Cardiovascular Impact in Patients Undergoing Maintenance Hemodialysis:
Clinical Management Considerations

Srisakul Chirakarnjanakorn, Sankar D. Navaneethan, Gary S. Francis,

W.H. Wilson Tang

PII: S0167-5273(17)30034-7
DOI: doi:10.1016/j.ijcard.2017.01.015
Reference: IJCA 24380

To appear in: International Journal of Cardiology

Received date: 5 September 2016

Revised date: 29 December 2016
Accepted date: 3 January 2017

Please cite this article as: Chirakarnjanakorn Srisakul, Navaneethan Sankar D., Francis
Gary S., Wilson Tang WH, Cardiovascular Impact in Patients Undergoing Maintenance
Hemodialysis: Clinical Management Considerations, International Journal of Cardiology
(2017), doi:10.1016/j.ijcard.2017.01.015

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
 ACCEPTED MANUSCRIPT

Cardiovascular Impact in Patients Undergoing Maintenance Hemodialysis:

Clinical Management Considerations

Srisakul Chirakarnjanakorn, MD1, 3, Sankar D. Navaneethan, MD MS2, Gary S. Francis,

PT
MD4, W.H. Wilson Tang, MD1

RI
1. Kaufman Center for Heart Failure, Heart and Vascular Institute, Cleveland Clinic,

Cleveland, OH

SC
2. Section of Nephrology, Department of Medicine, Baylor College of Medicine,

NU
Houston, TX

3. Division of Cardiology, Department of Medicine, Siriraj Hospital, Mahidol

MA
University, Bangkok, Thailand

4. Division of Cardiovascular Disease, University of Minnesota

D
TE

Short Title: The Heart in Maintenance Hemodialysis

Acknowledgments: None
P

Funding: Dr. Tang is supported in part by grants from the National Institutes of Health
CE

(R01HL103931).
AC

Conflict of Interest: None

Correspondence:

W.H. Wilson Tang, MD

Department of Cardiovascular Medicine, Desk J3-4

Cleveland Clinic

9500 Euclid Avenue

Cleveland, OH 44195

Tel: (216) 444-2121 / Fax: (216) 445-6165 / E-mail: [email protected]

1
 ACCEPTED MANUSCRIPT

ABSTRACT

Patients undergoing maintenance hemodialysis develop both structural and functional

cardiovascular abnormalities. Despite improvement of dialysis technology,

PT
cardiovascular mortality of this population remains high. The pathophysiological

RI
mechanisms of these changes are complex and not well understood. It has been

postulated that several non-traditional, uremic-related risk factors, especially the long-

SC
term uremic state, which may affect the cardiovascular system. There are many

NU
cardiovascular changes that occur in chronic kidney disease including left ventricular

hypertrophy, myocardial fibrosis, microvascular disease, accelerated atherosclerosis

MA
and arteriosclerosis. These structural and functional changes in patients receiving

chronic dialysis make them more susceptible to myocardial ischemia. Hemodialysis

D
TE

itself may adversely affect the cardiovascular system due to non-physiologic fluid

removal, leading to hemodynamic instability and initiation of systemic inflammation. In

P

the past decade there has been growing awareness that pathophysiological
CE

mechanisms cause cardiovascular dysfunction in patients on chronic dialysis, and there

AC

are now pharmacological and non-pharmacological therapies that may improve the poor

quality of life and high mortality rate that these patients experience.

Keywords: End stage renal disease, hemodialysis, cardiovascular complications

2
 ACCEPTED MANUSCRIPT

INTRODUCTION

In the United States there currently are more than 400,000 patients receiving

maintenance hemodialysis treatment. Despite recent improvement in dialysis process,

PT
patients receiving maintenance dialysis still have high hospitalization rates, poor quality

RI
of life, and high mortality. The all-cause mortality of this patient group remains more
(1)
than 20% a year and is 10 times greater than that of the general population . The 5-

SC
year survival rate is only about 40% irrespective of the dialysis mode, which is worse

NU
(1, 2)
than many types of cancer . Cardiovascular mortality accounts for 40% of all-cause

mortality in this group, and the majority of deaths are due to heart failure, acute
MA
myocardial infarction, and fatal arrhythmia (1, 3, 4).

The characteristics of cardiovascular dysfunction observed in dialysis patients

D
TE

are distinct from those noted in the general population. Although traditional

cardiovascular risk factors in patients with end stage renal disease (ESRD) are highly
P

prevalent, they play only a partial role on the excessive cardiovascular morbidity and
CE

mortality of this population. The paradoxical association between several traditional risk
AC

factors, such as body mass index, blood pressure (BP) and serum cholesterol, and
(5)
mortality have been previously reported . Moreover, several studies have failed to

demonstrate the benefit of statin therapy on cardiovascular mortality in the dialysis

population despite the fact that statin therapy has benefit on cardiovascular survival in
(6-8)
patients with chronic kidney disease (CKD) . Moreover hemodialysis itself has been

recognized to be a cause of hemodynamic instability, where intolerance is largely due to

the inability to maintain effective circulating volume rather than directly from uremia. We

postulate that repeated myocardial micro-injury during maintenance hemodialysis may

3
 ACCEPTED MANUSCRIPT

lead to irreversible cardiac dysfunction and subsequent heart failure and death in some

patients.

The objective of this review is to provide: (i) an overview of the pathological

PT
changes of the cardiovascular system in ESRD, (ii) a description of the putative

RI
pathophysiological mechanisms of hemodialysis-induced myocardial injury and

comprehensive overview of the current evidence for this condition and (iii) evidence-

SC
based management strategies that may off-set these cardiovascular risks.

NU
Cardiovascular changes in uremic patients
MA
Bidirectional interactions between the cardiovascular and renal systems play a

role in the maintenance of hemodynamic stability, blood volume and vascular tone. The
D
TE

primary dysfunction of one organ leads to progressive decline in both organ systems

and is referred to as the cardiorenal system. Reno-cardiac syndrome (so-called "Type

P

4" cardiorenal syndrome) has been defined as the development of secondary

CE

cardiovascular dysfunction following primary kidney disease. The pathophysiological

AC

mechanisms are complex and not completely understood. Several ESRD-related

factors, including activation of the renin-angiotensin-aldosterone system (RAAS),

sympathetic nervous system, abnormality of calcium-phosphate metabolism, oxidative

stress as well as accumulation of uremic toxin, drive the development of cardiovascular

dysfunction. These changes include cardiomyopathy (uremic cardiomyopathy), Left

ventricular (LV) hypertrophy, myocardial fibrosis, impaired diastolic filling, and

microvascular coronary disease. Vascular changes that include atherosclerosis, vessel

calcification and loss of vascular elasticity are shown in Figure 1.

4
 ACCEPTED MANUSCRIPT

Uremic cardiomyopathy

Left ventricular hypertrophy. LV hypertrophy is the most common cardiac finding

(9)
in dialysis patients, and it is nearly universal . It results from chronic volume and

PT
(10, 11)
pressure overload, neurohormonal activation and uremic toxin accumulation .

RI
Hypertrophy is typically a compensatory response of the left ventricle to increased

afterload, and LV hypertrophy acts to maintain wall stress in the face of long-term

SC
altered loading conditions. Continuing LV overload eventually can lead to structural

NU
(12)
changes in the LV and apoptosis of cardiomyocytes . Hypertrophied hearts have

reduced coronary blood flow reserve and are more subject to myocardial ischemia. Left
MA
atrial enlargement is universal, and atrial fibrillation is common.

Interstitial fibrosis. Diffuse interstitial cardiac fibrosis is demonstrated in uremic

D

(13-15)
TE

patients and is not totally explained by excessive non-renal hypertension . Several

other factors contribute to this fibrosis, including excessive RAAS activity,

P

hyperphosphatemia, parathyroid hormone, oxidative stresses, uremic toxins and cellular

CE

(10)
senescence . Interstitial collagen deposition likely contributes to ventricular diastolic
AC

dysfunction, impaired LV filling, and predisposes to atrial and ventricular arrhythmias

(16)
. This may explain the increased risk of sudden cardiac death (SCD) in uremic

patients.

Microvascular disease. At least 30% of dialysis patients with angina have only
(17)
moderate epicardial coronary artery disease (CAD) . However, endothelial

dysfunction with microvascular disease may occur. There are coronary functional

changes (increase in extra-coronary resistance secondary to LV hypertrophy and

endothelial dysfunction) and structural changes (wall thickening with reduced arteriolar

5
 ACCEPTED MANUSCRIPT

(10, 15, 18-21)

lumen of intramyocardial arteries and reduced cardiac capillary density) .

Myocardium-capillary mismatch is not specific to uremia and is not just a consequence

of hypertension with LV hypertrophy. Microvascular coronary disease exposes

PT
cardiomyocytes to the risk of hypoxemia under the condition of high oxygen demand or
(15, 20)

RI
low oxygen supply . In fact, there may be ongoing ischemic myocardial injury at

the microvascular level, which could explain why many of these patients have

SC
persistently elevated serum troponin levels.

NU
Uremic vasculopathy
MA
Atherosclerosis. In uremic patients, there are two different but overlapping

macrovascular changes: atherosclerosis and arteriosclerosis. Atherosclerosis is a

D
TE

primarily intimal disorder of medium-sized arteries characterized by plaque formation

and subsequently narrowing and occlusion of the vessels resulting in impaired conduit
P

(22)
function . The unique characteristics of coronary atheroma in ESRD patients are
CE

(23)
increased medial thickness and markedly calcified plaques . These changes lead to
AC

chronic myocardial ischemia, and subsequently development of myocardial fibrosis,

SCD and heart failure, rather than acute plaque rupture. This observation may explain
(24)
the unexpected low incidence of acute myocardial infarction in this population .

A high atherosclerotic burden in uremic patients is well established. Although the

traditional atherosclerotic risk factors are common in this setting, they only partially

contribute to increased cardiovascular burden (5, 25). Several randomized controlled trials

(RCTs) of statin therapy have failed to demonstrate a reduction in cardiovascular

(6, 8, 26)
outcomes in the hemodialysis population . A plausible explanation is that non-

6
 ACCEPTED MANUSCRIPT

traditional uremic-related risk factors, including chronic inflammation, oxidative stress

and activation of the RAAS, may play an important role in this setting (27, 28).

Arteriosclerosis. Arteriosclerosis, a hallmark of arterial remodeling in ESRD, is

PT
characterized by diffuse calcification in combination with dilatation and increased wall

RI
thickness of the medial layer of the aorta and its main branches leading to increased
(29)
arterial stiffness . Disturbance of calcium-phosphorus homeostasis, leading to

SC
hypocalcemia, hyperphosphatemia and secondary hyperparathyroidism, as well as

NU
uremic toxins may lead to accelerated calcification of arterial media and active
(30)
osteogenic differentiation of vascular smooth muscle cells .
MA
Consequences of uremic vasculopathy. The arterial system has two important
(29)
functions: conduit and cushioning . The latter function requires a compliant arterial
D
TE

tree to ensure that the pulsatile flow in large arteries maintains steady continuous
(31)
perfusion to peripheral organs without exposure to peak systolic pressures . When
P

aortic stiffening is markedly increased as in arteriosclerosis, loss of the cushioning effect

CE

occurs resulting in loss of the ability of the aorta to accommodate the ejected blood
AC

volume from the LV. This subsequently leads to an increase in augmentation of systolic

BP, whereas diastolic BP is lower due to a decrease in reservoir effect. There is an

increased stroke volume run-off during systole and less blood volume to be drained
(29, 32)
during diastole . While increasing systolic BP leads to an increase in afterload

contributing LV hypertrophy and increased myocardial oxygen consumption, decreasing

diastolic BP leads to decrease in diastolic coronary perfusion. These could lead to

subsequent myocardial ischemia, impaired diastolic function and decreased systolic

7
 ACCEPTED MANUSCRIPT

function. Moreover, increased systolic BP as well as increased pulse pressure lead to a

vicious cycle and more arterial stiffness (33).

PT
Effects of arteriovenous fistula on the cardiovascular system

RI
Arteriovenous (AV) fistula is the preferred vascular access for long-term
(34)
hemodialysis given its high blood flow rate, patency, and low infection risk and

SC
association with lower all-cause and cardiovascular mortality as compared to AV graft or

NU
(35)
central venous catheter . However, flow-related cardiovascular complications can

occur and are usually under-recognized. Creation of AV access shunts the blood from
MA
peripheral tissue, leading to instantaneous reduction in systemic vascular resistance.

Circulatory compensation subsequently occurs to maintain systemic BP and peripheral

D
TE

perfusion by activating the RAAS and sympathetic systems, enhancing the venous

return and increasing heart rate, and, in turn, leading to an increase in cardiac output
P

(34, 36)
and pulmonary pressure . Cardiac output typically rises equivalent to AV access
CE

(37)
blood flow of 1-2 L/min at rest and 3-4 L/min in the setting of high flow fistula and can
AC

increase as much as 10-12 L/min during exertion (38, 39).

A persistent high-output state accompanied by neurohormonal activation and

increased vascular stiffness in uremia may promote progressive LV hypertrophy and LV

chamber dilatation. This can occur as soon as within 2 weeks after creation of an AV
(40)
fistula . Hemodynamic stress represented by elevation of plasma atrial and brain

natriuretic peptides after creation of AV fistula has also been demonstrated in both
(38, 40)
animal experiments and in patients with CKD . Furthermore, increased oxygen

demand caused by increased LV mass in the setting of impaired coronary flow reserve,

8
 ACCEPTED MANUSCRIPT

as well as decreased diastolic BP, can lead to subendocardial myocardial ischemia after
(41)
formation of an AV fistula . High-output heart failure as defined by systemic or

pulmonary venous congestion combined with high cardiac output at rest of greater than

PT
8 L/min or a cardiac index of greater than 3.9 L/min/m 2 (42) can occur in ESRD patients

RI
with AV fistula. However, the true incidence of this condition in patients on chronic

dialysis has not been well described. Nevertheless, high blood flow across an AV fistula,

SC
(43)
defined by AV access blood flow of more than 2 L/min or the ratio of AV access flow

NU
(44)
to cardiac output of more than 0.3 , has been demonstrated to be at greater risk of

developing high-output heart failure. Awareness of this condition in ESRD patients is

MA
important as the vasodilatory effects of current standard neurohormonal antagonists

may cause deterioration of hypotension. Additionally, interventions to reduce the

D
TE

vascular access blood flow, including banding of the AV fistula or revision using a distal

inflow technique, can be effective in some patients with high-flow AV fistula by

P

(45, 46)
improving cardiac structure and hemodynamics and thereby reversing heart
CE

(47)
failure symptoms . However particular attention should be taken when considering
AC

AV access closure in patients with severe heart failure. Sudden death after surgical AV

fistula ligation in a renal transplant recipient who had severe heart failure has been

reported, believed to be caused by a sudden increase in systemic vascular resistance

after vascular fistula closure (48).

Pathogenesis of hemodialysis-induced myocardial injury

Hemodialysis has been used for decades in patients with advanced renal failure

to aid in the removal of uremic toxins from the blood and to correct metabolic

9
 ACCEPTED MANUSCRIPT

disturbances. Ultrafiltration is used to maintain volume control by removal of salt and

water excess. Although hemodialysis should theoretically improve cardiovascular

abnormalities in patients with uremia by correcting volume overload, cardiovascular

PT
mortality remains high despite improvements in dialysis technology. Several studies of

RI
conventional hemodialysis have failed to demonstrate LV hypertrophy regression of

vascular calcification or survival, suggesting inadequacy of uremic toxin clearance and

SC
failure to reduce adverse effects of hemodialysis on the cardiovascular system. Yet

NU
nocturnal or longer duration of hemodialysis has been associated with reduction in LV

hypertrophy and improved survival, suggesting the way we perform hemodialysis has
MA
major implications on long-term outcomes.

.
D
TE

Hemodialysis as Hemodynamic stressor

The rationale of thrice-weekly conventional hemodialysis is based on a

P

combination of physiological experiments, assessment of patient acceptance, feasibility,

CE

(49)
logistics and costs . Over the past decade, high-flux dialyzers have been commonly
AC

used in clinical practice, and urea removal can now be achieved more rapidly. Therefore

the length of a dialysis session has gradually diminished and more rapid fluid removal is

necessitated. Most dialysis patients have interdialytic weight gain of more than 1.5 kg,
(50)
and up to 40% gain more than 3 kg . Ultrafiltration may also produce rapidly non-

physiological fluid removal within a limited time and may promote hemodynamic

instability, either as an initiating event or a contributing insult to injury. During

hemodialysis, intravascular fluid is removed directly and counterbalanced by refilling

from the interstitial fluid compartment; the rapidly contracted circulating blood volume

10
 ACCEPTED MANUSCRIPT

that occurs when the fluid removal rate is greater than the plasma refilling rate can be

counter-productive. When cardiac preload is reduced in the setting of maladaptive

cardiovascular remodeling in uremic patients, it may contribute to intradialytic

PT
hypotension and subsequently impaired myocardial perfusion and injury. Intradialytic

RI
hypotension is found in as many as 15-25% of hemodialysis sessions and is to be

avoided, as it is predictive of increased mortality (51, 52).

SC
Impaired baroreceptor sensitivity and imbalance of sympathetic-parasympathetic

NU
activities in both at rest and during exercise, and has been demonstrated in CKD
(53-55)
patients . Autonomic function, especially the baroreceptor arc, is an important
MA
regulatory mechanism to maintain hemodynamic stability during hemodialysis, and

attenuated baroreceptor sensitivity can sometimes lead to intolerable symptoms during

D

(56, 57)
TE

hemodialysis . Reduced baroreceptor sensitivity is also related to worsening

outcomes in dialysis patients (58).

P

Activation of inflammatory response. Some investigators postulate that

CE

hemodialysis-induced transient LV systolic dysfunction may be produced by a systemic

AC

inflammatory response to hemodialysis. This response is due to the interaction between

blood and the hemodialysis membrane, synthetic vascular graft or catheter, exposure to
(59)
contaminated dialysate and vascular access infection . Inflammatory biomarkers are

substantially increased in uremic patients and are associated with increased risks of all-
(60, 61)
cause and cardiac mortalities in dialysis patients . Several studies reported

increase in circulating inflammatory markers including interleukin-6 and pentraxin during

(62, 63)
single session hemodialysis . A recent study also reported that predialysis

inflammatory markers including high sensitivity C-reactive protein, and the ratio of

11
 ACCEPTED MANUSCRIPT

interleukin-6 and 10 levels were independently associated with hemodialysis-induced

(63)
regional LV systolic dysfunction . Another possibility is hemodialysis-induced

systemic circulatory stress and recurrent regional ischemia of gut leading to endotoxin

PT
translocation. Endotoxin, a pro-inflammatory stimulus, has also been demonstrated to

RI
be correlated with myocardial stunning and elevated predialysis cardiac troponin T

(cTnT) levels (64).

SC
Hemodialysis-induced myocardial injury. Functional and structural abnormalities

NU
of the cardiovascular system in uremic patients may predispose the myocardium to

become ischemic even in asymptomatic patients. Approximately 70% of dialysis

MA
(65, 66)
patients with angiographically proven CAD were without angina . Absence of

ischemic symptoms may be caused by diabetic and uremic autonomic neuropathy, as

D

(67)
TE

well as reduction of exercise capacity . Subclinical myocardial ischemia during

hemodialysis is not uncommon as evidenced by several studies that are summarized in

P

Table 1.
CE

Electrocardiographic changes. Silent myocardial ischemia, defined by

AC

asymptomatic dynamic ST-T changes suggestive of ischemia, has been repeatedly

(68-72)
reported with a prevalence of 16-60% . Interestingly, studies where coronary

angiograms were performed found no correlation between silent ischemia and

(69, 72)
angiographic findings . This may be explained by the existence of microcirculatory

changes in the coronary system in ESRD. Some authors also raised the possibility of

coronary vasospasm contributed by neurohormonal perturbations and release of

(72)
vasoactive cytokines during dialysis . However, the frequent occurrence of abnormal

electrocardiograms found in dialysis patients, especially LV hypertrophy, may make

12
 ACCEPTED MANUSCRIPT

electrocardiographic interpretation difficult, and electrolyte changes during dialysis may

also contribute ST changes that resemble ischemia (73).

Reduction in global and segmental myocardial blood flow. McIntyre et al. studied

PT
4 dialysis patients (3 diabetic) without angiographically significant CAD and assessed

their intradialytic myocardial blood flow (MBF) by using H215O positron emission

RI
(74)
tomography . Concurrent echocardiography was used to evaluate LV function and

SC
regional wall motion abnormalities (RWMAs). Global MBF was acutely reduced during

NU
the dialysis session, progressively worsened overtime and partially restored after the

30-min recovery phase. Reduction in segmental MBF was significantly greater in

MA
segments with RWMAs, and a reduction in MBF of >30% from baseline was associated

with the development of RWMAs. These were confirmed by Dasselaar et al. who
D
TE

evaluated 7 relatively lower-risk, stable, non-diabetic patients with uneventful cardiac

(75)
histories . Significantly reduced global MBF without new RWMAs was observed 30
P

minutes after starting hemodialysis; there was a small cumulative ultrafiltration volume
CE

and insignificant change in hemodynamics at that time of reduced MBF.

AC

Segmental abnormalities of left ventricular systolic function. Burton et al. studied

70 hemodialysis patients, 40% with diabetes, using serial intradialytic echocardiography

(76)
to evaluate RWMAs . Sixty-four percent developed new or worsening RWMAs at the

fourth-hour of dialysis and partially returned towards pre-dialysis in the recovery period

which may imply the development of myocardial stunning. In multivariate analysis, age,

reduction in systolic BP, ultrafiltration volume and cTnT were independently associated

with hemodialysis-induced RWMAs. Interestingly, the risk associated with greater fluid

removal and decrease in systolic BP increased disproportionately with each additional

13
 ACCEPTED MANUSCRIPT

unit of measure. Ultrafiltration volume of 1 liter was associated with 5-fold greater risk of

development of hemodialysis-induced RWMAs, whereas the risk rose 26-fold for a 2-

liter fluid removal. This might be related to potential hemoconcentration with

PT
subsequently increasing microcirculatory shear stress and reduced microcirculatory
(7)

RI
blood flow, a potential exacerbating cause of myocardial ischemia . However, another

small (n=40) study did not find this association between either changes in BP,

SC
ultrafiltration volume or cTnT with the occurrence of hemodialysis-induced RWMAs, and

NU
only a history of heart failure was independently associated with this myocardial
(77)
ischemia . Assa et al. found only 27% of 105 dialysis patients developed
MA
hemodialysis-induced regional LV systolic dysfunction, and there was no significant

difference of intradialytic blood volume change between those with or without

D

hemodialysis-induced RWMAs.(78) This corresponds with findings in the previous study

TE

regarding reduction of MBF where there was no significant change in ultrafiltration

P

(75)
volume . Non-hemodynamic factors including inflammation, electrolyte shifts, acid-
CE

(75, 79)
base shifts or dialysis-induced temperature changes may play a role .
AC

Long-term consequences of hemodialysis induced myocardial injury. Myocardial

stunning after prolonged myocardial ischemia followed by return of myocardial perfusion

has been demonstrated in patients with CAD. Repetitive myocardial ischemia and

stunning may lead to irreversible LV systolic dysfunction and heart failure. Several

studies have reported the association of all-cause mortality and progressive heart failure

in patients with hemodialysis-induced myocardial stunning. Burton et al. observed that

patients with hemodialysis-induced myocardial stunning had significantly increased

mortality at 12 months.(76) Assa et al. confirmed significant increase in all-cause

14
 ACCEPTED MANUSCRIPT

(78)
mortality with adjusted hazard ratio of 4.6 . Moreover, patients with hemodialysis-

induced RWMAs who were alive at 12 months had a significantly decreased LV ejection

fraction (62.1±11.4% vs. 54.7±10.1%, p<0.001), whereas the LV ejection fraction of

PT
(76)
those without hemodialysis-induced RWMAs remained unchanged .

RI
Cardiac arrhythmias and sudden cardiac death

SC
(80)
The risk of SCD increases with a progressive deterioration of kidney function .

NU
It has been demonstrated that when estimated glomerular filtration rate (eGFR) was

less than 60 ml/min/1.73 m2, the risk of SCD increased 11% for each 10 ml/min/1.73 m2
MA
decline in eGFR (81). SCD is accountable for 26.5% of all-cause mortality, and about half
(82)
of cardiovascular death in ESRD patients is related to arrhythmias or SCD . The risk
D
TE

of SCD in hemodialysis patients is estimated to be 20- to 30-fold higher than in

population with normal kidney function, especially in the first 9 months after initiating the
P

(83, 84)
therapy which is known to be the period of heightened SCD risk . The incidence of
CE

SCD is higher in patients with hemodialysis when compared to the peritoneal dialysis.
AC

The pathogenesis or SCD in this population is thought to be multifactorial. Structural

and functional changes of cardiovascular system in patients with ESRD, as mentioned

before, play an important role in developing cardiac arrhythmias. Rapid blood volume

and electrolyte shifts, especially in potassium and calcium homeostasis, may also

contribute to abnormalities. These cause hemodynamic stress during hemodialysis as

well as mechanical and electrical alteration of cardiac myocytes, which may lead to

intra- and inter-dialytic arrhythmias and also increase the risk of SCD in patients

undergoing hemodialysis, especially during the initiation of this therapy. The increased

15
 ACCEPTED MANUSCRIPT

risk of SCD is related to longer dialytic intervals in patients undergoing hemodialysis

three times a week which may be explained by extreme fluid and electrolyte shifts
(83, 85, 86)
during this period . Although the incidence of SCD in this population from the

PT
(87)
national registry data seems to reduce , the number remains relatively high and the

RI
research studying the treatment strategy to decrease SCD and improve outcomes in

this population is still limited.

SC
CKD and ESRD patients undergoing dialysis is at risk for developing

NU
arrhythmias, especially atrial fibrillation and ventricular arrhythmias. There is limited

data regarding the actual burden of arrhythmias in patients with ESRD. In the Chronic
MA
(88)
Renal Insufficiency Cohort study, atrial fibrillation was found about 18% . In study of

non-dialysis CKD patients, the risk of atrial fibrillation increased for 1.51-2.86 times
D
TE

compared to subjects with normal renal function, and was associated to the degree of
(89)
renal impairment . CKD patients with atrial fibrillation have poorer outcomes than
P

those without atrial fibrillation, similar to the non-CKD population. Atrial fibrillation does
CE

not only increase risk of stroke of 9.8 fold in patients undergoing hemodialysis, but is
AC

(90)
also the independent risk for sudden death . Anticoagulation therapy to prevent the

thromboembolic complications also increases hemorrhagic risk and is complicated to

anticoagulation given during hemodialysis.

Therapeutic Interventions

Part of high cardiovascular morbidity and mortality in the ESRD population may

be related to the fact that risk-modifying interventions are underutilized compared to the

non-dialysis population. There may be potential fears of metabolic toxicity and

16
 ACCEPTED MANUSCRIPT

hemodynamic instability. Most randomized clinical trials usually exclude patients with

advanced renal impairment from their studies. Moreover applying the proven treatment

strategies from a non-dialysis population directly to dialysis patients may be

PT
inappropriate because of the different pathophysiology and altered drug metabolism.

RI
Pharmacological therapy

SC
Several neurohormonal blocking agents and statins are of proven benefit in the

NU
non-CKD population, especially with heart failure and CAD. However their benefit in

hemodialysis patients is still not clarified. Randomized controlled trials of these

MA
medications in hemodialysis patients are summarized in Tables 2 and 3.

Renin-angiotensin-aldosterone system blockade. Angiotensin-converting

D
TE

enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have

demonstrated benefit on reduction of LV hypertrophy and arterial stiffness of

P

(91-93)
hemodialysis patients in small non-randomized studies and also in recent meta-
CE

(94)
analyses . However their benefit on long-term cardiovascular mortality in patients
AC

receiving chronic hemodialysis is limited. A double-blind RCT, FOSIDIL (the Fosinopril

in Dialysis study), studied 397 hemodialysis patients with LV hypertrophy who were

ACEI naïve and indicated that fosinopril did not achieve statistically significant

improvement of the 2-year composite outcomes of fatal first major cardiovascular

events (95).

A small open-label RCT by Takahashi et al. in 80 hemodialysis patients showed

candesartan was effective in improvement of survival and composite cardiovascular

(96)
outcomes . However, two larger open-label randomized trials conducted recently by

17
 ACCEPTED MANUSCRIPT

(97) (98)
Suzuki et al. and Iseki et al. in hemodialysis patients demonstrated lack of

efficacy of ARB therapy, as shown in Table 3.

The beneficial effects of add on ARBs therapy to standard therapy (including

PT
ACEIs) in a hemodialysis population with heart failure was demonstrated in a study by
(99)

RI
Cice et al. . A double-blind RCT in 322 hemodialysis patients with moderate heart

failure and LV ejection fraction ≤40% indicated that the addition of telmisartan in

SC
addition to standard therapy of heart failure (100% ACEIs, 60% beta-blockers) led to a

NU
significant reduction in all-cause mortality (reduced 49%), and hospitalization due to

heart failure was reduced by 81% with a mean follow-up of 2 years. However,
MA
combining ACE inhibitors and ARBs in patients with ESRD is not recommended. There

are no RCT data available on add-on ARB therapy in ESRD patients without heart
D
TE

failure.

A recently published open-label randomized trial by Matsumoto et al. evaluated

P

the effect of low-dose spironolactone on cardiovascular and cerebrovascular outcomes

CE

in 309 hemodialysis patients. Spironolactone was associated with a 64% reduction in 3-

AC

year all-cause mortality, and also reduced cardiovascular and cerebrovascular events.

However the sample size was small and the study was not blinded. A larger, double-

blind RCT, ALCHEMIST (ALdosterone Antagonist Chronic HEModialysis Interventional

Survival Trial), is underway and may provide additional data on the safety and efficacy

of spironolactone in hemodialysis patients (100).

There have been obvious concerns about risks of hypotension and hyperkalemia

when using RAAS blockade and aldosterone antagonist in dialysis patients. In a study

of add-on telmisartan to standard therapy in hemodialysis patients with heart failure

18
 ACCEPTED MANUSCRIPT

(who are quite susceptible to developing hypotension), hypotension developed in 10.9%

of the telmisartan group compared to 4.2% of the placebo group (p<0.005). However

the beneficial effects of add-on ARB therapy on survival and cardiac function seemed to

PT
offset the risks of hypotension in this study Most studies of hemodialysis patients

RI
receiving spironolactone and/or ACEIs/ARBs demonstrated a modest rise in serum

potassium with only a small number of drug discontinuations because of hyperkalemia

SC
(99, 101-103)
. Moreover a novel polymeric potassium binder, patiromer (RLY5016), was

NU
recently demonstrated to prevent hyperkalemia in patients with heart failure receiving
(104)
standard therapy with spironolactone . This may provide a future strategy that will
MA
allow safer inhibition of RAAS in this population.

Beta-blockers. Beta-blockers have substantial mortality benefits in patients with

D
TE

acute coronary syndromes and heart failure. Because there may be subclinical

myocardial ischemia in patients on hemodialysis with a high prevalence of CAD, heart

P

failure and sympathetic over activity in the setting of ESRD, it may theoretically be
CE

possible to reduce hemodialysis-induced myocardial injury and mortality in ESRD

AC

patients. Cice et al. conducted an open-label RCT and studied the efficacy of carvedilol

in 114 dialysis patients with dilated cardiomyopathy, LVEF<35% and NYHA II-III (98%

on ACEIs, 2% on ARBs). Carvedilol significantly improved the 2-year cardiovascular

(105)
mortality and improved LV function and morphology . There are no RCT data

available on beta-blocker therapy in ESRD patients without heart failure. Based on

inconclusive results from multiple cohort studies, the benefit of beta-blocker used in
(106-108)
dialysis patients is still debated . Further large clinical trials would be necessary

to bring clarity to this debate.

19
 ACCEPTED MANUSCRIPT

Statins. Statin therapy has been widely used to prevent cardiovascular events in

the non-dialysis population. There have been two large-scale double-blind RCTs of

statin therapy in patients undergoing hemodialysis, Die Deutsche Diabetes Dialyse

PT
(6)
Studie (4D) and Study to Evaluate the Use of Rosuvastatin in Subjects on Regular
(26)

RI
Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) .

These trials have failed to demonstrate the benefit of statin therapy. The Study of Heart

SC
and Renal Protection (SHARP) study reported the effectiveness and safety of

NU
simvastatin plus ezetimibe in significant reduction of the major atherosclerotic events in
(8)
various stages of CKD . However, the subgroup analysis of dialysis patients in this
MA
study did not achieve success in improving the primary endpoint. The plausible

explanation for the negative study in dialysis patients is likely the unique pathology and
D
TE

pathophysiology of cardiovascular abnormalities in this population. Moreover, the

relationship between cardiovascular disease and conventional risk factors is poorly

P

(109)
correlated . Lower baseline cholesterol levels in these patients may be a marker of
CE

an inflamed and malnourished state, which is associated with decreased survival (110).
AC

Changing renal replacement therapy modality

Today, conventional hemodialysis is the most common modality used to treat ESRD

patients. However, other modalities of renal replacement therapy may be more effective

in removing uremic toxins, and may be gentler on volume removal and myocardial

stunning. Effectiveness and impact of the different dialysis modalities and renal

transplantation are shown in Table 4.

20
 ACCEPTED MANUSCRIPT

Peritoneal dialysis. Peritoneal dialysis theoretically has advantages beyond

conventional hemodialysis due to continuous fluid removal with better hemodynamic

stability, better preservation of residual renal function, improved clearance of medium-

PT
(111)
size uremic toxins and less systemic inflammation . Peritoneal dialysis may be the

RI
modality of choice, especially for patients with CAD and heart failure. Moreover, existing

evidence is controversial. LV hypertrophy is more severe and more frequent in patients

SC
receiving peritoneal dialysis because of subclinical over-hydration with resultant

NU
(112)
hypertension . However, development of icodextrin and hypertonic dialysate solution
(113)
use now allows for better control of volume status and less LV hypertrophy . Results
MA
of multiple, large observational cohort studies comparing the long-term outcomes of

ESRD patients treated with hemodialysis or peritoneal dialysis have been inconsistent
D

(114-117)
TE

. The most recent contemporary study in the United States demonstrated

(117)
insignificant differences in the 5-year survival between these two modalities ,
P

whereas from the French REIN registry, all-cause mortality in patients with peritoneal
CE

dialysis was greater than those treated with hemodialysis (85). The ongoing RCT in
AC

China named Comparison of the Impact of Dialysis Treatment Type on Patient Survival

study (ClinicalTrials.gov identifier: NCT00510549) may provide additional data

regarding this controversy.

Intensive hemodialysis. Existing evidence has demonstrated advantages of

intensive hemodialysis on several surrogate outcomes including improved BP control,

(49,
reduced LV mass, reduced intradialytic hypotension and improved phosphate control
118)
. Intensive hemodialysis is defined by more frequent and/or longer duration of

dialysis session. In general, intensive hemodialysis is when the duration of each dialysis

21
 ACCEPTED MANUSCRIPT

(119)
session is more than 5.5 hours and/or 3 to 7 times per week . The RCT by Culleton

et al. indicated regression of LV mass in patients receiving frequent nocturnal

(118)
hemodialysis . The Frequent Hemodialysis Network (FHN) Daily trial also

PT
demonstrated that frequent in-center hemodialysis 6 times per week improved the

RI
composite outcomes of death, LV mass and quality of life when compared to the

conventional hemodialysis, even though this strategy had more frequent interventions

SC
(49)
related to vascular access . However the FHN Nocturnal trial did not demonstrate

NU
that frequent nocturnal hemodialysis 5-6 times a week improved either death or LV

mass, or death or quality of life (120). Table 5 summarizes major randomized clinical trials
MA
of intensive hemodialysis.

It is not known if there is a survival benefit of intensive hemodialysis. Because of

D
TE

the inadequate power of existing RCTs to identify a survival benefit, multiple large-scale

propensity score matched cohort studies have been recently conducted (Table 6). Most
P

studies demonstrated reduction of mortality by 13-45% in patients receiving intensive

CE

hemodialysis, while the latest study showed that patients with in-center daily
AC

hemodialysis had an increase in 1.5-year mortality with a hazard ratio of 1.6 (119, 121-123).

Why intensive hemodialysis might improve outcomes in ESRD patients is

unclear. Longer and/or more frequent hemodialysis sessions have multiple

advantageous effects including effective improvement in fluid removal with reduction in

the ultrafiltration rate and less intradialytic hypotension. There is also more effective
(124)
clearance of middle-sized uremic toxins (such as β2-microglobulin) and phosphorus .

These observations may help explain why intensive hemodialysis may improve

cardiovascular abnormalities in uremic patients. Moreover, reduction in the ultrafiltration

22
 ACCEPTED MANUSCRIPT

rate may help reduce subclinical myocardial ischemia during dialysis. McIntyre and

colleagues conducted a cross-sectional study performing intradialytic echocardiography

in 46 patients and demonstrated that intradialytic hypotension and RWMAs were

PT
reduced in patients receiving frequent dialysis. There was also a trend toward lower

predialysis cTnT and NT-proBNP levels in the home-based dialysis groups (125).

RI
Online hemodiafiltration. Retention of middle- to large-sized uremic toxins

SC
appears to be an important in the pathogenesis of cardiovascular dysfunction of uremic

NU
patients. Conventional hemodialysis with low-flux membranes can remove only low

molecular weight molecules by diffusive transport. Despite use of high-flux membranes,

MA
which is a standard hemodialysis technique used in the United States at the present,

and enables the removal of larger uremic toxins by convective transport, though the
D

(126)
TE

amount of convection is uncontrollable and unpredictable . Two large-scale RCTs

did not demonstrate survival benefits of high-flow over low-flux hemodialysis (2, 127).
P

Hemodiafiltration, which integrates high-flux hemodialysis and the ultrafiltration of

CE

large amounts of plasma water, can increase the magnitude of convection transport.
AC

With the advanced online water treatment systems developed recently, high convection

and sterile substitution volume can be achieved safely, resulting in markedly augmented
(126)
removal of middle-sized uremic toxins . Advantages of hemodiafiltration have been

documented including better control of anemia, more effective removal of phosphate,

improved lipid profiles, reduced inflammation and oxidative stress, as well as lower
(128)
incidence of intradialytic hypotension . Two recent large-scale, open-label RCTs, the
(126)
Convective Transport Study (CONTRAST) and the Comparison of Post-dilution
(129)
Online Hemodiafiltration and Hemodialysis (Turkish OL-HDF) study , demonstrated

23
 ACCEPTED MANUSCRIPT

a trend towards improved survival using online hemodiafiltration over low- and high-flux

hemodialysis, respectively. Although these studies failed to achieve statistical

significance on the mortality outcomes, their post-hoc analysis showed a 39% and 46%

PT
risk reduction in mortality in patients treated with high convection volume. The most

RI
recent RCT, the On-Line Hemodiafiltration Survival Study (ESHOL), which achieved

higher convection volume than two earlier studies, demonstrated a 30% reduction in all-

SC
cause mortality of online hemodiafiltration compared to conventional high-flux

NU
(130)
hemodialysis with the number needed to treat being 8 to prevent 1 annual death .

The mortality reduction was mainly due to significant reduction in stroke and infection-
MA
related mortality. The incidence of intradialytic hypotension was also significantly lower

in the online hemodiafiltration arm. The survival benefit could be explained by more
D
TE

efficient removal of middle-sized and protein-bound uremic toxins which may impact on

endothelial function, inflammatory state, vascular calcification, as well as have

P

(130)
cardioprotective effects . Table 7 summarizes the clinical trials of online
CE

hemodiafiltration on mortality outcomes.

AC

Renal transplantation

Renal transplantation has been proven to have significant survival benefit beyond

dialysis. Adjusted rate of all-cause mortality reduces from 6.5-7.9 fold in the dialysis

population to 1-1.5 fold in renal transplant patients compared to individuals in the

(1)
general population . Improvement of LV function and structure after renal transplant
(131, 132)
has been reported in several studies . Interestingly, Wali et al. reported marked

improvement in LV ejection fraction, as well as functional status and survival after

24
 ACCEPTED MANUSCRIPT

kidney transplant in ESRD patients with systolic heart failure. Effective removal of

uremic toxins, including myocardial suppressants, as well as improvement of the

inflammatory state and anemia may explain some of the benefits of kidney

PT
transplantation (132).

RI
Conclusions and Future Perspectives

SC
Cardiovascular dysfunction in patients receiving hemodialysis impacts on global

NU
health and economic burdens. ESRD has been increasingly recognized as having a

grave prognosis and lack of an evidence-based treatment strategy. Despite data

MA
indicating the benefits of neurohormonal inhibition in this condition, especially when

there is heart failure, ACEIs and beta-blockers are prescribed in only 44% and 66%,
D

(1)
TE

respectively in US . Moreover, in routine clinical practice, most BP-lowering

medications are frequently stopped in the morning of hemodialysis days in order to

P

maintain hemodynamic stability throughout the hemodialysis session. Further

CE

investigations regarding how to better optimize medical therapy in this vulnerable

AC

population are much needed.

FIGURE LEGENDS

Figure 1: Pathophysiology of hemodialysis-induced myocardial injury

Abbreviations: AV, arterio-venous; AGE, advanced glycation end product; RAAS, renin

angiotensin aldosterone system; SNS, sympathetic nervous system.

25
 ACCEPTED MANUSCRIPT

REFERENCES

1. Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Ishani A, et al. US

PT
Renal Data System 2013 Annual Data Report. Am J Kidney Dis 2014; 63: A7.

RI
2. Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW, et al.

SC
Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med

2002; 347: 2010-9.

NU
3. de Jager DJ, Grootendorst DC, Jager KJ, van Dijk PC, Tomas LM, Ansell D, et
MA
al. Cardiovascular and noncardiovascular mortality among patients starting dialysis.

JAMA 2009; 302: 1782-9.

D

4. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular

TE

disease in chronic renal disease. Am J Kidney Dis 1998; 32: S112-9.

P

5. Kalantar-Zadeh K, Block G, Humphreys MH, Kopple JD. Reverse epidemiology

CE

of cardiovascular risk factors in maintenance dialysis patients. Kidney Int 2003; 63: 793-

808.
AC

6. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al. Atorvastatin

in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;

353: 238-48.

7. Breidthardt T, McIntyre CW. Dialysis-induced myocardial stunning: the other side

of the cardiorenal syndrome. Rev Cardiovasc Med 2011; 12: 13-20.

8. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The

effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with

26
 ACCEPTED MANUSCRIPT

chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-

controlled trial. Lancet 2011; 377: 2181-92.

9. Foley RN, Parfrey PS, Harnett JD, Kent GM, Martin CJ, Murray DC, et al. Clinical

PT
and echocardiographic disease in patients starting end-stage renal disease therapy.

RI
Kidney Int 1995; 47: 186-92.

10. Gross ML, Ritz E. Hypertrophy and fibrosis in the cardiomyopathy of uremia--

SC
beyond coronary heart disease. Semin Dial 2008; 21: 308-18.

NU
11. Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Wang BH, Krum H. Does

indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and
MA
myocytes? Eur Heart J 2010; 31: 1771-9.

12. Ikram H, Lynn KL, Bailey RR, Little PJ. Cardiovascular changes in chronic
D
TE

hemodialysis patients. Kidney Int 1983; 24: 371-6.

13. Mall G, Huther W, Schneider J, Lundin P, Ritz E. Diffuse intermyocardiocytic

P

fibrosis in uraemic patients. Nephrol Dial Transplant 1990; 5: 39-44.

CE

14. Mall G, Rambausek M, Neumeister A, Kollmar S, Vetterlein F, Ritz E. Myocardial

AC

interstitial fibrosis in experimental uremia--implications for cardiac compliance. Kidney

Int 1988; 33: 804-11.

15. Amann K, Breitbach M, Ritz E, Mall G. Myocyte/capillary mismatch in the heart of

uremic patients. J Am Soc Nephrol 1998; 9: 1018-22.

16. Bakth S, Arena J, Lee W, Torres R, Haider B, Patel BC, et al. Arrhythmia

susceptibility and myocardial composition in diabetes. Influence of physical conditioning.

J Clin Invest 1986; 77: 382-95.

27
 ACCEPTED MANUSCRIPT

17. Rostand SG, Kirk KA, Rutsky EA. The epidemiology of coronary artery disease in

patients on maintenance hemodialysis: implications for management. Contrib Nephrol

1986; 52: 34-41.

PT
18. Tok D, Gullu H, Erdogan D, Topcu S, Ciftci O, Yildirim I, et al. Impaired coronary

RI
flow reserve in hemodialysis patients: a transthoracic Doppler echocardiographic study.

Nephron Clin Pract 2005; 101: c200-6.

SC
19. Amann K, Wiest G, Zimmer G, Gretz N, Ritz E, Mall G. Reduced capillary density

NU
in the myocardium of uremic rats--a stereological study. Kidney Int 1992; 42: 1079-85.

20. Tyralla K, Amann K. Cardiovascular changes in renal failure. Blood Purif 2002;
MA
20: 462-5.

21. Meyer C, Heiss C, Drexhage C, Kehmeier ES, Balzer J, Muhlfeld A, et al.

D
TE

Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and

impairs vascular function. J Am Coll Cardiol 2010; 55: 454-9.

P

22. London GM, Drueke TB. Atherosclerosis and arteriosclerosis in chronic renal
CE

failure. Kidney Int 1997; 51: 1678-95.

AC

23. Schwarz U, Buzello M, Ritz E, Stein G, Raabe G, Wiest G, et al. Morphology of

coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial

Transplant 2000; 15: 218-23.

24. Herzog CA. Sudden cardiac death and acute myocardial infarction in dialysis

patients: perspectives of a cardiologist. Semin Nephrol 2005; 25: 363-6.

25. Coresh J, Longenecker JC, Miller ER, 3rd, Young HJ, Klag MJ. Epidemiology of

cardiovascular risk factors in chronic renal disease. J Am Soc Nephrol 1998; 9: S24-30.

28
 ACCEPTED MANUSCRIPT

26. Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et

al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl

J Med 2009; 360: 1395-407.

PT
27. Moody WE, Edwards NC, Madhani M, Chue CD, Steeds RP, Ferro CJ, et al.

RI
Endothelial dysfunction and cardiovascular disease in early-stage chronic kidney

disease: cause or association? Atherosclerosis 2012; 223: 86-94.

SC
28. Drueke TB, Massy ZA. Atherosclerosis in CKD: differences from the general

NU
population. Nat Rev Nephrol 2010; 6: 723-35.

29. London GM, Marchais SJ, Guerin AP. Arterial stiffness and function in end-stage
MA
renal disease. Adv Chronic Kidney Dis 2004; 11: 202-9.

30. Chue CD, Townend JN, Steeds RP, Ferro CJ. Arterial stiffness in chronic kidney
D
TE

disease: causes and consequences. Heart 2010; 96: 817-23.

31. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et

P

al. Expert consensus document on arterial stiffness: methodological issues and clinical
CE

applications. Eur Heart J 2006; 27: 2588-605.

AC

32. Davies JE, Parker KH, Francis DP, Hughes AD, Mayet J. What is the role of the

aorta in directing coronary blood flow? Heart 2008; 94: 1545-7.

33. O'Rourke M. Mechanical principles in arterial disease. Hypertension 1995; 26: 2-

9.

34. MacRae JM, Pandeya S, Humen DP, Krivitski N, Lindsay RM. Arteriovenous

fistula-associated high-output cardiac failure: a review of mechanisms. Am J Kidney Dis

2004; 43: e17-22.

29
 ACCEPTED MANUSCRIPT

35. Wasse H, Speckman RA, McClellan WM. Arteriovenous fistula use is associated

with lower cardiovascular mortality compared with catheter use among ESRD patients.

Semin Dial 2008; 21: 483-9.

PT
36. Holman E. Abnormal arteriovenous communications. Great variability of effects

RI
with particular reference to delayed development of cardiac failure. Circulation 1965; 32:

1001-9.

SC
37. Wasse H, Singapuri MS. High-output heart failure: how to define it, when to treat

NU
it, and how to treat it. Semin Nephrol 2012; 32: 551-7.

38. Iwashima Y, Horio T, Takami Y, Inenaga T, Nishikimi T, Takishita S, et al. Effects

MA
of the creation of arteriovenous fistula for hemodialysis on cardiac function and

natriuretic peptide levels in CRF. Am J Kidney Dis 2002; 40: 974-82.

D
TE

39. Bailey WB, Talley JD. High-output cardiac failure related to hemodialysis

arteriovenous fistula. J Ark Med Soc 2000; 96: 340-1.

P

40. Ori Y, Korzets A, Katz M, Perek Y, Zahavi I, Gafter U. Haemodialysis

CE

arteriovenous access--a prospective haemodynamic evaluation. Nephrol Dial

AC

Transplant 1996; 11: 94-7.

41. Savage MT, Ferro CJ, Sassano A, Tomson CR. The impact of arteriovenous

fistula formation on central hemodynamic pressures in chronic renal failure patients: a

prospective study. Am J Kidney Dis 2002; 40: 753-9.

42. Anand IS, Florea VG. High Output Cardiac Failure. Curr Treat Options

Cardiovasc Med 2001; 3: 151-9.

30
 ACCEPTED MANUSCRIPT

43. Basile C, Lomonte C, Vernaglione L, Casucci F, Antonelli M, Losurdo N. The

relationship between the flow of arteriovenous fistula and cardiac output in

haemodialysis patients. Nephrol Dial Transplant 2008; 23: 282-7.

PT
44. Pandeya S, Lindsay RM. The relationship between cardiac output and access

RI
flow during hemodialysis. ASAIO J 1999; 45: 135-8.

45. van Duijnhoven EC, Cheriex EC, Tordoir JH, Kooman JP, van Hooff JP. Effect of

SC
closure of the arteriovenous fistula on left ventricular dimensions in renal transplant

NU
patients. Nephrol Dial Transplant 2001; 16: 368-72.

46. Movilli E, Viola BF, Brunori G, Gaggia P, Camerini C, Zubani R, et al. Long-term
MA
effects of arteriovenous fistula closure on echocardiographic functional and structural

findings in hemodialysis patients: a prospective study. Am J Kidney Dis 2010; 55: 682-9.
D
TE

47. Parmar CD, Chieng G, Abraham KA, Kumar S, Torella F. Revision using distal

inflow for treatment of heart failure secondary to arteriovenous fistula for hemodialysis. J
P

Vasc Access 2009; 10: 62-3.

CE

48. Pascual J, Martins J, Bouarich H, Galeano C, Barrios V, Marcen R, et al. Sudden

AC

death after arteriovenous fistula ligation in a renal transplant patient. Ann Vasc Surg

2008; 22: 134-5.

49. Chertow GM, Levin NW, Beck GJ, Depner TA, Eggers PW, Gassman JJ, et al.

In-center hemodialysis six times per week versus three times per week. N Engl J Med

2010; 363: 2287-300.

50. Kalantar-Zadeh K, Regidor DL, Kovesdy CP, Van Wyck D, Bunnapradist S,

Horwich TB, et al. Fluid retention is associated with cardiovascular mortality in patients

undergoing long-term hemodialysis. Circulation 2009; 119: 671-9.

31
 ACCEPTED MANUSCRIPT

51. Tisler A, Akocsi K, Borbas B, Fazakas L, Ferenczi S, Gorogh S, et al. The effect

of frequent or occasional dialysis-associated hypotension on survival of patients on

maintenance haemodialysis. Nephrol Dial Transplant 2003; 18: 2601-5.

PT
52. Shoji T, Tsubakihara Y, Fujii M, Imai E. Hemodialysis-associated hypotension as

RI
an independent risk factor for two-year mortality in hemodialysis patients. Kidney Int

2004; 66: 1212-20.

SC
53. Robinson TG, Carr SJ. Cardiovascular autonomic dysfunction in uremia. Kidney

NU
Int 2002; 62: 1921-32.

54. Chesterton LJ, Sigrist MK, Bennett T, Taal MW, McIntyre CW. Reduced
MA
baroreflex sensitivity is associated with increased vascular calcification and arterial

stiffness. Nephrol Dial Transplant 2005; 20: 1140-7.

D
TE

55. Fotbolcu H, Duman D, Ecder SA, Oduncu V, Cevik C, Tigen K, et al. Attenuated

cardiovascular response to sympathetic system activation during exercise in patients

P

with dialysis-induced hypotension. Am J Nephrol 2011; 33: 491-8.

CE

56. Barnas MG, Boer WH, Koomans HA. Hemodynamic patterns and spectral
AC

analysis of heart rate variability during dialysis hypotension. J Am Soc Nephrol 1999;

10: 2577-84.

57. Chesterton LJ, Selby NM, Burton JO, Fialova J, Chan C, McIntyre CW.

Categorization of the hemodynamic response to hemodialysis: the importance of

baroreflex sensitivity. Hemodial Int 2010; 14: 18-28.

58. Fukuta H, Hayano J, Ishihara S, Sakata S, Mukai S, Ohte N, et al. Prognostic

value of heart rate variability in patients with end-stage renal disease on chronic

haemodialysis. Nephrol Dial Transplant 2003; 18: 318-25.

32
 ACCEPTED MANUSCRIPT

59. Clementi A, Virzi GM, Goh CY, Cruz DN, Granata A, Vescovo G, et al.

Cardiorenal syndrome type 4: a review. Cardiorenal Med 2013; 3: 63-70.

60. Meuwese CL, Stenvinkel P, Dekker FW, Carrero JJ. Monitoring of inflammation

PT
in patients on dialysis: forewarned is forearmed. Nat Rev Nephrol 2011; 7: 166-76.

RI
61. Zhang W, He J, Zhang F, Huang C, Wu Y, Han Y, et al. Prognostic role of C-

reactive protein and interleukin-6 in dialysis patients: a systematic review and meta-

SC
analysis. J Nephrol 2013; 26: 243-53.

NU
62. Yamamoto T, Nascimento MM, Hayashi SY, Qureshi AR, Waniewski J, Brodin

LA, et al. Changes in circulating biomarkers during a single hemodialysis session.

MA
Hemodial Int 2013; 17: 59-66.

63. Assa S, Hummel YM, Voors AA, Kuipers J, Westerhuis R, Groen H, et al.
D
TE

Hemodialysis-Induced Regional Left Ventricular Systolic Dysfunction and Inflammation:

A Cross-sectional Study. Am J Kidney Dis 2013.

P

64. McIntyre CW, Harrison LE, Eldehni MT, Jefferies HJ, Szeto CC, John SG, et al.
CE

Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular

AC

disease in chronic kidney disease. Clin J Am Soc Nephrol 2011; 6: 133-41.

65. Koch M, Gradaus F, Schoebel FC, Leschke M, Grabensee B. Relevance of

conventional cardiovascular risk factors for the prediction of coronary artery disease in

diabetic patients on renal replacement therapy. Nephrol Dial Transplant 1997; 12: 1187-

91.

66. Braun WE, Phillips DF, Vidt DG, Novick AC, Nakamoto S, Popowniak KL, et al.

Coronary artery disease in 100 diabetics with end-stage renal failure. Transplant Proc

1984; 16: 603-7.

33
 ACCEPTED MANUSCRIPT

67. De Vriese AS, Vandecasteele SJ, Van den Bergh B, De Geeter FW. Should we

screen for coronary artery disease in asymptomatic chronic dialysis patients? Kidney Int

2012; 81: 143-51.

PT
68. Zuber M, Steinmann E, Huser B, Ritz R, Thiel G, Brunner F. Incidence of

RI
arrhythmias and myocardial ischaemia during haemodialysis and haemofiltration.

Nephrol Dial Transplant 1989; 4: 632-4.

SC
69. Kremastinos D, Paraskevaidis I, Voudiklari S, Apostolou T, Kyriakides Z,

NU
Zirogiannis P, et al. Painless myocardial ischemia in chronic hemodialysed patients: a

real event? Nephron 1992; 60: 164-70.

MA
70. Abe S, Yoshizawa M, Nakanishi N, Yazawa T, Yokota K, Honda M, et al.

Electrocardiographic abnormalities in patients receiving hemodialysis. Am Heart J 1996;

D
TE

131: 1137-44.

71. Conlon PJ, Krucoff MW, Minda S, Schumm D, Schwab SJ. Incidence and long-
P

term significance of transient ST segment deviation in hemodialysis patients. Clin

CE

Nephrol 1998; 49: 236-9.

AC

72. Mohi-ud-din K, Bali HK, Banerjee S, Sakhuja V, Jha V. Silent myocardial

ischemia and high-grade ventricular arrhythmias in patients on maintenance

hemodialysis. Ren Fail 2005; 27: 171-5.

73. Selby NM, McIntyre CW. The acute cardiac effects of dialysis. Semin Dial 2007;

20: 220-8.

74. McIntyre CW, Burton JO, Selby NM, Leccisotti L, Korsheed S, Baker CS, et al.

Hemodialysis-induced cardiac dysfunction is associated with an acute reduction in

global and segmental myocardial blood flow. Clin J Am Soc Nephrol 2008; 3: 19-26.

34
 ACCEPTED MANUSCRIPT

75. Dasselaar JJ, Slart RH, Knip M, Pruim J, Tio RA, McIntyre CW, et al.

Haemodialysis is associated with a pronounced fall in myocardial perfusion. Nephrol

Dial Transplant 2009; 24: 604-10.

PT
76. Burton JO, Jefferies HJ, Selby NM, McIntyre CW. Hemodialysis-induced cardiac

RI
injury: determinants and associated outcomes. Clin J Am Soc Nephrol 2009; 4: 914-20.

77. Dubin RF, Beatty AL, Teerlink JR, Schiller NB, Bolger AF, Alokozai D, et al.

SC
Determinants of hemodialysis-induced segmental wall motion abnormalities. Hemodial

NU
Int 2013.

78. Assa S, Hummel YM, Voors AA, Kuipers J, Westerhuis R, de Jong PE, et al.
MA
Hemodialysis-induced regional left ventricular systolic dysfunction: prevalence, patient

and dialysis treatment-related factors, and prognostic significance. Clin J Am Soc

D
TE

Nephrol 2012; 7: 1615-23.

79. Toussaint N, Cooney P, Kerr PG. Review of dialysate calcium concentration in

P

hemodialysis. Hemodial Int 2006; 10: 326-37.

CE

80. Kannel WB, Wilson PW, D'Agostino RB, Cobb J. Sudden coronary death in
AC

women. Am Heart J 1998; 136: 205-12.

81. Pun PH, Smarz TR, Honeycutt EF, Shaw LK, Al-Khatib SM, Middleton JP.

Chronic kidney disease is associated with increased risk of sudden cardiac death

among patients with coronary artery disease. Kidney Int 2009; 76: 652-8.

82. Atlas of chronic kidney disease and end-stage renal disease in the United States,

national institutes of health, national institute of diabetes and digestive and kidney

disease. U.S. renal data system, USRDS 2012 annual data report.

35
 ACCEPTED MANUSCRIPT

83. Pun PH, Middleton JP. Sudden cardiac death in hemodialysis patients: a

comprehensive care approach to reduce risk. Blood Purif 2012; 33: 183-9.

84. USRDS annual data report. Bethesda, Naitonal institutes of health, national

PT
institute of diabetes and digestive and kidney diseases, 2006.

RI
85. Bleyer AJ, Hartman J, Brannon PC, Reeves-Daniel A, Satko SG, Russell G.

Characteristics of sudden death in hemodialysis patients. Kidney Int 2006; 69: 2268-73.

SC
86. Bleyer AJ, Russell GB, Satko SG. Sudden and cardiac death rates in

NU
hemodialysis patients. Kidney Int 1999; 55: 1553-9.

87. US Renal Data System USRDS 2013 Annual Data Report. National Institutes of
MA
Health, National Institute of Diabetes and Digestive and Kidnay Diseases, Bethesda.

http:///www.usrds.org/2013/pdf/v2_ch4_13.pdf.
D
TE

88. Soliman EZ, Prineas RJ, Go AS, Xie D, Lash JP, Rahman M, et al. Chronic

kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort
P

(CRIC). Am Heart J 2010; 159: 1102-7.

CE

89. Baber U, Howard VJ, Halperin JL, Soliman EZ, Zhang X, McClellan W, et al.
AC

Association of chronic kidney disease with atrial fibrillation among adults in the United

States: REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

Circ Arrhythm Electrophysiol 2011; 4: 26-32.

90. Vazquez E, Sanchez-Perales C, Garcia-Garcia F, Castellano P, Garcia-Cortes

MJ, Liebana A, et al. Atrial fibrillation in incident dialysis patients. Kidney Int 2009; 76:

324-30.

91. London GM, Pannier B, Guerin AP, Marchais SJ, Safar ME, Cuche JL. Cardiac

hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage

36
 ACCEPTED MANUSCRIPT

renal disease. Comparative effects of ACE inhibition and calcium channel blockade.

Circulation 1994; 90: 2786-96.

92. Paoletti E, Cassottana P, Bellino D, Specchia C, Messa P, Cannella G. Left

PT
ventricular geometry and adverse cardiovascular events in chronic hemodialysis

RI
patients on prolonged therapy with ACE inhibitors. Am J Kidney Dis 2002; 40: 728-36.

93. Mitsuhashi H, Tamura K, Yamauchi J, Ozawa M, Yanagi M, Dejima T, et al.

SC
Effect of losartan on ambulatory short-term blood pressure variability and cardiovascular

NU
remodeling in hypertensive patients on hemodialysis. Atherosclerosis 2009; 207: 186-

90.
MA
94. Tai DJ, Lim TW, James MT, Manns BJ, Tonelli M, Hemmelgarn BR.

Cardiovascular effects of angiotensin converting enzyme inhibition or angiotensin

D
TE

receptor blockade in hemodialysis: a meta-analysis. Clin J Am Soc Nephrol 2010; 5:

623-30.
P

95. Zannad F, Kessler M, Lehert P, Grunfeld JP, Thuilliez C, Leizorovicz A, et al.

CE

Prevention of cardiovascular events in end-stage renal disease: results of a randomized

AC

trial of fosinopril and implications for future studies. Kidney Int 2006; 70: 1318-24.

96. Takahashi A, Takase H, Toriyama T, Sugiura T, Kurita Y, Ueda R, et al.

Candesartan, an angiotensin II type-1 receptor blocker, reduces cardiovascular events

in patients on chronic haemodialysis--a randomized study. Nephrol Dial Transplant

2006; 21: 2507-12.

97. Suzuki H, Kanno Y, Sugahara S, Ikeda N, Shoda J, Takenaka T, et al. Effect of

angiotensin receptor blockers on cardiovascular events in patients undergoing

37
 ACCEPTED MANUSCRIPT

hemodialysis: an open-label randomized controlled trial. Am J Kidney Dis 2008; 52:

501-6.

98. Iseki K, Arima H, Kohagura K, Komiya I, Ueda S, Tokuyama K, et al. Effects of

PT
angiotensin receptor blockade (ARB) on mortality and cardiovascular outcomes in

RI
patients with long-term haemodialysis: a randomized controlled trial. Nephrol Dial

Transplant 2013; 28: 1579-89.

SC
99. Cice G, Di Benedetto A, D'Isa S, D'Andrea A, Marcelli D, Gatti E, et al. Effects of

NU
telmisartan added to Angiotensin-converting enzyme inhibitors on mortality and

morbidity in hemodialysis patients with chronic heart failure a double-blind, placebo-

MA
controlled trial. J Am Coll Cardiol 2010; 56: 1701-8.

100. Pitt B, Rossignol P. Mineralocorticoid receptor antagonists in patients with end

D
TE

stage renal disease (ESRD ) on chronic hemodialysis. J Am Coll Cardiol 2014; 63: 537-

8.
P

101. Matsumoto Y, Mori Y, Kageyama S, Arihara K, Sugiyama T, Ohmura H, et al.

CE

Spironolactone reduces cardio- and cerebrovascular morbidity and mortality in

AC

hemodialysis patients. J Am Coll Cardiol 2014; 63: 528-36.

102. Matsumoto Y, Kageyama S, Yakushigawa T, Arihara K, Sugiyama T, Mori Y, et

al. Long-term low-dose spironolactone therapy is safe in oligoanuric hemodialysis

patients. Cardiology 2009; 114: 32-8.

103. Hussain S, Dreyfus DE, Marcus RJ, Biederman RW, McGill RL. Is spironolactone

safe for dialysis patients? Nephrol Dial Transplant 2003; 18: 2364-8.

104. Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ. Evaluation of

the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind,

38
 ACCEPTED MANUSCRIPT

placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur

Heart J 2011; 32: 820-8.

105. Cice G, Ferrara L, D'Andrea A, D'Isa S, Di Benedetto A, Cittadini A, et al.

PT
Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a

RI
prospective, placebo-controlled trial. J Am Coll Cardiol 2003; 41: 1438-44.

106. Foley RN, Herzog CA, Collins AJ. Blood pressure and long-term mortality in

SC
United States hemodialysis patients: USRDS Waves 3 and 4 Study. Kidney Int 2002;

NU
62: 1784-90.

107. Abbott KC, Trespalacios FC, Agodoa LY, Taylor AJ, Bakris GL. Beta-blocker use
MA
in long-term dialysis patients: association with hospitalized heart failure and mortality.

Arch Intern Med 2004; 164: 2465-71.

D
TE

108. Kitchlu A, Clemens K, Gomes T, Hackam DG, Juurlink DN, Mamdani M, et al.

Beta-blockers and cardiovascular outcomes in dialysis patients: a cohort study in

P

Ontario, Canada. Nephrol Dial Transplant 2012; 27: 1591-8.

CE

109. Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic

AC

renal failure. Lancet 2000; 356: 147-52.

110. Liu Y, Coresh J, Eustace JA, Longenecker JC, Jaar B, Fink NE, et al. Association

between cholesterol level and mortality in dialysis patients: role of inflammation and

malnutrition. JAMA 2004; 291: 451-9.

111. Sens F, Schott-Pethelaz AM, Labeeuw M, Colin C, Villar E. Survival advantage

of hemodialysis relative to peritoneal dialysis in patients with end-stage renal disease

and congestive heart failure. Kidney Int 2011; 80: 970-7.

39
 ACCEPTED MANUSCRIPT

112. Enia G, Mallamaci F, Benedetto FA, Panuccio V, Parlongo S, Cutrupi S, et al.

Long-term CAPD patients are volume expanded and display more severe left ventricular

hypertrophy than haemodialysis patients. Nephrol Dial Transplant 2001; 16: 1459-64.

PT
113. Konings CJ, Kooman JP, Schonck M, Gladziwa U, Wirtz J, van den Wall Bake

RI
AW, et al. Effect of icodextrin on volume status, blood pressure and echocardiographic

parameters: a randomized study. Kidney Int 2003; 63: 1556-63.

SC
114. Liem YS, Wong JB, Hunink MG, de Charro FT, Winkelmayer WC. Comparison of

NU
hemodialysis and peritoneal dialysis survival in The Netherlands. Kidney Int 2007; 71:

153-8.
MA
115. Huang CC, Cheng KF, Wu HD. Survival analysis: comparing peritoneal dialysis

and hemodialysis in Taiwan. Perit Dial Int 2008; 28 Suppl 3: S15-20.

D
TE

116. McDonald SP, Marshall MR, Johnson DW, Polkinghorne KR. Relationship

between dialysis modality and mortality. J Am Soc Nephrol 2009; 20: 155-63.
P

117. Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar

CE

outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal
AC

disease. Arch Intern Med 2011; 171: 110-8.

118. Culleton BF, Walsh M, Klarenbach SW, Mortis G, Scott-Douglas N, Quinn RR, et

al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left

ventricular mass and quality of life: a randomized controlled trial. JAMA 2007; 298:

1291-9.

119. Nesrallah GE, Lindsay RM, Cuerden MS, Garg AX, Port F, Austin PC, et al.

Intensive hemodialysis associates with improved survival compared with conventional

hemodialysis. J Am Soc Nephrol 2012; 23: 696-705.

40
 ACCEPTED MANUSCRIPT

120. Rocco MV, Lockridge RS, Jr., Beck GJ, Eggers PW, Gassman JJ, Greene T, et

al. The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis

Network Nocturnal Trial. Kidney Int 2011; 80: 1080-91.

PT
121. Lacson E, Jr., Xu J, Suri RS, Nesrallah G, Lindsay R, Garg AX, et al. Survival

RI
with three-times weekly in-center nocturnal versus conventional hemodialysis. J Am Soc

Nephrol 2012; 23: 687-95.

SC
122. Weinhandl ED, Liu J, Gilbertson DT, Arneson TJ, Collins AJ. Survival in daily

NU
home hemodialysis and matched thrice-weekly in-center hemodialysis patients. J Am

Soc Nephrol 2012; 23: 895-904.

MA
123. Suri RS, Lindsay RM, Bieber BA, Pisoni RL, Garg AX, Austin PC, et al. A

multinational cohort study of in-center daily hemodialysis and patient survival. Kidney Int
D
TE

2013; 83: 300-7.

124. Mehrotra R, Himmelfarb J. Dialysis in 2012: Could longer and more frequent
P

haemodialysis improve outcomes? Nat Rev Nephrol 2013; 9: 74-5.

CE

125. Jefferies HJ, Virk B, Schiller B, Moran J, McIntyre CW. Frequent hemodialysis
AC

schedules are associated with reduced levels of dialysis-induced cardiac injury

(myocardial stunning). Clin J Am Soc Nephrol 2011; 6: 1326-32.

126. Grooteman MP, van den Dorpel MA, Bots ML, Penne EL, van der Weerd NC,

Mazairac AH, et al. Effect of online hemodiafiltration on all-cause mortality and

cardiovascular outcomes. J Am Soc Nephrol 2012; 23: 1087-96.

127. Locatelli F, Martin-Malo A, Hannedouche T, Loureiro A, Papadimitriou M,

Wizemann V, et al. Effect of membrane permeability on survival of hemodialysis

patients. J Am Soc Nephrol 2009; 20: 645-54.

41
 ACCEPTED MANUSCRIPT

128. Canaud B, Bowry SK. Emerging clinical evidence on online hemodiafiltration:

does volume of ultrafiltration matter? Blood Purif 2013; 35: 55-62.

129. Ok E, Asci G, Toz H, Ok ES, Kircelli F, Yilmaz M, et al. Mortality and

PT
cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux

RI
dialysis: results from the Turkish OL-HDF Study. Nephrol Dial Transplant 2013; 28: 192-

202.

SC
130. Maduell F, Moreso F, Pons M, Ramos R, Mora-Macia J, Carreras J, et al. High-

NU
efficiency postdilution online hemodiafiltration reduces all-cause mortality in

hemodialysis patients. J Am Soc Nephrol 2013; 24: 487-97.

MA
131. Burt RK, Gupta-Burt S, Suki WN, Barcenas CG, Ferguson JJ, Van Buren CT.

Reversal of left ventricular dysfunction after renal transplantation. Ann Intern Med 1989;
D
TE

111: 635-40.

132. Wali RK, Wang GS, Gottlieb SS, Bellumkonda L, Hansalia R, Ramos E, et al.
P

Effect of kidney transplantation on left ventricular systolic dysfunction and congestive

CE

heart failure in patients with end-stage renal disease. J Am Coll Cardiol 2005; 45: 1051-
AC

60.

42
 ACCEPTED MANUSCRIPT

Table 1: Review of prospective observational studies on hemodialysis-induced myocardial injury in patients with
maintenance hemodialysis

PT
RI
First Author, Study Design Main Findings
Year (Ref #)

SC
Studies on dynamic ST-T changes during hemodialysis

NU
Zuber et al., Intradialytic ECG ECG changes of ischemia found in 25% with half of them were

MA
1989 (68). monitoring (n = 32) asymptomatic and ischemia occurred predominantly during the last hour
of hemodialysis session

ED
Kremastinos et Intradialytic ECG ECG changes of ischemia found in 16% during and immediately after
al., 1992 (69). monitoring (n = 45) dialysis and no correlation of silent myocardial ischemia with the existence

PT
of cardiac dysfunction and angiographic proven CAD
CE
Abe et al., 1996 Intradialytic ECG ECG changes of ischemia found in 60%; ST depression in 43%, elevation
AC

(70)
. monitoring (n = 72) in 11%, and T inversion in 6%.

Conlon et al., Intradialytic ECG Asymptomatic transient ST depression developed in 23% during
1998 (71). monitoring (n = 70) hemodialysis and not significantly associated with 2-year survival

Mohi-ud-din K Intradialytic ECG Asymptomatic transient ST depression developed in 22% during

et al., 2005 (72). monitoring (n = 70) hemodialysis and not associated with angiographic evidenced CAD

Studies on reduction of MBF during hemodialysis

43
 ACCEPTED MANUSCRIPT

McIntyre et al., Intradialytic MBF Acutely reduction of global MBF during dialysis with progressively
2008 (74). assessment by H215O PET worsening over time and partially restored during recovery phase.

PT
(n=4 without
angiographically Significantly greater reduction in segmental MBF in segments that

RI
significant CAD) developed RWMAs

SC
Dasselaar et Intradialytic MBF Acutely reduction of global MBF at 30 minutes after hemodialysis started
al., 2009 (75). assessment by 13N-NH3 with progressively worsened over time

NU
PET (n=7, non-diabetic
and no eventful cardiac Significantly greater reduction in segmental MBF in segments that

MA
histories) developed RWMAs

ED
Studies on development of echocardiographic LV wall motion abnormalities during hemodialysis

Burton et al., Intradialytic RWMA Significant RWMAs developed in 64% during hemodialysis and
2009 (76). assessment by PT
independently associated with age, UF volumes, intradialytic hypotension,
CE
echocardiography (n=70) and predialysis cTnT level. Hemodialysis-induced myocardial stunning
was significantly associated with mortality and decreased LVEF at 12
months
AC

Assa et al., Intradialytic RWMA Significant RWMAs developed in 27% during hemodialysis and did not
2012 (78). assessment by associated with changes of blood volume, BP, heart rate, electrolytes, and
echocardiography (n=105) acid–base parameters

Hemodialysis induced myocardial stunning was significantly associated

with mortality with adjusted HR of 4.6 (95% CI, 1.15-18.5; P=0.03) with
the median duration of follow-up of 16.4 months

Dubin et al., Intradialytic RWMA Significant RWMAs developed in 23% during hemodialysis and

44
 ACCEPTED MANUSCRIPT

2013 (77). assessment by independently associated with history of heart failure with adjusted HR of
echocardiography (n=105) 3.1 (95% CI, 1.1-9; P=0.04)

PT
Abbreviations: ECG, electrocardiogram; CAD, coronary artery disease; MBF, myocardial blood flow; PET, positron

RI
emission tomography; RWMAs, regional wall motion abnormalities; UF, ultrafiltration; cTnT, cardiac troponin T; LVEF, left

SC
ventricular ejection fraction; BP, blood pressure; HR, hazard ratio.

NU
MA
ED
PT
CE
AC

45
 ACCEPTED MANUSCRIPT

Table 2: Major randomized controlled trials of cardiovascular medications in hemodialysis patients with heart

PT
failure

RI
First Inclusio Interventi Du Concomitant All-cause mortality Cardiovascular HF hospitalization (%)

SC
autho n criteria on rati drugs (%) (%) mortality (%)
r, on,

NU
year ye ACE ARB BB Interv Place HR Interv Place HR Interv Place HR
(ref #) ars I entio bo (95% entio bo (95% entio bo (95%
n CI) n CI) n CI)

MA
Cice HD, Carvedilol 2 98 2 - 51.7 73.2 0.51 29.3 67.9 0.32 13.8 57.1 0.19
et al., NYHA titrated up (0.32- (0.18- (0.09-

ED
2003 II-III HF, to 25 mg 0.82) 0.57) 0.41)
(105)
. LVEF<3 twice a
5%
(n=114)
day
PT
CE

Cice HD, Telmisar 3 100 - 60 31.5 54.4 0.51 30.3 43.7 0.32 33.9 55.1 0.38
AC

et al., NYHA tan (0.32- (0.18- (0.19-

2010 II-III HF, titrated 0.82) 0.57) 0.51)
(99)
. LVEF≤4 up to 8o
0%, on mg/day
ACEI
(n=332)

46
 ACCEPTED MANUSCRIPT

Table 3: Major randomized controlled trials of cardiovascular medications in hemodialysis patients

PT
First Inclusion Intervention Durat Composite fatal and All-cause mortality (%) Cardiovascular
author, criteria ion, non-fatal mortality (%)

RI
year (ref #) years cardiovascular events

SC
Inter Place HR Interv Place HR Interv Place HR
venti bo (95%C entio bo (95%C entio bo (95%C

NU
on I) n I) n I)

MA
FOSIDIAL, HD, LVH Fosinopril 2 NA NA 0.80 - - - - - -
2006 (95). (n=397) titrated up to 20 (0.59-
mg/day 1.1)

ED
Takahashi HD (n=80) Candesartan 4- 19.4 16.3 45.9 0.29 - 18.9 NA - - -

PT
et al., 2006 8 mg/day mo (0.12-
(96)
. 0.70)
CE
Suzuki et HD, SBP Losartan up to 3 19 33 0.51 14 21 0.64 - - -
al., 2008 >160 mmHg 100 mg, or (0.33- (0.39-
AC

(97)
. or >150 candesartan up 0.79) 1.06)
mmHg if to 12 mg/day or
receiving valsartan up to
anti-HT drugs 160 mg/day
(n=366)

OCTOPUS HD, Olmesartan 10- 3.5 35.3 34 1.00 24 22.2 0.97 - - -

, 2013 (98). BP≥140/90 40 mg/day until (0.71- (0.62-
mmHg achieved target 1.40) 1.52)

47
 ACCEPTED MANUSCRIPT

(n=469) BP of <140/90
mmHg

PT
DOHAS, HD, serum K Spironolactone 3 5.7 15.1 0.40 6.4 19.7 0.36 2.5 4.6 0.57
2014 (101). <6.5 mEq/L 25 mg/day (0.20- (0.19- (.18-

RI
(n=309) 0.81) 0.66) 1.87)

SC
4D, 2005 HD, type 2 Atorvastatin 20 4 37 38 0.92 48 50 0.93 20 23 0.81
(6)
. DM, LDL 90- mg/day (0.77- (0.79- (0.64-

NU
180 mg/dL 1.10) 1.08) 1.03)
(n=1255)

MA
AURORA, HD (n=2776) Rosuvastatin 10 3.8 28.5 29.5 0.96 45.8 47.7 0.96 23.3 23.4 1.00
2009 (26). mg/day (0.84- (0.86- (0.85-

ED
1.11) 1.07) 1.16)

SHARP,
2011 (8).
CKD Cr≥1.7
mg/dL in
Simvastatin 20
mg/day plus PT
4.9 11.3 13.4 0.83
(0.74-
24.6 24.1 1.02
(0.94-
5.4 5.9 0.93
(0.78-
CE
men or 1.5 ezetimibe 10 0.94) 1.1) 1.10)
mg/dL in mg/day
AC

women

(n = 9270)

Dialysis Simvastatin 20 4.9 15 16.5 0.90 - - - - - -

subgroup mg/day plus (0.75-
(n=3023; ezetimibe 10 1.08)
HD=2527, mg/day
PD=496 )

48
 ACCEPTED MANUSCRIPT

Table 4: Effectiveness of the different dialysis modalities and renal transplantation

PT
Modality Conventional Peritoneal Intensive Hemodia- Renal

RI
hemodialysis dialysis hemodialysis filtration transplantation

SC
Uremic toxin removal + + ++ ++ +++

NU
Hemodynamic stability + ++ ++ ++ +++

MA
Effective fluid removal ++ + +++ +++ +++

ED
Improved survival and + + +/++ ++ +++

cardiovascular outcomes PT
CE
AC

49
 ACCEPTED MANUSCRIPT

Table 5: Major randomized controlled trials of changing hemodialysis modalities

PT
First author, Inclusion Intervention Durat Co-primary outcomes HR Number of complications related to

RI
year (ref #) criteria ion, (95%CI) vascular access
years

SC
Death or Death or Intervention Placebo HR
change in change in (95%CI)

NU
LV mass physical-
health

MA
composite
score

ED
FHN Daily HD In-center frequent 1 0.61 0.70 (0.53- 95 65 1.71
trial, 2010 (n=245) HD 6 times/week vs. (0.46- 0.92) (1.08-
(49)

PT
. conventional HD 3 0.82) 2.73)
times/week
CE
FHN HD Frequent nocturnal 1 0.68 0.91 (0.58- 34 21 1.88
Nocturnal (n=87) HD 6 times/week vs. (0.44- 1.43) (0.97-
AC

trial, 2011 conventional HD 3 1.07) 3.64)

(120)
. times/week

50
 ACCEPTED MANUSCRIPT

Table 6: Published large-scale observational cohort studies using propensity score matching demonstrate the

mortality risk reductions with intensive hemodialysis

PT
RI
Mean follow-up
First author, year (ref #) Modality N Mortality rate (%) HR (95%CI)

SC
time (years)

NU
Lacson et al., 2012 (121). NIHD 746 2 19 0.75 (0.61-0.91)

MA
Nesrallah et al., 2012 (119). DHHD 388 1.8 13 0.55 (0.34-0.87)

ED
Weinhandl et al., 2012 (122). DHHD 1873 1.8 19 0.87 (0.78-0.97)

Suri et al., 2012 (123). DIHD PT 318 1.5 20 1.6 (1.1-2.3)

CE
AC

Abbreviations: HR, hazard ratio; CI, confidence interval; NIHD, nocturnal in-center hemodialysis; DHHD, Daily home

hemodialysis; DIHD, Daily in-center hemodialysis.

51
 ACCEPTED MANUSCRIPT

Table 7: Major prospective randomized clinical trials of online hemodiafiltration and survival outcomes

PT
First author, Inclusion Intervention Durat Composite fatal and All-cause mortality (%) Cardiovascular mortality
year (ref #) criteria ion, non-fatal cardiovascular (%)

RI
years events (%)

SC
OL- Conve HR OL- Conve HR OL- Conve HR
HDF ntiona (95% HDF ntiona (95% HDF ntiona (95%

NU
l HD CI) l HD CI) l HD CI)

MA
CONSTRAST, Maintena Online post- 3 32.4 31.5 1.07 36.6 38.8 0.95 10.3 12.9 0.80
2012 (126). nce HD dilution (0.83- (0.75- (0.52-
(n=714) hemodiafiltrati 1.39) 1.20) 1.24)

ED
on vs. low-flux
hemodialysis

Turkish OL- Maintena Online post- 2

PT 22.4 25.2 0.82 13.3 16.6 0.79 8.1 11.2 0.72
CE
HDF, 2013 nce HD dilution (0.59- (0.55- (0.45-
(129)
.. (n=782) hemodiafiltra 1.16) 1.14) 1.13)
tion vs. high-
AC

flux
hemodialysis

ESHOL, 2013 Maintena Online post- 3 NA NA NA 18.6 27.1 0.70 8.1 12.2 0.67
(130)
. nce HD dilution (0.53- (0.44-
(n=906) hemodiafiltra 0.92) 1.02)
tion vs. high-
flux
hemodialysis

52
 ACCEPTED MANUSCRIPT

Figure 1

PT
RI
SC
NU
MA
D
TE
P
CE
AC

53
 ACCEPTED MANUSCRIPT

HIGHLIGHTS

 Patients undergoing maintenance hemodialysis have a mix of ischemic, metabolic, and structural

changes, coupled with the stress of hemodialysis.

PT
 The “classic” heart failure manifestations of patients with end-stage renal disease (ESRD) are

somewhat atypical and therapeutic options are limited.

RI
 There have been advances in dialysis technologies as well as newer insights with novel imaging

SC
techniques.

NU
Clinicians need to better appreciate the spectrum as well as the current understanding of this

unique patient population. MA

D
P TE
CE
AC

54