secondary to ventricular fibrillation.75 the risk of ventricular fibrillation was
much higher after the dialysis session compared with the
period during dialysis.77 most cardiac arrests occurred
on the first day after the weekend;77 76% of patients who
arrested died immediately in the dialysis unit or in hospital, while only 15% survived for more than 1 year.77
34 cardiac arrests occurred after an automated external
defibrillator (aeD) was made available within the dialysis units.77 However, these aeDs were only used in 50%
of these arrests.77 a shock was delivered on 83% of the
occasions when the aeD was used.77 survival to hospital
discharge was not notably different between patients who
arrested before or after aeD was provided at the dialysis
unit.77 although data do not exist to support a survival
benefit of aeD placement in dialysis centers, it seems
reasonable to provide aeDs for use in patients who want
resuscitation if they arrest.
Implantable cardioverter-defibrillators
Cardioverter-defibrillator implantation decreases the risk
of sudden cardiac death, but the majority of trials using
these devices have excluded patients with advanced renal
insufficiency.78–80 Dasgupta et al. reported complication
rates for cardiac rhythm management devices (permanent
pacemakers or implantable cardioverter-defibrillators
[iCDs]) in 41 patients with esrD and in 123 control
participants without esrD.80 major complications (such
as pneumothorax requiring a chest tube, pocket infection
requiring device extraction, or thrombosis) occurred in
29% of esrD patients versus 5% of controls (P <0.001),
while minor complications occurred in 17% of esrD
patients versus 6% of controls (P <0.03). 80 no fatal
complications occurred in either group.80 Furthermore,
data suggest that patients with advanced renal insufficiency could be less responsive to iCD therapy, probably
owing to higher defibrillation thresholds.80 in a retrospective study of 230 patients who received an iCD for
primary or secondary indications, renal insufficiency was
a strong predictor of appropriate iCD shocks.81 Patients
with higher degrees of renal dysfunction were more likely
to have shorter times to iCD therapy (defined as shock
and antitachycardia pacing).81 Patients were divided
into three groups according to their serum creatinine
level (<88 μmol/l, 88–124 μmol/l, and >124 μmol/l).
the 1-year incidence of appropriate iCD shock was
3.8%, 10.8%, and 22.7% in these groups, respectively
(P = 0.003). the 1-year incidence of any appropriate iCD
therapy was 8.8%, 20.8%, and 26.3% (P = 0.02).81 serum
creatinine was an independent predictor of the time to
first appropriate iCD shock (Hr 6.0 for the third group
compared with the first group, P = 0.001) or first appropriate iCD therapy (Hr 3.0 for the third compared with
the first group, P = 0.015).81 seven patients (3%) were on
hemodialysis at the time of device implantation.81 these
patients experienced more appropriate iCD shocks for
documented ventricular tachyarrhythmias than those not
undergoing dialysis (57% versus 11%, P = 0.006).81 the
1-year incidence of appropriate iCD shock was 37.5% for
patients on dialysis and 10.7% for those not on dialysis
(P <0.0001), and the 1-year incidence of any appropriate
iCD therapy for patients on dialysis versus those not on
dialysis was 33.3% versus 16.5% (P = 0.0005).81
in a study by Cuculic and colleagues, 229 patients
who received an iCD for primary prevention of sudden
cardiac death were stratified by CKD, defined as serum
creatinine ≥176.8 μmol/l or on dialysis.82 1-year survival
for patients with (n = 35) and without (n = 194) CKD
was 61.2% and 96.3%, respectively (P <0.00001). 82
CKD was the most significant independent predictor
of mortality (Hr 10.5, 95% Ci 4.8–23.1, P <0.00001).82
Furthermore, each 10 ml/min drop in serum creatinine
clearance was associated with a 55% rise in the Hr of
death (P <0.0001).82 the investigators of this study concluded that in patients receiving an iCD for primary
prevention of sudden cardiac death, CKD significantly
reduced long-term survival which may limit the impact
of iCD therapy in this patient population.
a decision analysis and markov modeling of whether
or not to implant a cardioverter-defibrillator for primary
prevention of sudden cardiac death in patients with
CKD83 found that the benefit of iCD use depends primarily on the patient’s age, and secondarily on the stage
of kidney disease. iCDs reduce mortality in patients with
stage 1 and 2 CKD, whereas the benefit is less notable
in patients with stage 3–5 CKD, and the effect is age
dependent. 83 these findings could be attributed to a
higher procedural risk and complications in addition to
decreased life expectancy in patients with advanced CKD
compared with control individuals.83
with a standard procedural mortality of 0.5% per
procedure, cardioverter-defibrillator implantation is
preferential in patients aged <80 years for stage 3 CKD
(GFr 30–59 ml/min/1.73 m2), ages <75 years for stage 4
152 | MARCH 2011 | voluMe 7
© 2011 Macmillan Publishers Limited. All rights reserved
CKD (GFr 15–29 ml/min/1.73 m2), and ages <65 years
for stage 5 CKD (GFr <15 ml/min/1.73 m2).83 thus,
advanced stages of CKD and older age favor the ‘no iCD’
strategy.83 no health technology assessment of iCD use
in patients with CKD is available. However, a study published in 2005 showed that prophylactic cardioverterdefibrillator implantation in patients with heart failure
has a cost-effectiveness ratio below us$100,000 per
quality-adjusted life year gained, provided that iCDs
reduced mortality for 7 years or more.84
CKD is a risk factor for sudden cardiac death. the rate of
sudden cardiac death is very high in patients undergoing
dialysis. Cardiomyopathy and ischemic heart disease
predispose to conduction abnormalities and arrythmogenesis, which can be exacerbated by electrolyte shifts,
sympathetic overactivity, and baroreflex abnormalities.
inflammatory markers and diabetes are predictors of
sudden death. Cardiac arrests in dialysis units occur
in 7 per 100,000 hemodialysis sessions and are associated with the underutilization of automated external
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Review criteria
Material for this article was obtained from the Cochrane
Library, MEDLINE, PubMed, Medical Subject Headings,
and UpToDate databases, the American Society of
Nephrology website, the websites of the Journal of the
American Society of Nephrology, Clinical Journal of
the American Society of Nephrology, Kidney International,
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C. P. Vega, University of California, Irvine, CA, is the
author of and is solely responsible for the content of
the learning objectives, questions and answers of the
MedscapeCME-accredited continuing medical
education activity associated with this article.
Author contributions
M. K. Shamseddin and P. S. Parfrey contributed
equally to all aspects of this manuscript.
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