JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 77, NO.

11, 2021

ª 2021 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

JACC REVIEW TOPIC OF THE WEEK

Chronic Kidney Disease and

Cardiovascular Disease:
A Personalized Approach
JACC Review Topic of the Week

Ashton C. Lai, MD, PHD,a,* Solomon W. Bienstock, MD,a,* Raman Sharma, MD,a Karl Skorecki, MD,b
Frans Beerkens, MD,a Rajeev Samtani, MD,a Andrew Coyle, MD,a Tonia Kim, MD,a Usman Baber, MD, MS,a
Anton Camaj, MD, MS,a David Power, MD,a Valentin Fuster, MD, PHD,a,c Martin E. Goldman, MDa

ABSTRACT

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease (ESRD). The
initiation of dialysis for treatment of ESRD exacerbates chronic electrolyte and hemodynamic perturbations. Rapid
large shifts in effective intravascular volume and electrolyte concentrations ultimately lead to subendocardial
ischemia, increased left ventricular wall mass, and diastolic dysfunction, and can precipitate serious arrhythmias
through a complex pathophysiological process. These factors, unique to advanced kidney disease and its treatment,
increase the overall incidence of acute coronary syndrome and sudden cardiac death. To date, risk prediction
models largely fail to incorporate the observed cardiovascular mortality in the CKD population; however,
multimodality imaging may provide an additional prognostication and risk stratification. This comprehensive review
discusses the cardiovascular risks associated with hemodialysis, and explores the pathophysiology and the novel
utilization of multimodality imaging in CKD to promote a personalized approach for these patients with
implications for future research. (J Am Coll Cardiol 2021;77:1470–9) © 2021 by the American College of
Cardiology Foundation.

C hronic kidney disease (CKD) has a myriad of

direct negative effects on the cardiovascular
system (1–3). The progression to hemodialy-
sis (HD) generates major intravascular shifts in volume
and electrolytes. This leads to HD-related cardiovas-
cular injuries that include intradialytic hypotension
(IDH) and myocardial stunning, which place patients
at risk for acute ischemic syndromes, arrhythmias,
and sudden cardiac death (SCD) (Figure 1). As CKD pro-
gresses, cardiovascular mortality rises, eventually
becoming the most common cause of death among
end-stage renal disease (ESRD) patients (4). In this re-
view, we summarize the evidence linking CKD and car-
diovascular disease (CVD) with a particular emphasis
on the impact of HD on CVD. We review the epidemi-
ology, pathophysiology, and challenges in care of car-
diac disease in ESRD patients. Furthermore, we
discuss the role of imaging in risk stratification and
propose a novel algorithm to minimize CVD risk in pa-
tients progressing from CKD to ESRD.

Listen to this manuscript’s

audio summary by
Editor-in-Chief
Dr. Valentin Fuster on
JACC.org.
From the aIcahn School of Medicine at Mount Sinai Hospital, New York, New York, USA; bAzrieli Faculty of Medicine, Bar-Ilan
University, Safed, Israel; and the cCentro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. *Drs. Lai and
Bienstock contributed equally to this work. George Bakris, MD, served as Guest Associate Editor for this paper. Christie Ballantyne,
MD, served as Guest Editor-in-Chief for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received October 19, 2020; revised manuscript received December 30, 2020, accepted January 4, 2021.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2021.01.028

JACC VOL. 77, NO. 11, 2021 Lai et al. 1471
MARCH 23, 2021:1470–9 CKD and CVD: A Personalized Approach

EPIDEMIOLOGY AND SCOPE OF data notes that 40% of ESRD deaths are due ABBREVIATIONS

THE PROBLEM to SCD, followed by acute myocardial infarc- AND ACRONYMS

tion at 18% (4). Paradoxically, HD, the stan-

CACS = coronary artery
The increase in cardiovascular risk that accompanies dard life-sustaining therapeutic intervention calcium scoring
CKD has been demonstrated in many retrospective for patients with ESRD, may accelerate car-
CMR = cardiac magnetic
studies, and it is recognized as an independent risk diovascular complications. All-cause mortal- resonance
factor for CVD (5,6). The prevalence of CVD among ity among patients over age 65 years peaks at CTA = coronary computed
patients older than age 65 years who have CKD in the 615 deaths per 1,000 patient-years within tomography angiography

United States is 64.5%, compared with only 32.4% 2 months of initiating HD, and decreases CVD = cardiovascular disease

among those without CKD (4). Mortality rates also substantially by 12 months to 278 deaths per IDH = intradialytic hypotension
increase with each progressive stage of CKD, and 1,000 patient-years (4) (Figure 2B). Much of RRT = renal replacement
dramatically increase when glomerular filtration rate this CVD risk arises from the direct physio- therapy

(GFR) drops below 45 ml/min. After adjusting for age, logical effects of HD on the cardiac myocar- SCD = sudden cardiac death

sex, and race, death rates for CKD stage I to II were 79 dium, in addition to inadequate control of SPECT = single-photon
per 1,000 patient-years and increased to 170 deaths volume overload and insufficient dialytic emission tomography

per 1,000 patient-years for CKD stage IV to V (4) clearance of uremic molecules (7,8).
(Figure 2A). As the leading cause of death in ESRD, the
prevalence of CVD among ESRD patients age 22 to 44 PATHOPHYSIOLOGIC EFFECTS OF
years is approximately 50% and increases substan- HEMODIALYSIS ON THE
tially among ESRD patients over age 65 years to above CARDIOVASCULAR SYSTEM
75% (4).
Notably, nonatherosclerotic events, such as SCD or Elevation of cardiovascular risk begins when GFR
arrhythmias, are more common in patients with ESRD drops below 60 ml/min and dramatically increases at
than atherosclerotic events, such as acute myocardial GFR <45 ml/min (9–11). Cardiac risk is especially sig-
infarction or stroke. The 2018 U.S. Renal Data System nificant upon initiating HD. In patients with

F I G U R E 1 Associations Between CKD and CVD

Venous pressure monitor

Air trap and air detector
Saline Clean blood
solution

Fresh dialysate
Dialyser
Progressive Used dialysate
Patient

CKD ESRD Inflow

pressure
monitor

Blood pump
Heparin pump Arterial Removed
(to prevent clotting) pressure blood
monitor for cleaning

Myocardial fibrosis
Volume Overload IDH Arrhythmias
Progressive LVH Subendocardial Ischemia Sudden Cardiac
Death

Increased CVD Mortality

Progressive GFR Decline

With progressive chronic kidney disease (CKD), there is progressive volume overload leading to left ventricular hypertrophy (LVH). With initiation of dialysis and
progression to end-stage renal disease (ESRD), there is an increased risk of intradialytic hypotension (IDH) leading to subendocardial ischemia in a predisposing
hypertrophic myocardium. Finally, with thrice weekly dialysis, there is higher risk of sudden cardiac death secondary to arrhythmias likely due to myocardial fibrosis.
Thus, there is increased cardiovascular disease (CVD) mortality with progressive glomerular filtration rate (GFR) decline.
1472 Lai et al. JACC VOL. 77, NO. 11, 2021

CKD and CVD: A Personalized Approach MARCH 23, 2021:1470–9

F I G U R E 2 Mortality Trends Stratified by CKD Stage and Treatment Modality

A All-Cause Mortality Rates

250

Deaths per 1,000 Patient-Years at Risk

200

150

100

50

0
No CKD All CKD Stages Stage Stages Stage
1-2 3 4-5 unk/unspc
CKD Status and Stages
Unadjusted Adjusted

B Adjusted Mortality by Treatment Modality

800
Deaths per 1,000 Patient-Years

600

400

200

0
0 2 4 6 8 10 12
Months after Dialysis Initiation
HD PD

(A) Unadjusted and adjusted mortality (per 1,000 patient-years at risk) for Medicare patients age 66 years and older by chronic kidney disease
(CKD) status and stage, 2018. (B) Adjusted mortality (deaths/1,000 patient-years) by treatment modality and number of months after
treatment initiation among end-stage renal disease patients undergoing hemodialysis (HD) and peritoneal dialysis (PD), 2015. Data from
special analyses, U.S. Renal Data System ESRD Data Base (4). unk/unspc ¼ unknown/unspecified.
JACC VOL. 77, NO. 11, 2021
MARCH 23, 2021:1470–9
progressive CKD, renal replacement therapy (RRT) is
often required for clearance of blood and volume
control. As the most common form of RRT in the United
States, conventional HD takes place over 3 to 4 h, 3
times per week, and results in dramatic fluctuations in
systolic pressure, intravascular volume status, and
electrolytes homeostasis immediately before, during,
and for hours after each HD session (12–15). These
dramatic fluctuations in physiology, in turn, produce
significant injury to the cardiac myocardium via
intradialytic hypotension, myocardial stunning, and
electrolyte imbalances.
INTRADIALYTIC HYPOTENSION. IDH, defined as a
decrease in systolic blood pressure (SBP) by $20 mm
Hg or a decrease in mean arterial pressure by 10 mm
Hg, is a frequent complication seen in up to 30% of all
HD treatments (16,17). IDH increases as ultrafiltration
volume and rates increase, leading to dialysis-
induced myocardial injury and regional wall motion
abnormalities as demonstrated on transthoracic
echocardiography (TTE) (18). Pressure and volume
overload contribute significantly in the pathogenesis
of hypertension among HD patients and ineffective
dry-weight reduction has been of concern in the
development of myocardial remodeling and left
ventricular hypertrophy (LVH) (19,20). Those with
LVH, which is present in more than 70% of ESRD
patients, are nearly 10-fold more likely to develop
IDH than those with a normal LV mass (21,22). Inter-
estingly, ultrafiltration volumes and episodes of
intradialytic SBP reductions were consistently lower
in those receiving home-based HD with sessions
longer than the typical 3- to 4-h clinic session,
resulting in reductions in dialysis-induced regional
wall motion abnormalities (23,24). When HD patients
have prolonged interdialysis intervals (due to missed
sessions or by virtue of the weekend gap on a thrice
weekly schedule), interdialysis weight gain and pul-
monary venous congestion are more pronounced (25).
Thus, the ensuing HD session after a prolonged hiatus
tends to require more ultrafiltration to remove the
accumulated fluid. As a result, patients are at a higher
risk of IDH, leading to increased risk of hospitaliza-
tion and mortality (16,21,26). Additionally, the inci-
dence of SCD is greater on Mondays and Tuesdays
following the 2-day HD-free interval with subsequent
longer interdialytic times than other days of the
week (25,27,28).
The effects of IDH on the myocardium have been
observed in H215O positron emission studies by
measuring myocardial blood flow during HD; signifi-
cant reductions in blood flow during “peak dialytic
stress” consistent with myocardial ischemia have
Lai et al. 1473
CKD and CVD: A Personalized Approach
been observed (15). Even in patients with normal
angiographic coronary circulation, myocardial stun-
ning from episodes of IDH is a proposed mechanism
of heart failure resulting from HD (15,29). Repeated
episodes of hypoperfusion with reductions in
myocardial blood flow, rapid volume replacement,
and elevated LV diastolic pressure due to thrice
weekly HD are the likely mechanisms by which
microvascular ischemia and myocardial remodeling
occur, eventually leading to chronic LV dysfunction
and arrhythmias (30,31).
HD-INDUCED ARRHYTHMIAS. In addition to compli-
cations due to IDH, HD may also overcorrect electro-
lyte imbalances. Electrolyte imbalances associated
with missed HD, intradialysis electrolyte fluctuations,
and increased ultrafiltration rates may independently
contribute to higher mortality and increased ar-
rhythmias (32–34). Based on U.S. Renal Data System
data, cardiac arrest and fatal arrhythmias account for
37% of all deaths in the ESRD population (4). Studies
have shown that the prevalence of SCD is commen-
surate with decreases in GFR (35–37). Reviewing data
collected from 24-h Holter ambulatory monitors, the
left ventricular (LV) mass index was the strongest
predictor of ventricular arrhythmia, seen in 35% of
patients (38). Another retrospective study that
included HD patients with automated implantable
cardioverter-defibrillators (AICDs) showed that 79%
of cardiac arrests were a result of ventricular tachy-
arrhythmia (39). Conversely, 2 recent studies
observed that in HD patients with implantable loop
recorders (ILR), the most common cause of
arrhythmic death was a progression from bradycardia
to asystole (40). The discrepancy may be due to a
selection bias: patients who had a history of ventric-
ular arrhythmias necessitated an AICD in the first
place; thus, interrogation of the devices will reveal a
higher prevalence of arrhythmias. On the other hand,
those HD patients presenting with syncope or palpi-
tations, necessitating an ILR, were more likely to
have a bradyarrhythmia. A pilot study with 30 pa-
tients, the Cardio Renal Arrhythmia Study in Hemo-
dialysis Patients Using Implantable Loop Recorders,
found that, after >300,000 h of continuous ILR data,
33% of patients had significant arrhythmic events,
including 2 SCDs and 3 pacemaker implantations for
bradyarrhythmia (37). Silva et al. (41) found that
lengthening of the PR interval and QTc are the most
reliable predictors of bradyarrhythmia. The etiology
of bradyarrhythmias in SCD remains unknown;
perhaps, the cyclic IDH, myocardial stunning, and
chronic inflammatory response may induce progres-
sive myocardial fibrosis involving the conduction
1474 Lai et al.
CKD and CVD: A Personalized Approach
system. This diseased conduction system is then
further stressed by the large electrolyte shifts. In
support of this hypothesis, IDH has been associated
with a 9-fold greater rate of developing intradialytic
arrhythmias; furthermore, even small declines in SBP
(0 to 20 mm Hg from pre-dialysis) were associated
with a 7-fold greater rate of arrhythmia (42,43).
ALTERNATIVE RENAL REPLACEMENT STRATEGIES.
Given the concerns for wide fluctuations in fluid sta-
tus with 3 times weekly HD, nonconventional dial-
ysis, such as more frequent in-facility HD and nightly
home HD, have been investigated as alternative reg-
imens. A randomized trial of 378 patients assigned to
HD either 6 times per week or 3 times per week
demonstrated that those who received more frequent
HD had improved LV mass and hypertension control
(44). Other trials with either daily or nightly HD have
reinforced these findings (45–49). Additionally, peri-
toneal dialysis (PD) provides a slow ultrafiltration
with potential benefits of gentler fluid shifts,
although studies have seen excessive fluid overload
with PD over HD (50). At this time, the survival and
physiological benefits of PD in comparison with HD
remains an active area of investigation (51). Despite
the benefits of more frequent dialysis with daily HD
or nightly HD, patient selection, patient burden, and
economic costs become important considerations
(52). Identifying those who would most likely benefit
from nonconventional hemodialysis with multi-
modality imaging may help allocate resources, reduce
patient burden, and improve patient outcomes.
MULTIMODALITY IMAGING
Given the significant baseline cardiovascular risk
present in CKD and the heightened risk of initiation
and maintenance of dialysis, proper risk stratification
and prognostication is essential in managing patients
with CKD. Multimodality imaging studies including
echocardiography, stress testing, coronary artery
calcium scoring (CACS), and cardiac magnetic reso-
nance (CMR) imaging may identify HD patients at risk
for complications during routine HD, warranting a
more personalized approach to their RRT.
Through the combined consequences of long-
standing hypertension, microvascular ischemia, and
progressive diffuse atherosclerosis, the LV myocar-
dium may develop diffuse intramyocardial fibrosis
while coronary arteries may develop significant calci-
fication (53,54). The result is a hypertrophied, non-
compliant LV with significant diastolic dysfunction. At
the time HD is initiated, approximately 70% of
patients will have evidence of clinically significant
JACC VOL. 77, NO. 11, 2021
MARCH 23, 2021:1470–9
diastolic dysfunction detectable by TTE (12,13). LV
systolic dysfunction has a prevalence ranging from
15% to 28% in HD patients, with a steady increase in
E/eʹ ratios on TTE as CKD stages progress (55).
Furthermore, the standard echocardiographic mea-
sure of diastolic dysfunction has been found to predict
all-cause mortality in ESRD patients (56,57). While
LVH increases myocardial oxygen demand, the
increased LV end-diastolic pressure reduces the dia-
stolic transmural gradient, potentially leading to
microvascular ischemia, especially for those patients
with pre-existing coronary artery disease (CAD).
In the assessment of clinically significant
CAD, there are currently higher rates of testing in
CKD patients compared with non-CKD patients (58).
For patients with CKD, nonimaging stress electro-
cardiography tends to be limited, as many of these
patients have underlying electrocardiography abnor-
malities given the prevalence of LVH, while stress
echocardiography may be an alternative. Pharmaco-
logical single-photon emission tomography (SPECT)
functional stress testing appears to be the most
common form of testing, with modest prognostica-
tion value for overall mortality in patients with CKD
(58,59). In 1 meta-analysis, the diagnostic accuracy of
SPECT in potential renal transplant candidates was
found to be 74% sensitive with a specificity of 70% for
CAD (60). A hybrid approach with the addition of
anatomic testing with coronary computed tomogra-
phy angiography (CTA) or CACS to SPECT testing does
not improve overall diagnostic accuracy; however, a
sequential hybrid approach with coronary CTA per-
formed first followed by SPECT does seem to improve
the positive predictive value (61). A caveat to this
sequential approach is that coronary CTA may be
prohibitive in CKD given the contrast load. In a
separate study, the diagnostic use of coronary CTA
and CACS has been established in patients undergo-
ing evaluation for renal transplant, with a sensitivity
and specificity for obstructive CAD as follows: coro-
nary CTA, 93% and 63%; and CACS, 67% and 77% (61).
Studies using CTA have also demonstrated that HD
increases myocardial blood flow heterogeneity,
manifested by reduced coronary blood flow, although
the exact mechanism is unclear. This myocardial
blood flow heterogeneity has been associated with
ventricular arrhythmias in hypertrophic cardiomy-
opathy via positron emission tomography (62). There
has been some evidence that dialysate cooling ther-
apy may improve myocardial blood flow by vasodi-
lation of smaller blood vessels (63,64).
CMR imaging has the potential to detect myocar-
dial fibrosis, which may predispose to the
JACC VOL. 77, NO. 11, 2021 Lai et al. 1475
MARCH 23, 2021:1470–9 CKD and CVD: A Personalized Approach

F I G U R E 3 Proposed Algorithm for Early Surveillance in CKD

Early Identification
of CKD

Personalized Interdisciplinary
Social Media Lifestyle Discussions with Consider Early
Outreach Interventions to Nephrology & TTE
Etiology Cardiology

Monitoring and Progression

No No Large LVMI
Surveillance of Disease

Yes Yes

Consideration of
HD
Large LV Cavity Size Small

Preference Consider
Diuretics over CCBs/BBs over
CCBs/BBs Diuretics

Consider Work-up Consider Work-up

for Infiltrative for Restrictive
Disease Pathologies

Early identification of chronic kidney disease (CKD) can help lead to targeted strategies to limit progression of disease. Social media outreach, such as mass
screening and aggressive hypertensive therapies, in at-risk populations may be particularly beneficial. Hypertension screening in supermarkets, barber
shops, and other public venues may detect disease at a much earlier stage and heighten public awareness. Early TTE may guide antihypertensive strategies:
those with large LVMI and small cavities may tolerate calcium-channel blockers (CCBs) and beta-blockers (BBs) better than diuretic agents; those with
larger cavities may benefit from a diuretic-based strategy to reduce left ventricular volumes and remodeling. HD ¼ hemodialysis; ILR ¼ implantable loop
recorder; LVMI ¼ left ventricular mass index; TTE ¼ transthoracic echocardiography.

development of re-entrant and fatal arrhythmias (65).
However, CMR imaging has the risk of nephrogenic
systemic fibrosis with the administration
gadolinium-based contrast agents to patients with
reduced GFR. Thus, noncontrast-based techniques,
such as native T 1 spin sequences and T 1 mapping of
extracellular volume, have been employed to assess
coarse cardiac fibrosis (66,67). Recent studies have
found that extracellular volume on CMR T 1 mapping
for myocardial fibrosis has been shown to be an in-
dependent risk factor for adverse cardiovascular
events (65).
These imaging techniques may provide insight into
the pathophysiological effects of HD on the cardiac
of myocardium. Echocardiography can quantify LVH
and diastolic dysfunction associated with CKD. Stress
echocardiography, SPECT, coronary CTA, and CACS
permit a functional and anatomic evaluation of
obstructive CAD and risk prognostication of ischemic
disease. Finally, CMR imaging provides additional
insight into myocardial function and fibrosis, possibly
surrogate markers for malignant arrhythmias and
SCD. Thus, an integrated multimodality imaging
approach could be implemented to risk-stratify
1476 Lai et al. JACC VOL. 77, NO. 11, 2021

CKD and CVD: A Personalized Approach MARCH 23, 2021:1470–9

F I G U R E 4 Proposed Algorithm for Assessment of Cardiovascular Hemodynamics Prior to Hemodialysis

Consideration for Consider ILR

HD Implantation

Yes Segmental TTE Large LVMI Yes

WMAs

No No
Consult
Diastolic Cardiology for
Dysfunction Yes
Interdisciplinary
Discussions

Consult No
Cardiology for
Testing Proceed with
Large LV Cavity Size
Intermittent HD

Small
Consider SPECT,
Surveillance and Consider Slow HD,
CACS or
Monitoring Daily HD or PD
Coronary CTA

For those under consideration for HD, ILR implantation may help identify those who would benefit from either early device or antiarrhythmic therapies. Early
transthoracic echocardiography (TTE) may help personalize management of those undergoing HD: those with segmental wall motion abnormalities (WMAs) at risk for
ischemic disease may warrant early stress testing; those with diastolic dysfunction may benefit with slow or frequent dialysis strategies; additionally, those with large
LVMI and small cavities may also benefit with slow dialysis strategies. CACS ¼ coronary artery calcium scoring; CTA ¼ computed tomography angiography;
PD ¼ peritoneal dialysis; SPECT ¼ single-photon emission computed tomography; other abbreviations as in Figure 3.

patients and provide a tailored approach to person-
alize care of patients with CKD with respect to the
preferred method of RRT.
CLINICAL MANAGEMENT AND
FUTURE DIRECTIONS
Patients with CKD are at an increased risk of cardiac
events, with especially increased risk as they progress
toward ESRD. However, the increased risk with both
initiation and with each HD session is potentially
underappreciated by both patients and clinicians.
Therefore, better awareness of the challenges and the
development of population- and patient-specific ap-
proaches to early prevention and identification of at-
risk populations is needed.
With early social media outreach to increase public
awareness and earlier lifestyle interventions to
address CKD risk factors, it may be possible to mini-
mize cardiac complications in at-risk populations.
Early TTE imaging may help guide management of
disease. Those with hypertrophied LVs with small
cavities and diastolic dysfunction may not tolerate
aggressive diuretic strategies, as they may be
dependent on ventricular filling; thus, these patients
may benefit more from early usage of calcium-
channel blockers (CCBs) or beta-blockers as antihy-
pertensive agents and for reducing LV wall stress. In
contrast, those with larger LV cavities may benefit
more from angiotensin-converting enzyme inhibitors
and diuretic agents to reduce ventricular volume and
remodeling as a method of blood pressure control
(Figure 3).
For those with inexorable progression of CKD to
ESRD, silent cardiac disease may approach or
exceed 50%. A proposed algorithm for risk assess-
ment and management may consist of a resting TTE
to assess LVH and LV systolic and diastolic func-
tion; echocardiographic stress testing may then be
used to assess for ischemia prior to HD initiation in
JACC VOL. 77, NO. 11, 2021
MARCH 23, 2021:1470–9
C ENTR AL I LL U STRA T I O N Risk Stratification with Multimodality Approach May Personalize Renal
Replacement Strategies
Lai, A.C. et al. J Am Coll Cardiol. 2021;77(11):1470–9.
Through a multimodality approach with (A) echocardiography, (B) cardiac magnetic resonance imaging, (C) implantable loop recorder, and (D) stress testing, proper
risk stratification may help personalize the renal replacement method, including peritoneal dialysis, slow dialysis, or even daily home dialysis. CVD ¼ cardiovascular
disease.
stable patients to better stratify cardiac risk
(Figure 4). For patients with noncompliant LVs, the
preferable modes of RRT may include PD, slow
continuous HD, daily or home HD, or more frequent
and slower in-facility HD with continuous blood
pressure and rhythm monitoring to avoid significant
IDH events (68). In collaboration with colleagues in
nephrology, improved HD technology incorporating
artificial intelligence could potentially integrate
hemodynamics and noninvasive ventricular filling
pressures to control dialysis flow rates, minimize
fluid and electrolyte shift, and avoid IDH to offer a
safer RRT. Current technology used during the
coronavirus disease-2019 pandemic may allow 1
clinician to monitor numerous patients in real time
simultaneously from a remote site.
For patients who are committed to chronic HD, the
risk of SCD should be better assessed; imaging and
cardiac monitoring studies may provide crucial in-
formation to elucidate this risk on a patient-specific
level. In addition to the consideration of TTE and
stress testing in patients prior to initiation of HD, the
Lai et al. 1477
CKD and CVD: A Personalized Approach
potential value of CACS and CMR warrants further
investigation in CKD to assess ischemic disease and
myocardial fibrosis. Despite the interesting early data
on the use of ILR and other continuous ambulatory
cardiac monitoring devices, we lack a risk model for
determining arrhythmic risk in this high-risk popu-
lation. Given the marked increase in risk of SCD
during the period immediately following HD initia-
tion, ILR-based studies should focus on the
arrhythmic burden in these patients.
A better understanding of the characteristics of
the most common fatal arrhythmias may result in
changes in practice; perhaps, ILR may even become
a standard-of-care for patients initiating HD and
those already with ESRD to identify patients who
may best benefit from prophylactic pacemakers,
AICDs, or early initiation of antiarrhythmic drugs. As
the efficacy of first-line agents, such as angiotensin-
converting enzyme inhibitors and diuretic agents,
tends to decrease with progressive renal dysfunc-
tion, the options of antihypertensive agents in renal
disease tend to be limited; thus, many ESRD patients
1478 Lai et al. JACC VOL. 77, NO. 11, 2021

CKD and CVD: A Personalized Approach MARCH 23, 2021:1470–9

are prescribed CCBs and beta-blockers as first-line remains an urgent unmet and underappreciated need
antihypertensive agents. As the most common ter- to establish a more reliable risk-stratification
minal arrhythmias are bradyarrhythmias in ESRD, strategy incorporating multimodality imaging data
the usage of CCBs and beta-blockers may be more (Central Illustration). From this strategy, a patient-
harmful than beneficial for these high-risk patients. tailored interdisciplinary approach to renal replace-
Thus, an ILR- or CMR-guided approach could help ment therapies and cardiac disease surveillance may
stratify patients to alternate antihypertensive regi- improve long-term outcomes in the growing CKD and
mens, early devices, or an RRT with gentler elec- CVD population.
trolyte shifts.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
Finally, the clear interplay between kidney and
cardiac disease should prompt closer collaboration The authors have reported that they have no relationships relevant to
between cardiologists and nephrologists. Special the contents of this paper to disclose.
consideration should be given to include a cardio-
logist on the front-line dialysis team caring for ADDRESS FOR CORRESPONDENCE: Dr. Martin E.
patients with progressive CKD to ensure appropriate Goldman, Zena and Michael A. Wiener Cardiovascular
screening, prognostication, and early intervention to Institute, Icahn School of Medicine at Mount Sinai,
minimize cardiovascular mortality. As highlighted in One Gustave L. Levy Place, Box 1030, New York, New
this review, there exist multiple potential consider- York 10029, USA. E-mail: Martin.Goldman@
ations with patients progressing to ESRD. There mountsinai.org.

REFERENCES

1. Di Lullo L, House A, Gorini A, Santoboni A,
Russo D, Ronco C. Chronic kidney disease and
cardiovascular complications. Heart Fail Rev 2015;
20:259–72.
2. Gansevoort RT, Correa-Rotter R,
Hemmelgarn BR, et al. Chronic kidney disease and
cardiovascular risk: epidemiology, mechanisms,
and prevention. Lancet 2013;382:339–52.
3. Shlipak MG, Fried LF, Cushman M, et al. Car-
diovascular mortality risk in chronic kidney dis-
ease: comparison of traditional and novel risk
factors. JAMA 2005;293:1737–45.
4. United States Renal Data System. 2018 USRDS
Annual Data Report: Epidemiology of kidney dis-
ease in the United States. Bethesda, MD: National
Institutes of Health, National Institute of Diabetes
and Digestive and Kidney Diseases, 2018.
5. Briasoulis A, Bakris GL. Chronic kidney disease
as a coronary artery disease risk equivalent. Curr
Cardiol Rep 2013;15:340.
6. Foley RN. Clinical epidemiology of cardiovas-
cular disease in chronic kidney disease. J Ren Care
2010;36 Suppl 1:4–8.
7. Moradi H, Sica DA, Kalantar-Zadeh K. Cardio-
vascular burden associated with uremic toxins in
patients with chronic kidney disease. Am J Nephrol
2013;38:136–48.
8. Cozzolino M, Mangano M, Stucchi A, Ciceri P,
Conte F, Galassi A. Cardiovascular disease in dial-
ysis patients. Nephrol Dial Transplant 2018 Suppl
3;33:iii28–34.
9. Fox CS, Matsushita K, Woodward M, et al. As-
sociations of kidney disease measures with mor-
tality and end-stage renal disease in individuals
with and without diabetes: a meta-analysis. Lan-
cet 2012;380:1662–73.
10. Go AS, Chertow GM, Fan D, McCulloch CE,
Hsu C-y. Chronic kidney disease and the risks of
death, cardiovascular events, and hospitalization.
N Engl J Med 2004;351:1296–305.
11. Tonelli M, Muntner P, Lloyd A, et al. Risk of
coronary events in people with chronic kidney
disease compared with those with diabetes: a
population-level cohort study. Lancet 2012;380:
807–14.
12. Chiu DY, Sinha S, Kalra PA, Green D. Sudden
cardiac death in haemodialysis patients: preven-
tative options. Nephrology (Carlton) 2014;19:
740–9.
13. de Bie MK, Ajmone Marsan N, Gaasbeek A,
et al. Left ventricular diastolic dysfunction in
dialysis patients assessed by novel speckle
tracking strain rate analysis: prevalence and de-
terminants. Int J Nephrol 2012;2012:963504.
14. McIntyre CW. Recurrent circulatory stress: the
dark side of dialysis. Semin Dial 2010;23:449–51.
15. McIntyre CW, Burton JO, Selby NM, et al. He-
modialysis-induced cardiac dysfunction is associ-
ated with an acute reduction in global and
segmental myocardial blood flow. Clin J Am Soc
Nephrol 2008;3:19–26.
16. Sands JJ, Usvyat LA, Sullivan T, et al. Intra-
dialytic hypotension: frequency, sources of varia-
tion and correlation with clinical outcome.
Hemodial Int 2014;18:415–22.
17. Sherman RA. Intradialytic hypotension: an
overview of recent, unresolved and overlooked
issues. Semin Dial 2002;15:141–3.
18. Ronco C, Feriani M, Chiaramonte S, et al.
Impact of high blood flows on vascular stability in
haemodialysis. Nephrol Dial Transplant 1990;5
Suppl 1:109–14.
19. Agarwal R, Alborzi P, Satyan S, Light RP. Dry-
weight reduction in hypertensive hemodialysis
patients (DRIP): a randomized, controlled trial.
Hypertension 2009;53:500–7.
20. Agarwal R, Weir MR. Dry-weight: a concept
revisited in an effort to avoid medication-directed
approaches for blood pressure control in hemo-
dialysis patients. Clin J Am Soc Nephrol 2010;5:
1255–60.
21. Stefansson BV, Brunelli SM, Cabrera C, et al.
Intradialytic hypotension and risk of cardiovascu-
lar disease. Clin J Am Soc Nephrol 2014;9:
2124–32.
22. Wizemann V, Timio M, Alpert MA, Kramer W.
Options in dialysis therapy: significance of car-
diovascular findings. Kidney Int Suppl 1993;40:
S85–91.
23. Jefferies HJ, Crowley LE, Harrison LE, et al.
Circulating endotoxaemia and frequent haemo-
dialysis schedules. Nephron Clin Pract 2014;128:
141–6.
24. Jefferies HJ, Virk B, Schiller B, Moran J,
McIntyre CW. Frequent hemodialysis schedules are
associated with reduced levels of dialysis-induced
cardiac injury (myocardial stunning). Clin J Am Soc
Nephrol 2011;6:1326–32.
25. Foley RN, Gilbertson DT, Murray T, Collins AJ.
Long interdialytic interval and mortality among
patients receiving hemodialysis. N Engl J Med
2011;365:1099–107.
26. Shoji T, Tsubakihara Y, Fujii M, Imai E. Hemo-
dialysis-associated hypotension as an independent
risk factor for two-year mortality in hemodialysis
patients. Kidney Int 2004;66:1212–20.
27. Makar MS, Pun PH. Sudden cardiac death
among hemodialysis patients. Am J Kidney Dis
2017;69:684–95.
28. Wong MC, Kalman JM, Pedagogos E, et al.
Temporal distribution of arrhythmic events in
chronic kidney disease: Highest incidence in the
long interdialytic period. Heart Rhythm 2015;12:
2047–55.
JACC VOL. 77, NO. 11, 2021
MARCH 23, 2021:1470–9
29. McIntyre CW. Haemodialysis-induced
myocardial stunning in chronic kidney disease - a
new aspect of cardiovascular disease. Blood Purif
2010;29:105–10.
30. Braunwald E, Rutherford JD. Reversible
ischemic left ventricular dysfunction: evidence for
the “hibernating myocardium”. J Am Coll Cardiol
1986;8:1467–70.
31. Cooper HA, Braunwald E. Clinical importance
of stunned and hibernating myocardium. Coron
Artery Dis 2001;12:387–92.
32. Waks JW, Tereshchenko LG, Parekh RS. Elec-
trocardiographic predictors of mortality and sud-
den cardiac death in patients with end stage renal
disease on hemodialysis. J Electrocardiol 2016;49:
848–54.
33. Morales MA, Gremigni C, Dattolo P, et al.
Signal-averaged ECG abnormalities in haemodial-
ysis patients. Role of dialysis. Nephrol Dial
Transplant 1998;13:668–73.
34. Korgaonkar S, Tilea A, Gillespie BW, et al.
Serum potassium and outcomes in CKD: insights
from the RRI-CKD cohort study. Clin J Am Soc
Nephrol 2010;5:762–9.
35. Chonchol M, Goldenberg I, Moss AJ, McNitt S,
Cheung AK. Risk factors for sudden cardiac death
in patients with chronic renal insufficiency and left
ventricular dysfunction. Am J Nephrol 2007;27:
7–14.
36. 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 dis-
ease. Kidney Int 2009;76:652–8.
37. Zachariah D, Kalra PR, Roberts PR. Sudden
cardiac death in end stage renal disease: unlocking
the mystery. J Nephrol 2015;28:133–41.
38. Bonato FO, Lemos MM, Cassiolato JL,
Canziani ME. Prevalence of ventricular arrhythmia
and its associated factors in nondialyzed chronic
kidney disease patients. PLoS One 2013;8:
e66036.
39. Wan C, Herzog CA, Zareba W, Szymkiewicz SJ.
Sudden cardiac arrest in hemodialysis patients
with wearable cardioverter defibrillator. Ann
Noninvasive Electrocardiol 2014;19:247–57.
40. Sacher F, Jesel L, Borni-Duval C, et al. Car-
diac rhythm disturbances in hemodialysis pa-
tients: early detection using an implantable loop
recorder and correlation with biological and
dialysis parameters. J Am Coll Cardiol EP 2018;
4:397–408.
41. Silva RT, Martinelli Filho M, Peixoto Gde L,
et al. Predictors of arrhythmic events detected by
implantable loop recorders in renal transplant
candidates. Arq Bras Cardiol 2015;105:493–502.
42. Mc Causland FR, Tumlin JA, Roy-Chaudhury P,
et al. Intradialytic hypotension and cardiac ar-
rhythmias in patients undergoing maintenance
hemodialysis: results from the Monitoring in
Dialysis Study. Clin J Am Soc Nephrol 2020;15:
805–12.
43. Kalra PA, Green D, Poulikakos D. Arrhythmia in
hemodialysis patients and its relation to sudden
death. Kidney Int 2018;93:781–3.
44. Chertow GM, Levin NW, Beck GJ, et al. for the
FHN Trial Group. In-center hemodialysis six times
per week versus three times per week. N Engl J
Med 2010;363:2287–300.
45. Ayus JC, Mizani MR, Achinger SG, Thadhani R,
Go AS, Lee S. Effects of short daily versus con-
ventional hemodialysis on left ventricular hyper-
trophy and inflammatory markers: a prospective,
controlled study. J Am Soc Nephrol 2005;16:
2778–88.
46. Culleton BF, Walsh M, Klarenbach SW, et al.
Effect of frequent nocturnal hemodialysis vs con-
ventional hemodialysis on left ventricular mass
and quality of life: a randomized controlled trial.
JAMA 2007;298:1291–9.
47. Rydell H, Ivarsson K, Almquist M, Clyne N,
Segelmark M. Fewer hospitalizations and pro-
longed technique survival with home hemodialy-
sis- a matched cohort study from the Swedish
Renal Registry. BMC Nephrol 2019;20:480.
48. Ting GO, Kjellstrand C, Freitas T, Carrie BJ,
Zarghamee S. Long-term study of high-
comorbidity ESRD patients converted from con-
ventional to short daily hemodialysis. Am J Kidney
Dis 2003;42:1020–35.
49. Weinhandl ED, Liu J, Gilbertson DT,
Arneson TJ, Collins AJ. Survival in daily home
hemodialysis and matched thrice-weekly in-center
hemodialysis patients. J Am Soc Nephrol 2012;23:
895–904.
50. Plum J, Schoenicke G, Kleophas W, et al.
Comparison of body fluid distribution between
chronic haemodialysis and peritoneal dialysis pa-
tients as assessed by biophysical and biochemical
methods. Nephrology Dialysis Transplantation
2001;16:2378–85.
51. Oliver MJ, Quinn RR. 30 - the use and out-
comes of peritoneal dialysis. In: Himmelfarb J,
Ikizler TA, editors. Chronic Kidney Disease, Dial-
ysis, and Transplantation. Fourth Edition. Phila-
delphia, PA: Elsevier, 2019:470–9.e4.
52. Suri RS, Larive B, Hall Y, et al. Effects of
frequent hemodialysis on perceived caregiver
burden in the Frequent Hemodialysis Network
Trials. Clin J Am Soc Nephrol 2014;9:936–42.
53. Aoki J, Ikari Y, Nakajima H, et al. Clinical and
pathologic characteristics of dilated cardiomyop-
athy in hemodialysis patients. Kidney Int 2005;67:
333–40.
54. Park S, Lee CJ, Jhee JH, et al. Extracellular
fluid excess is significantly associated with coro-
nary artery calcification in patients with chronic
kidney disease. J Am Heart Assoc 2018;7:
e008935.
55. Bansal N, Keane M, Delafontaine P, et al.
A longitudinal study of left ventricular function
and structure from CKD to ESRD: the CRIC study.
Clin J Am Soc Nephrol 2013;8:355–62.
56. Shizuku J, Yamashita T, Ohba T, Kabaya T,
Nitta K. Left atrial volume is an independent
Lai et al. 1479
CKD and CVD: A Personalized Approach
predictor of all-cause mortality in chronic hemo-
dialysis patients. Intern Med 2012;51:1479–85.
57. Sharma R, Pellerin D, Gaze DC, et al. Mitral
peak Doppler E-wave to peak mitral annulus ve-
locity ratio is an accurate estimate of left ven-
tricular filling pressure and predicts mortality in
end-stage renal disease. J Am Soc Echocardiogr
2006;19:266–73.
58. Herzog CA, Natwick T, Li S, Charytan DM.
Comparative utilization and temporal trends in
cardiac stress testing in U.S. Medicare beneficiaries
with and without chronic kidney disease. J Am Coll
Cardiol Img 2019;12:1420–6.
59. Al-Mallah MH, Hachamovitch R, Dorbala S,
Carli MFD. Incremental prognostic value of
myocardial perfusion imaging in patients referred
to stress single-photon emission computed to-
mography with renal dysfunction. Circ Cardiovasc
Imaging 2009;2:429–36.
60. Wang LW, Fahim MA, Hayen A, et al. Cardiac
testing for coronary artery disease in potential
kidney transplant recipients. Cochrane Database
Syst Rev 2011;12:CD008691.
61. Winther S, Svensson M, Jørgensen HS, et al.
Diagnostic performance of coronary CT angiog-
raphy and myocardial perfusion imaging in kidney
transplantation candidates. J Am Coll Cardiol Img
2015;8:553–62.
62. Lu D-Y, Yalçin H, Yalçin F, et al. Stress
myocardial blood flow heterogeneity is a positron
emission tomography biomarker of ventricular
arrhythmias in patients with hypertrophic cardio-
myopathy. Am J Cardiol 2018;121:1081–9.
63. Kharche SR, So A, Salerno F, et al. Computa-
tional assessment of blood flow heterogeneity in
peritoneal dialysis patients’ cardiac ventricles.
Front Physiol 2018;9:511.
64. Marants R, Qirjazi E, Grant CJ, Lee T-Y,
McIntyre CW. Renal perfusion during hemodialysis:
intradialytic blood flow decline and effects of dial-
ysate cooling. J Am Soc Nephrol 2019;30:1086–95.
65. Xu H-Y, Yang Z-G, Zhang Y, et al. Prognostic
value of heart failure in hemodialysis-dependent
end-stage renal disease patients with myocardial
fibrosis quantification by extracellular volume on
cardiac magnetic resonance imaging. BMC Car-
diovasc Disord 2020;20:12.
66. Edwards NC, Moody WE, Yuan M, et al. Diffuse
interstitial fibrosis and myocardial dysfunction in
early chronic kidney disease. Am J Cardiol 2015;
115:1311–7.
67. Graham-Brown MP, March DS,
Churchward DR, et al. Novel cardiac nuclear
magnetic resonance method for noninvasive
assessment of myocardial fibrosis in hemodialysis
patients. Kidney Int 2016;90:835–44.
68. Pladys A, Bayat S, Kolko A, et al. French patients
on daily hemodialysis: clinical characteristics and
treatment trajectories. BMC Nephrol 2016;17:107.
KEY WORDS cardiovascular disease,
chronic kidney disease, hemodialysis