The Cardio-Renal Relationship

Konstantinos Dean Boudoulas, Filippos Triposkiadis, John Parissis, Javed

Butler, Harisios Boudoulas

PII: S0033-0620(16)30140-2
DOI: doi: 10.1016/j.pcad.2016.12.003
Reference: YPCAD 772

To appear in: Progress in Cardiovascular Diseases

Received date: 11 December 2016

Accepted date: 11 December 2016

Please cite this article as: Boudoulas Konstantinos Dean, Triposkiadis Filippos, Paris-
sis John, Butler Javed, Boudoulas Harisios, The Cardio-Renal Relationship, Progress in
Cardiovascular Diseases (2016), doi: 10.1016/j.pcad.2016.12.003

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

The Cardio-Renal Relationship

Konstantinos Dean Boudoulas, MD1; Filippos Triposkiadis, MD2; John Parissis, MD3; Javed
Butler, MD, MPH4; Harisios Boudoulas, MD, Dr., Dr. Hon5

PT
1

RI
Associate Professor of Medicine/Cardiovascular Medicine, Director of Interventional
Cardiology Fellowship Program, Associate Director of Cardiac Catheterization Laboratory,

SC
Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, United
States of America (USA); 2Professor of Cardiology, Director of the Department of Cardiology,

NU
Larissa University Hospital, Larissa, Greece; 3Associate Professor of Cardiology, Medical
School University of Athens, Attikon Hospital, Athens, Greece; 4Professor of Cardiology,
MA
Director Division of Cardiology, School of Medicine, Stony Brook University, Stony Brook,
New York, USA; 5Professor of Medicine/Cardiovascular Medicine and Pharmacy (emeritus),
D

The Ohio State University, Columbus, Ohio, USA; Honorary Professor, Academician (an.
TE

mem.); Aristotle University of Thessaloniki, Thessaloniki, Greece.

P

Key words: cardiorenal interrelationship, stiff aorta, heart failure, kidney disease, coronary
CE

artery disease
Short title: CardioRenal
AC

Word Count: 5247 (including abstract)

Disclosure and Conflict of Interest: None
Corresponding Author: Konstantinos Dean Boudoulas, MD
Associate Professor of Medicine/Cardiovascular Medicine
The Ohio State University, Columbus Ohio USA
Division of Cardiovascular Medicine
473 W. 12th Avenue, Suite 200
Columbus, Ohio 43210
Phone: 614-293-7885
Fax: 614-247-7789
Email: kdboudoulas@osumc.edu

1
 ACCEPTED MANUSCRIPT

Abstract
The heart and the kidney are of utmost importance for the maintenance of cardiovascular
(CV) homeostasis. In healthy subjects, hemodynamic changes in either organ may affect
hemodynamics of the other organ. This interaction is fine-tuned by neurohumoral activity,

PT
including atrial natriuretic peptides, renin-angiotensin aldosterone system and sympathetic

RI
activity. Dysfunction or disease of one organ may initiate, accentuate, or precipitate
dysfunction or disease state in the other organ, often leading to a vicious cycle. Further, the

SC
interaction between the heart and the kidney may occur in the setting of processes and
diseases that may affect both organs simultaneously, such as advanced age, hypertension,

NU
diabetes mellitus, atherosclerosis, etc. In this regard, a stiff aorta that occurs with aging due
to mechanical stress may independently initiate or precipitate dysfunction and disease in the
MA
heart and the kidney. All of these factors contribute to a high prevalence of coexistent CV
and kidney disease, especially in the elderly. In advanced kidney disease, hemodynamic and
D

neurohumoral homeostasis is lost, volume and pressure overload may coexist, and the
TE

elimination of certain pharmacologic agents may be substantially impaired. Thus,

coexistence of CV and kidney disease complicates diagnosis, propagates pathophysiology,
P

adversely affects prognosis, and hinders management.

CE
AC

2
 ACCEPTED MANUSCRIPT

Abbreviations

AA = aldosterone antagonists

ACE-I = angiotensin converting enzyme inhibitors

PT
AF = atrial fibrillation

ANP = atrial natriuretic peptide

RI
ARB = angiotensin receptor blocker

SC
BB = beta-blocker

BNP = brain natriuretic peptide

NU
BP = blood pressure

CHD = coronary heart disease

MA
CKD=chronic kidney disease

CO = Cardiac output
D

CRS = cardiorenal syndrome

TE

CV = cardiovascular
P

CVD = cardiovascular disease

CE

CysC = cystatin-C

DM = diabetes mellitus
AC

GFR = glomerular filtration rate

H-FABP = heart fatty acid binding proteins

HF = heat failure

HFpEF = heart failure with preserve left ventricular ejection fraction

HFrEF = heart failure with reduce ejection fraction

HTN = hypertension

IL-18 = interleukin-18

KIM-1 = kidney injury molecule-1

L-FABP = liver isoform of fatty acid binding proteins

3
 ACCEPTED MANUSCRIPT

LV = left ventricle or ventricular

LVH = left ventricular hypertrophy

MERIT-HF= meteprolol CR/XL randomized intervention trial in congestive heart failure

PT
NAG = N-acetyl-beta-D-glucosaminidase

NGAL = neutrophil gelatinase-associated lipocalin

RI
NO = nitric oxide

SC
NP = natriuretic peptide

PWV = pulse wave velocity

NU
RAAS = renin-angiotensin-aldosterone system

SNS = sympathetic nervous system

MA
VHD = valvular heart disease
D
P TE
CE
AC

4
 ACCEPTED MANUSCRIPT

I. Introduction

“I have never yet examined the body of a patient dying of dropsy attended by coagulable urine,
in whom some obvious derangement was not discovered in the kidneys”- Richard Bright, 1827

PT
The heart and kidney are essential for cardiovascular (CV) homeostasis. Cardiac

RI
function provides sufficient blood and oxygen to all the organs of the body, whereas the
kidney plays a key role in the clearance of metabolic waste products and the maintenance of

SC
acid/base and fluid and electrolytes equilibrium. Hemodynamic changes in the heart affect
the kidney and visa-versa, and may impact on these essential functions. This

NU
interrelationship is fine-tuned by neurohumoral activity, including atrial natriuretic peptides
(ANP), renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS).
MA
Maintenance of intravascular volume and hemodynamic homeostasis depends on a set of
complex and delicate interactions between the heart and kidney [1,2].
D

Dysfunction or disease of the heart has the ability to initiate or precipitate disease of
TE

the kidney, and vice-versa, via common hemodynamic and neurohumoral activation
pathways leading to a vicious cycle. However, in clinical practice the cardiorenal interaction
P

are far more complex. The coexistence of CV and renal dysfunction often may be the result
CE

of common risk factors, such as hypertension (HTN), diabetes mellitus (DM), smoking or
lipid disorders. Moreover, the stiffening of the aorta that occurs with aging with or without
AC

atherosclerosis and the presence of other disorders/diseases may affect both organs (Figure
1) [1, 3]. In this review, the cardiorenal interrelationship under normal conditions and in
patients with heart failure (HF) and chronic kidney disease (CKD) will be discussed.

II. CardioRenal Interrelationship Under Normal Conditions

“The whole is greater than the sum of the parts” - Aristotle

Under normal conditions, when atrial pressure and stretch decreases, ANP release is
diminished, activity of the SNS increases and RAAS is activated. All these changes lead to salt
and water retention, intravascular volume expansion and vasoconstriction, leading to

5
 ACCEPTED MANUSCRIPT

restoration of atrial blood pressure (BP) and cardiac function (Figure 2A). If atrial pressure
rises, SNS activity is inhibited, ANP release is reduced and RAAS activity is diminished. These
effects result in a fall of atrial pressure and intravascular volume, restoring homeostasis
[1,3,4].

PT
When renal perfusion falls due to a diminished cardiac output (CO) or decrease BP,

RI
renin and erythropoietin is released from the juxtaglomerular apparatus. Activation of the
RAAS contributes to salt and water retention, expansion of intravascular volume and

SC
vasoconstriction. Erythropoietin results in an increase in red blood cell mass and further
expansion of intravascular volume. Increased intravascular volume and vasoconstriction

NU
leads to an increase in CO and BP that restores renal perfusion and function (Figure 2B). If
excessive activation of the RAAS occurs and the BP and atrial pressure increase, ANP is
MA
released, SNS activity diminishes and renin secretion decreases. These hemodynamic and
hormonal interactions regulate almost all cardiac and renal functions [1-6].
D

The effects of ANP, RAAS and SNS are important for renal function, cardiac function
TE

and the cardiorenal interrelationship. ANP is a 28-amino-acid peptide that is synthesized in

the atrial myocytes in response to atrial distension. Angiotensin, endothelin, and an increase
P

in SNS activity also increase ANP secretion (Figure 3). Brain natriuretic peptide (BNP) is
CE

mostly synthesized in the ventricles, and much less in the brain and is mainly involved in
patients with HF and much less in normal individuals. It is stored with ANP in the atria. ANP
AC

and BNP exert their physiologic effects via two pathways. One involves a direct vasodilatory
effect and the other has a direct renal effect. Venous dilatation induced by natriuretic
peptides (NP) result in a decrease in central venous pressure, BP and ventricular preload.
The vasodilatory effect of NPs on the arteries/arterioles results in a decrease in systemic
vascular resistance and a decrease in BP. The direct effect of NPs on the kidneys results in
an increase in the glomerular filtration rate and a decrease in renin secretion; this decrease
in the activity of angiotensin and aldosterone results in salt and water excretion. Lower
levels of angiotensin contribute to vasodilatation and to a decrease in BP, atrial pressure and
ANP secretion. NPs also inhibit norepinephrine release from sympathetic nerve terminals.

6
 ACCEPTED MANUSCRIPT

Thus, alterations in NPs secretion or RAAS activity regulate function in both organs via
multiple pathways [2-6] (Figures 2 and 3).

III. Cardiorenal Interrelationship in Cardiac and Renal Disease

PT
RI
In 1827, Dr Richard Bright described for the first time the close association between
cardiac and kidney disease. Today, it is well appreciated that CV disorders and diseases

SC
affect renal function and vice-versa. In this regard, significant effects of HF on renal function
and effects of renal dysfunction on CV function are briefly presented.

NU
1. Heart Failure: In HF with reduce ejection fraction (HFrEF), various conditions, such as
MA
coronary heart disease (CHD), primary cardiomyopathy (heritable or acquired), arterial HTN
and valvular heart disease (VHD) most often serve as the initiating lesion in the development
D

of left ventricular (LV) dysfunction and HF. Ventricular systolic/diastolic dysfunction and
TE

atrial dysfunction may result in a decrease in stroke volume, CO and perfusion of the
peripheral organs including the kidney [1] (Figure 4). In response to these changes, the SNS
P

and RAAS are activated resulting in an increase in ventricular diastolic filling volume and
CE

pressure, and augmentation of stroke volume and CO, restoring tissue perfusion. The
activation of the SNS also increases myocardial contractility, vascular resistance and LV
AC

afterload. Further, a decrease in renal perfusion and enhanced sympathetic tone provokes
release of renin that activates angiotensin and aldosterone production, resulting in salt and
water retention, which maintains intravascular volume, increases BP and improves CO.
Vasopressin levels may also elevated contributing to the expansion of intravascular volume
and increase in vascular resistance. In contrast to normal conditions, in HF, renin release
often cannot be inhibited by an increase in intravascular volume. Thus, while the kidneys
help to maintain homeostasis under normal conditions, in HF the kidney may contribute to
progression and worsening of the disease. Current medical management is therefore in part
based on the blockade of the SNS and RAAS axis [1-5,7-11].

7
 ACCEPTED MANUSCRIPT

In patients with HF with preserve left ventricular ejection fraction (HFpEF), a stiff
aorta is often present (Figure 5, see later and Figure 7). Stiff aorta usually results in systolic
HTN, impairment of LV relaxation and diastolic dysfunction, and kidney damage, especially in
the elderly. Neurohumoral activity in patients with HFpEF is increased, but to a lesser

PT
degree than in HFrEF.

RI
Plasma NPs are elevated in HF. This increase is noted in the early stages of mild HF
with a progressive rise as the condition advances in severity. As patients undergo successful

SC
medical management, NP levels gradually decline. As HF progresses, resistance to NPs may
develop. Among other factors, arterial endothelial dysfunction may contribute to the

NU
resistance of NPs. In addition, plasma levels of NPs may be reduced in end stage HF due to
marked dilatation and fibrosis of the atria and the ventricles, especially if atrial fibrillation
MA
(AF) is present. Thus, it appears that the regulatory effects of NPs is lost in advanced HF [1,
4-6, 12-16].
D

Congestion of the kidney due to high venous pressure may result in a decrease in
TE

renal blood flow and deterioration of renal function. Venous congestion may also increase
gut endotoxin absorption contributing to the inflammation present in HF (see later) [16-19].
P
CE

2. Renal dysfunction: In CKD, several pathophysiologic mechanisms lead to endothelial

dysfunction and damage that in turn may result in the development of cardiomyopathy, stiff
AC

arteries, stiff aorta and atherosclerosis. Further, decrease in renal perfusion, often present in
CKD, results in activation of RAAS, which is important for homeostasis under normal
conditions; however, excess activation of RAAS may contribute to the development of
arterial HTN, volume overload, endothelial dysfunction and damage, atherosclerosis, stiff
arteries and stiff aorta (Figure 6). In CKD, the release of erythropoietin is attenuated
resulting in anemia and increase ventricular work. Further, there is an increase in adrenergic
activity contributing to endothelial dysfunction and damage, and vascular and myocardial
damage. Certain other metabolic abnormalities present in CKD accelerate the entire process
and precipitate the development of CV disease (CVD). Abnormal calcium and phosphorus
metabolism contributes to the acceleration of coronary atherosclerosis in CKD. In addition

8
 ACCEPTED MANUSCRIPT

to all these factors that promote CVD, “uremic toxins” often present in advanced kidney
disease also contribute to the development and progression of cardiomyopathy [1,3,20-33].
Patients with CKD have higher levels of NPs than age and gender matched patients
with normal renal function. This probably represents both an increase in cardiac production

PT
and a decrease in renal clearance. Clearly, AF is more common in patients with CKD

RI
compared to the general population, and elimination of AF by catheter ablation is associated
with improvement in renal function in these patients [1,34-37].

SC
3. Linking HF with renal failure

NU
3.1 Sharing risk factors: In the majority of patients, and especially in the elderly,
several conditions and diseases are present that may directly affect both the heart and the
MA
kidney [1, 3]. Certain polymorphisms may accelerate coronary artery calcification and CHD in
patients with CKD suggesting that a genetic predisposition may be present in certain cases
D

[38, 39]. Age, arterial HTN, obesity, DM, dyslipidemia, smoking, sedentary lifestyle, sleep
TE

deprivation, stress and depression may act as risk factors for the development of both CVD
and CKD [40-49] (Figure 6). Obesity may be associated with increase incidence of CKD even
P

with no other detectable abnormalities in young and middle age individuals [50].
CE

3.2 Inflammation: Risk factors can induce a low grate systemic inflammation that may
lead to an increase in oxidative stress implicated as the final pathway for endothelial
AC

dysfunction/damage. In addition, activation of the immune system further increases

inflammation [1, 3, 41-43]. Moreover, following ischemia or mechanical injury of the
cardiomyocytes, the innate immune system is activated resulting in a release of interleukins,
tumor necrosis factor and other cytokines. All these inflammatory products following
myocardial injury lead to an inflammation that in addition to the effects on the myocardium
result in distal organ damage. High angiotensin and aldosterone levels following activation
of RAAS also contributes to inflammation and oxidative stress at the cellular level.
Inflammation deteriorates CV and renal function and contributes to anemia increasing
ventricular work and further accelerating HF. Inflammation that increases myocardial
stiffness has been reported in both HFrEF and HFpE. It has been shown that coronary

9
 ACCEPTED MANUSCRIPT

microvascular endothelial inflammation is associated with a reduction of nitric oxide ( NO)

availability, especially in patients with HFpEF. Further, recent studies suggested that
histamine H2 receptor antagonists that have been shown to decrease inflammation may
improve LV remodeling. As is the case with HF, renal tubular injury contributes to circulatory

PT
levels of inflammatory cytokines and promotes inflammation [5, 40-43].

RI
3.3 Stiff aorta: In addition to smoking and risk factors related to metabolic and other
abnormalities, significant changes in the wall of the aorta in elderly individuals, which may

SC
be accelerated by atherosclerosis, are commonly present; these changes of the aortic wall in
combination with risk factors or alone may initiate or precipitate CVD and CKD [49] (Figure

NU
7). In the elderly, the endothelial cells of the aorta become flattened, enlarged and
dysfunctional. Thus, NO production decreases and endothelial dependent vasodilation is
MA
impaired. Further, fragments of endothelial cells circulating in the blood of these individuals
can initiate or precipitate an inflammatory process. The aorta and the proximal elastic
D

arteries in young individuals expand by approximately 10% with each LV contraction; due to
TE

repetitive stretch of the aortic wall over time, fatigue and fracture of the elastic lamellae
occur. This results in an increase in the collagen content and decrease in the elastic
P

properties of the aorta (i.e., increases aortic stiffness) [49]. In addition, vasa-vasorum flow
CE

that supplies the outer portion of the aortic wall of the thoracic aorta decreases with age,
especially if arterial HTN is present resulting in further decrease in the elastic properties of
AC

the aorta. These changes are in addition and independent to those occurring secondary to
an atherosclerotic process [23, 24].
Decrease elastic properties of the aorta are associated with an increase in pulse wave
velocity (PWV) and an increase in reflected wave velocity that results in organ damage and
systolic HTN, the mechanisms of which are outlined. A fast PWV produces stretch in the
arterioles and results in vascular and organ damage, especially in those organs with a high
blood supply at rest such as the brain and kidney. When the elastic properties of the aorta
diminish, the reflected wave velocity increases. Thus, reflected waves reach the root of the
aorta during late systole (not in early diastole as occurs in individuals with normal aortic
function) and fuses with the systolic part of the pulse wave resulting in a late systolic peak of

10
 ACCEPTED MANUSCRIPT

the aortic pressure and the disappearance of the diastolic wave. All these hemodynamic
changes may lead to subendocardial ischemia, especially in patients with LV hypertrophy
(LVH). In addition, a stiff aorta is associated with impaired myocardial microcirculatory
function and decrease coronary blood flow reserve. LV-vascular coupling that depends on

PT
the aortic function is an important factor determining LV performance. All these changes

RI
due to stiffening of the aorta may be more profound in short individuals. This may at least
partially explain why LVH and HFpEF are more common in women compared to men. All

SC
these factors mentioned above explain the high incidence of co-existence CVD and CKD in
the elderly [23, 24, 49].

NU
IV. Cardiorenal Syndrome: A Simplistic Definition to a Complex Problem
MA
Sir Thomas Lewis was the first to use the term “cardiorenal” in 1913 in order to
D

describe paroxysmal dyspnea in patients with CVD and CKD [7]. Almost a century later, a
TE

working group appointed by the National Heart, Lung and Blood Institute in 2004, defined
cardiorenal syndrome (CRS) as an extreme form of cardiorenal dysregulation characterized
P

by a failure of therapy to relieve congestive symptoms of HF due to a decline in renal

CE

function. Since that time, 5 types of CRS have been proposed [40, 51-53]: type 1 - acute
deterioration of CV function or acute HF leading to acute renal injury and dysfunction; type 2
AC

- chronic cardiac dysfunction resulting in CKD; type 3 - acute decompensation of renal

function leading to acute cardiac dysfunction; type 4 - CKD resulting in chronic cardiac
dysfunction; type 5 - different disorders and diseases affecting both kidney and heart [52].
The pathogenesis of kidney disease in HF, and vice-versa, is related to their close
interrelationships as described earlier in this paper. Among other factors, CV function is
directly depended on the regulation of salt and water content of the body provided by the
kidney, while kidney function is directly depended on blood flow and pressure provided by
the heart. These interrelationships in both organs can result in a vicious cycle where
deterioration of function in one organ results in deterioration of function in the other organ,
a self-perpetuating progression of disease. Moreover, as stated earlier, CKD, especially in the

11
 ACCEPTED MANUSCRIPT

elderly, is often a manifestation of a broader age-related diffuse vascular damage affecting a

number of target organs including the kidney and the heart [45].

Comorbidities in HF and renal failure

PT
“Ariadne’s Thread”-Greek Mythology

RI
The CRS, as defined above, describes renal involvement in acute and chronic HF,

SC
cardiac involvement in acute and chronic renal disease, and disorders and diseases that
affect both of these organs. There are several issues associated with these classifications. In

NU
the vicious cycle of the cardiorenal interrelationship, often it is difficult in clinical practice to
be certain which organ, the kidney or the heart, was affected first. Thus, subclinical renal
MA
dysfunction may beget HF, and vice-versa, i.e., occult HF may precipitate asymptomatic
kidney disease. Further, this classification does not take into consideration the
D

pathophysiologic link between multiple comorbidities present in HF and renal failure [1, 3, 5].
TE

Comorbidities in HF and renal failure, and their interrelationships, adversely affect prognosis
and are part of the CRS that cannot be ignored. Moreover, pathophysiologic mechanisms in
P

CRS, to a certain degree, are directly related to underlying comorbidities (e.g., arterial HTN,
CE

CHD, DM, etc.).

In chronic HF, there are multiple associated interactions and morbidities in addition
AC

to renal dysfunction. Arterial HTN, CHD, AF, chronic obstructive pulmonary disease, anemia,
DM, obesity, sleep-disordered breathing, depression, liver dysfunction and skeletal
myopathy are often present in HF and adversely affect prognosis [5, 40] (Figure 8A).
Likewise, in chronic renal failure, HTN, DM, anemia, dyslipidemia, parathyroid disorders and
neuromuscular disorders are frequently present. In addition, CVD, such as cardiomyopathy,
VHD, CHD, myocardial ischemia, pericardial disease, arterial stiffening and calcification, stiff
aorta (that may worsen renal and cardiac function), cardiac arrhythmias and other morbid
CV conditions are often present in renal failure (Figure 8B) [1, 3]. Moreover, inflammatory
processes present in HF and renal failure further deteriorate CV and renal function, and also
adversely affect the function of multiple other organs in the body [1, 3, 5, 12, 40, 45, 52, 53].

12
 ACCEPTED MANUSCRIPT

This may at least partially explain why specific treatments of comorbidities in HF and renal
failure, with the exception of HTN, CHD and perhaps anemia, typically are not associated
with a lower incidence of CVD events [5]. In this regard, however, it is of interest to mention
that the anti-DM drug empagliflozin that has multiple functions (i.e., improves arterial

PT
stiffness, decreases BP, facilitates the balance between oxygen supply and demand,

RI
improves myocardial and renal function, and decreases body weight, visceral fat and blood
glucose) has been shown to improve outcomes [54]. The extent and prognostic implications

SC
of the common comorbidities seen in renal failure have been studied to some degree in
dialysis patients; comorbidities were included in risk scores to assist in clinical decision

NU
making for transplant evaluation in the elderly, but essentially there has been a lack of
studies in the earlier stages of the disease [55].
MA
Deficiencies related to the classification of the CRS have been recognized by the
investigators who performed pioneering work on the topic and recently have incorporated
D

the lung into the CRS [12]; however, inclusion of one more organ into the labyrinth of
TE

multiple comorbidities present in HF and renal failure with their multiple interrelationships
does not solve the problem since most comorbidities never exist in isolation, but in a
P

complex pathophysiological interplay (Figure 7A and 7B). To solve this problem, one needs a
CE

better understanding of the basic pathophysiologic mechanisms and how these mechanisms
are interrelated with each other in the development of HF, renal failure, and their multiple
AC

associations. To get out of this labyrinth of multiple comorbidities, one needs a new way of
thinking, as it was the case with Ariadne who helped Theseus get out of the Labyrinth.
According to Greek mythology of the Labyrinth and Minotaur, Ariadne provided to Theseus
(son of King Aegean) a skein of red thread allowing him to find his way out of the Labyrinth.
Based on these facts, defining only one of these multiple interactions present in HF
and CKD is misleading and distracts the clinician from the “big picture” of the multiple,
complex and clinically important interactions into focusing on only one interaction. Thus, in
our opinion the definition of the CRS is based on a simplistic interpretation and does not
portray the complex and multifactorial biological associations of the cardiorenal link.

13
 ACCEPTED MANUSCRIPT

V. Cardiorenal Interrelationship: Diagnostic and Therapeutic Considerations

The close interrelationships between the heart and the kidney should be taken into
consideration for the diagnosis and management of patients with CVD and/or CKD. The
multiple coexistent interactions and morbidities that are present in CVD and CKD should be

PT
carefully evaluated. In CKD, especially in advance disease, hemodynamic and neurohumoral

RI
homeostasis is lost. Often pressure and volume load are present in these patients. Fatigue,
exercise intolerance, dyspnea and chest pain are frequent in these patients, especially in

SC
those who are on hemodialysis. Jugular venous distension and peripheral edema mostly due
to volume overload are also seen. Rales in both bases of the lungs, gallop rhythm due to

NU
high cardiac output secondary to anemia and/or to arterio-venous fistula, and murmurs due
to anemia or arterio-venous fistula in patients who are on hemodialysis are not uncommon
MA
[1, 3].
Electrocardiographic abnormalities such as non-specific ST and T wave changes, intra-
D

ventricular conduction defect, LVH and P-wave abnormalities may be seen. On the
TE

echocardiogram, increase LV wall thickness, pericardial involvement, VHD, including valvular

calcification, and left atrial enlargement are also common findings. A totally normal heart in
P

patients with advance CKD is the exception, rather than the rule [1, 20-22, 26, 27].
CE

Several biomarkers have been used in patients with HF that have helped clinicians
establish diagnosis, determine prognosis, and better guide management. Biomarkers,
AC

however, that were established in HF trials predominantly included non-elderly patients

without significant renal disease or major comorbidities. An assumption that the same
processes can be applied to patients with renal failure or other comorbidities, at best, is
based on extrapolation of these data. Most of these biomarkers are based on factors related
to hemodynamic load (e.g., NPs); oxidative stress, apoptosis, and necrosis (e.g., high
sensitivity protein); inflammatory processes (e.g. interleukin-18 (IL-18), tumor necrosis
factors, galactin-3 other); and to collagen synthesis and degradation (e. g., matrix
metalloproteinase, tissue inhibitor of metalloproteinase, procollagen 1-C terminal,
procollagen III-N terminal peptide, collagen 1-C terminal telopeptide) [5, 40, 56, 57].

14
 ACCEPTED MANUSCRIPT

Serum cystatin-C (CysC) is a marker of glomerular function, while urine CysC is a

marker of tubular function. In chronic HF, CysC seems to offer incremental prognostic value
compared to serum creatinine, whereas in acute HF, worsening renal function as defined by
CysC levels, was not predictive of outcomes. Neutrophil gelatinase-associated lipocalin

PT
(NGAL) is a marker of tubular function that indicates the presence of tubular damage both in

RI
stable and acute HF. Kidney injury molecule-1 (KIM-1) is a marker of proximal tubular injury
and inflammation. Despite the initial encouraging results, the prognostic significance of KIM-

SC
1 in HF remains controversial. N-acetyl-beta-D-glucosaminidase (NAG) is localized in the
proximal tubule lysosomes and has been associated with acute kidney injury. In chronic HF,

NU
NAG was a predictor of long-term outcomes of renal function. As inflammation plays a key
role in acute kidney injury, IL-18 is highly expressed in this setting. In a study with a small
MA
number of patients with acute HF, urinary IL-18 was associated with an increase in all-cause
mortality. The limitation of IL-18, however, is that it is expressed in many other inflammatory
D

conditions. The liver isoform of fatty acid binding proteins (L-FABP) is expressed in the
TE

proximal renal tubular cells and it appears to be protective against oxidative stress, while
the heart FABP (H-FABP) isoform is located in both distal tubules and in myocardium.
P

Urinary L-FABP has been shown to have prognostic implications in acute kidney injury after
CE

cardiac surgery and in critically ill patients treated in the intensive care unit. Combining
several biomarkers, or a multi-marker approach, has been proposed for early detection of
AC

acute kidney injury (56, 57).

At present, most commonly used biomarkers in clinical practice in patients with HF or
renal failure include the NPs and troponins. BNP plasma levels are elevated in patients with
CKD even in patients without HF; BNP elevation in these patients constitutes a poor
prognostic indicator. Data, however, are mostly extrapolated from patients with HF or renal
failure and limited information is present in patients who have both diseases. Current
knowledge, however, suggests that a BNP reduction of more than 30% during therapy
compared to baseline is associated with improved outcomes in these patients [5, 40].
Troponin levels are also often elevated in patients with CKD in the absence of acute
myocardial injury and constitute a poor prognostic indicator. It has been suggested that a

15
 ACCEPTED MANUSCRIPT

dynamic increase in troponin concentration of greater than 20% should be considered as an

indicator of myocardial damage [58, 59]. Biomarkers related to inflammation and collagen
turnover potentially could prove useful in patients with HF and kidney disease where
inflammatory processes and collagen synthesis and degradation appear to be high,

PT
respectively. This notion, however, remains to be proven.

RI
All these factors, as well as the multiple coexistent diseases and multiple
interrelationships in HF and CKD, should be considered during diagnostic evaluation. It

SC
should be noted that available information always, especially in this group of patients,
should be individualized. Further, diagnostic studies that require the use of contrast material

NU
(e.g., coronary arteriography) may produce kidney damage or deterioration of renal
function when renal disease is present and results in a worsening prognosis [1, 5, 6, 12, 60-
MA
62].
The first step in the management of patients with CKD is to restore volume and
D

pressure homeostasis. Volume load with fluid and/or salt restriction or diuretics should be
TE

optimized. Loop diuretics should be used when such therapy is indicated. Anemia when
symptomatic should be treated with erythropoietin stimulating agents as needed and blood
P

transfusions should be avoided. Arterial HTN, if present, should be optimally controlled.

CE

Dose of pharmacologic agents should be adjusted when renal excretion is the major route of
drug elimination [1,63-66].
AC

In patients with HF, all medications [angiotensin converting enzyme inhibitors (ACE-I),
angiotensin receptor blockers (ARBs), beta-blockers (BBs), aldosterone antagonists (AAs),
hydralazine, isosorbite dinitrate, diuretics, ivabradine] and device therapy that are used in
patients without renal disease can also be used cautiously in patients with CKD [67-78].
Pharmacologic agents that reduce morbidity and mortality in HF, such as RAAS inhibitors,
are associated with a decline in renal function upon initiation of therapy. An initial elevation
of serum creatinine by 20% within two to three months after initiation of therapy with ACE-
I/ARBs should be expected; this transient elevation, however, is not associated with
adverse outcomes. Special considerations should be taken when AAs are used, especially in
combination with ACE-I/ARBs, to avoid hyperkalemia. Renal function should be closely

16
 ACCEPTED MANUSCRIPT

monitored when ACE-Is or ARBs are used. In regards to BB therapy, MERIT-HF (Meteprolol
CR/XL Randomized Intervention Trial in Congestive Heart Failure) showed that the effect of
metoprolol was at least as effective in reducing death or hospitalization for worsening HF in
patients with an estimated glomerular filtration rate (GFR) < 45ml/min/1.73 m2 as compared

PT
to those with a GFR > 60ml/min/1.73 m2. Although there is no definite conclusive evidence,

RI
BBs most likely also improve outcomes in patients with end stage renal disease [76].
When treating HF, one should keep in mind the bidirectional link between congestion

SC
and renal function. Impaired renal function may initiate salt and water retention resulting in
congestion, which in turn promotes renal dysfunction by increasing right side filling

NU
pressures and intra-abdominal congestion. Moreover, deterioration of renal function alone
following treatment of an episode of acute HF was not an independent determinant of
MA
outcomes, but had an additive effect on prognosis only in patients with persistent signs of
congestion [5, 17, 18, 77]. Device therapy, such as cardiac resynchronization therapy and/or
D

implantable cardioverter defibrillator (incidence of sudden cardiac death is high in patients

TE

with CKD), can be used [67]. Careful assessment of the multiple problems related to the
patient including life expectancy should be taken into consideration before a device therapy
P

is implanted. Information, however, related to use of these devices is limited in patients with
CE

advanced stages of CKD. Studies suggest that suppressed LV ejection fraction can improve
substantially after kidney transplantation; this improvement partially may be due to a rise of
AC

hemoglobin after transplantation [68,69]. Likewise, improvement of CV function after

implantation of LV assist device has been reported [1,67, 70].
In patients with CHD, all medications (statins, BBs, ACE-I/ARBs, ranolazine,
ivabradine) that are used in patients without renal disease can also be used with in those
with renal disease. In certain cases, intestinal cholesterol absorption is increased and
therapy with statins is less effective in these patients. As a general rule, therapy with statins
is beneficial in reducing CVD events even in patients who are on hemodialysis and in certain
cases, may slow the progression of renal dysfunction. Data suggest that dysfunctional high
density lipoprotein cholesterol may be present and may contribute to the high incidence of

17
 ACCEPTED MANUSCRIPT

CVD events in patients with CKD, particularly those on hemodialysis. Use of fibrates may
reduce CVD risk in patients with mild to moderate CKD [79-86].
Percutaneous or surgical coronary revascularization can be performed when
indicated; however, results are inferior compared to patients without renal disease. Special

PT
attention should be taken to prevent kidney injury from contrast medium and during surgery

RI
as kidney injury during these procedures worsen prognosis. The possibility that a patient
with CKD may require dialysis after these procedures should be discussed with the patient in

SC
advance. High platelet reactivity is more common in patients with CKD compared to patients
with normal renal function. At present, ticagrelor appears to be the antiplatelet of choice

NU
along with aspirin in patients with CKD after stent placement or following an acute coronary
syndrome; however, most of the recommendations are based on single center data or on
MA
post-hoc analysis [1,87-92].
D

VI. Conclusion
TE

The interrelationship between the heart and the kidney are important for the
P

maintenance of circulatory homeostasis in health and disease. Clearly, CV disorders often

CE

coexist with renal disorders and in a large proportion of patients is due to multiple factors
including shared risk factors, direct interactions between the two organs, shared coexistent
AC

morbidities, inflammation, and a stiff aorta. Volume and pressure overload, anemia and
electrolyte-metabolic abnormalities may initiate or precipitate cardiac symptoms or cardiac
arrhythmias in patients with CKD even in those without significant underlying CVD. In the
elderly, the effect of common abnormalities, such as arterial HTN, obesity, DM, smoking and
hyperlipidemia often coexist. The combination of these abnormalities lead to neurohumoral
activation, endothelial dysfunction, oxidative stress and inflammation that promote CV and
kidney damage. In addition, a stiff aorta that is almost always present in the elderly and may
initiate and precipitate CVD and CKD independently of other risk factors. Thus in the elderly,
the high incidence of renal and CVD simply may reflect the coexistence of these common
risk factors and the presence of aortic dysfunction.

18
 ACCEPTED MANUSCRIPT

Management of patients with CVD and CKD requires understanding of the basic renal
and CV physiology/pathophysiology, cardiorenal interrelationships, as well as,
pharmacokinetics and pharmacodynamics of the pharmacologic agents. Clinical science
based on system biology will help to better understand the interrelationships of these

PT
abnormalities that lead to CVD and CKD. Moreover, translational research will help the

RI
clinician to apply the knowledge gained from the bench to the bedside [1, 45, 49, 51, 54, 93].

SC
NU
MA
D
P TE
CE
AC

19
 ACCEPTED MANUSCRIPT

References
1. Leier CV, Boudoulas H eds. Cardiorenal Disorders and diseases. Second edition revised
and expanded Futura Publishing Company Inc Mount Kisco, New York 1992.
2. Klabunde RE ed. Cardiovascular Physiology Concepts. Lippincott Williams and Wilkins 2011

PT
3. Boudoulas KD, Boudoulas H. Cardiorenal interrelationship. Cardiology 2011; 120: 135-138

RI
4. Boudoulas KD, Paraskevaidis JA, Boudoulas H, Triposkiadis F. The left atrium: from the
research laboratory to the clinic. Cardiology 2014; 129: 1-17

SC
5. Triposkiadis F, Giamouzis G, Parissis J, et al. Reframing the association and significance of
comorbidities in HF. Eur J HF in press

NU
6. Triposkiadis , Pieske B, Butler J, et al. Global left atrial ailure in HF. Eur J HF in press
7. Lewis T. Paroxysmal dyspnea in cardiorenal patients: with particular reference to cardiac
MA
and uremic asthma. Br Med J 1913; 29: 1417-1420
8. Hillege HL, van Gilst WH, Van Veldehuisen DJ, et al. Accelerated decline and prognostic
D

impact of renal function after myocardial infarction and the benefits of ACE inhibition: the
TE

CAST randomized trial. Eur Heart J 2003; 24: 412-420

9. Bichet DG. Central vasopressin: dendritic and axonal secretion and renal actions. Clinical
P

Kidney J. 2014; 7: 242-247

CE

10. Floras JS, Ponikowski P. The sympathetic/parasympathetic imbalance in HF with reduced

ejection fraction. Eur Heart J 2015; 36: 1974-1982
AC

11. Charloux A, Piquard F, Doutreleau S, et al. Mechanisms of renal hyporesponsiveness to

ANP in HF. Eur J Clin Inv 2003; 33: 769-778
12. Husain-Syed F, McCullough PA, Birk HW, et al. Cardio-pulmonary-renal interactions. J Am
Coll Cardiol 2015; 65: 2433-2448
13. Schaub JA, Coca SG, Moledina D, et al. Amino-terminal pro-B- type NP for diagnosis and
prognosis in patients with renal dysfunction. JACC HF 2015; 3: 977-989
14. Takahashi Y, Takahashi A, Kuwahara T, et al. Renal function after catheter ablation of
atrial fibrillation. Circulation 2011; 124: 2380-2387

20
 ACCEPTED MANUSCRIPT

15. Schrirmer SH, Sayet MY, Reil JC, et al. Atrial remodeling following catheter –based renal
denervation occurs in a blood pressure –and heart rate –independent manner . J Am Coll
Cardiol Intv 2015; 8: 972-980
16. Van den Berg MP, Tjeerdsma G, de Kam J, et al. Longstanding atrial fibrillation causes

PT
depletion of atrial NP in patients with advanced congestive HF. Eur J HF 2002; 4: 255-262

RI
17. Verbrugge FH, Dupont M, Steels P, et al. Abdominal contributions to cardiorenal
dysfunction in congestive HF, J Am Coll Cardiol 2013; 62: 485-495

SC
18. Hanberg JS, Sury K, Wilson B, et al. Reduced cardiac index is not the dominant driver of
renal dysfunction in HF. J Am Coll Cardiol 2016; 67: 2199-2208

NU
19. Salah K, Kok WE, Eurlings LW, et al. Competing risk of cardiac status and renal function
during hospitalization for acute decompensated HF. J Am Coll Cardiol HF2015; 3: 751-761
MA
20. Schiffrin EL, Lipman ML, Mann JFE. CKD. Effects on the cardiovascular system. Circulation
2007; 116: 88-98
D

21. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C. CKD and the risk of death,
TE

cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296-1305

22. Himmerlfarb J, Ikilzler TA. Hemodialysis N Engl J Med 2010; 363: 1833-1845
P

23.Boudoulas H, Stefanadis Ch eds. The Aorta: structure, function, dysfunction, and diseases.
CE

New York, Informa Health Care, 2009.

24. Boudoulas KD, Vlachopoulos C, Raman S, et al. Aortic function: from the research
AC

laboratory to the clinic Cardiology 2012; 121: 31-42

25. Aoki J, Ikari Y, Nakajima H, et al. Clinical and pathologic characteristics of dilated
cardiomyopathy in hemodialysis patients. Kidney International 2005; 67: 333-340
26. Schiffrin EL, Lipman ML, Mann JF. CKD effects on the cardiovascular system. Circulation
2007; 116: 85-97
27. Hickson LJ, Negrotto SM, Onuigbo M, et al. Echocardiography criteria for structural heart
disease in patients with end-stage renal disease initiating hemodialysis. J Am Coll Cardiol
2016; 67: 1173-1182

21
 ACCEPTED MANUSCRIPT

28. Weiner DE, Tighiouart H, Amin MG, et al. CKD as a risk factor for cardiovascular disease
and all-cause mortality: a pooled analysis of community –based studies. J Am Soc Nephrol
2004; 15: 1307-1315
29. Cao XF, Yan L, Han L, et al. Association of mild to moderate kidney dysfunction with

PT
coronary artery calcification in patients with suspected coronary artery disease. Cardiology

RI
2011; 120: 211-216
30. Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with CKD

SC
compared with those with diabetes: a population –level cohort study. The Lancet 2012; 380:
807-814

NU
31. Charytan DM, Li S, Liu J, Herzog CA. Risks of death and end-stage renal disease after
surgical compared with percutaneous coronary revascularization in elderly patients with
MA
CKD. Circulation 2012; 126 (suppl 1): S164-S169
32. Gori M, Senni M, Gupta DK, et al. Association between renal function and cardiovascular
D

structure and function in HF with preserved ejection fraction. Eur Heart J 2014; 35: 3442-3451
TE

33. De Nicola L, Gabbai FB, Agarwal R, et al. Prevalence and prognosis of resistant
hypertension in CKD patients. J Am Coll Cardiol 2013; 61: 2461-2467
P

34. Bohm M, Ezekowitz MD, Connolly SJ et al. Changes in renal function in patients with
CE

atrial fibrillation. F Am Coll Cardiol 2015; 65: 2481-2493

35. Bonde AN, Lip GYH, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in
AC

patients with atrial fibrillation and CKD. J Am Coll Cardiol 2014; 64: 2471-2482
36. Alonso A, Lopez FL, Matsushita K, et al. CKD is associated with incidence of atrial
fibrillation. The atherosclerosis risk in communities (ARIC) study. Circulation 2011; 123: 2946-
2953
37. Bansal N, Fan D, Hsu C, et al. Incident atrial fibrillation and risk of end-stage renal disease
in adults with CKD. Circulation 2013; 127: 569-574
38. Ferguson JF, Matthews GJ, Towensend RR, et al. Candidate gene association study of
coronary artery calcification in CKD. J Am Coll Cardiol 2013; 62: 789-798

22
 ACCEPTED MANUSCRIPT

39. Mehta NN, Matthews GJ, Krishnamoorthy P, et al. Higher plasma CXCL12 levels predict
incident myocardial infarction and death in CKD: findings from the chronic renal insufficiency
cohort study. Eur Heart J 2014; 35: 2115-2122
40. Triposkiadis F, Starling RC, Boudoulas H, Giamouzis G, Butler J. The cardiorenal syndrome

PT
I HF: cardiac? Renal? Syndrome? Heart Fail Rev 2012; 17: 355-366

RI
41. Gomberg-Maitland M, Shah SJ, Guazzi M. Inflammation in HF with preserved ejection
fraction. JACC HF 2016; 4: 325-327

SC
42. Franssen C, Chen S, Unger A, et al. Myocardial microvascular inflammatory endothelial
activation in HF with preserved ejection fraction. JACC HF 2016; 4: 312-324

NU
43. Leary PJ, Tedford RJ, Bluemke DA, et al. Histamine H2 receptor antagonists, left
ventricular morphology, and HF risk. J Am Coll Cardiol 2016; 67: 154-1552
MA
44. Marenzi G, Cosentino N, Bartorelli AL Acute kidney injury in patients with acute coronary
syndromes. Heart 2015; 101: 1778-1785
D

45. El Nahas M. Cardio-kidney damage: a unifying concept. Kidney Int. 2010; 78: 14-18
TE

46. Levey AS, Inker LA, Coresh J. CKD in older people. JAMA 2015; 314: 557-558
47. Glassock R, Delanaye P, El Nahas m. An age-calibrated classification of CKD. JAMA 2015;
P

314: 559-560
CE

48. Rebholz C, Anderson C, Grams M, et al. Relationship of the American Heart Association's
Impact Goals (Life's Simple 7) With Risk of CKD: Results From the Atherosclerosis Risk in
AC

Communities (ARIC) Cohort Study. J Am Heart Assoc. 2016; 5: e003192

49. O’ Rourke MF, Safar ME, Dzau V. The cardiovascular continuum extended: aging effects
of the aorta and microvasculature. Vascular Medicine 2010; 15: 461-468
50. Chang Y, Ryu S, Choi Y, et al. Metabolically healthy obesity and development of CKD: a
cohort study. Ann Intern Med 2016; 64: 305-312
51. National Heart, Lung, Blood Institute: NHLBI Working Group. Cardio-renal connections in
HF and cardiovascular disease. August 20, 2004. Available at
http://www.nhlbi.nih.gov/research/reports/2004-cardiorenal-hf-hd
52. Waldrum B, Os I. The cardiorenal syndrome: what the cardiologist needs to know.
Cardiology 2013; 126: 175-186

23
 ACCEPTED MANUSCRIPT

53. Zoccali C, Goldsmith D, Agarwal R, et al. The complexity of the cardio-renal link:
taxonomy, syndromes, and disease. Kidney International 2011 Suppl 1, 2-5
54. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and
mortality in type 2 diabets. N Engl J Med 2015; 373: 2117-2128

PT
55. Dusseux E, Albano L, Falin C, et al. A simple clinical tool to inform the decision-making

RI
process to refer elderly incident dialysis patients for kidney transplant evaluation. Kidney Int
2015; 88: 121-129

SC
56. Sun RR, Lu L, Liu M, et al. Biomarkers and heart disease. Eur Med Pharmacol Sci 2014; 19:
2927-2935

NU
57. Ivyatt CM, Schlondorff D. Precision medicine comes of age in nephrology: identification
of novel biomarkers and therapeutic targets for chroniv kidney disease, Kidney Int 2016; 89:
MA
734-737
58. Reichlin T, Irfan A, Twerenbod R, et al. Utility of absolute and relative changes in cardiac
D

troponin concentrations in the early diagnosis of acute myocardial infarction. Circulation

TE

2011; 124: 136-145

59. Twerenbold R, Wildi K, Jaeger C, et al. Optimal cut-off levels of more sensitive cardiac
P

troponin assays for the early diagnosis of myocardial infarction in patients with renal
CE

dysfunction. Circulation 2015; 131: 2041-2050

60. Stacy SR, Suarez-Cuervo C, Berger Z, et al. Role of troponin in patients with CKD and
AC

suspected acute coronary syndrome: a systematic review. Ann Intern Med 2014; 161: 502-512
61. Bonventre J, Yang L. Cellular pathophysiology of ischemic acute kidney injury. J Clin
Invest 2011; 121: 4210-4221
62. Ohno Y, MaekawaY, Miyata H, et al. Impact of periprocedural bleeding on incidence of
contrast –induced acute kidney injury in patients treated with percutaneous coronary
intervention. J Am Coll Cardiol 2013; 62: 1260-1266
63. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular
and renal outcomes: updated systematic review and meta-analysis. The Lancet 2015;
November 6

24
 ACCEPTED MANUSCRIPT

64. Rifkin DF, Ix JH, Wassel CL, et al. Renal artery calcification and mortality among clinically
asymptomatic adults. J Am Coll Cardiol 2012; 60: 1079-1085
65. Brandt MC, Reda S, Maffoud F, et al. Effects of renal denervation on arterial stiffness and
central hemodynamics in patients with resistant hypertension. J Am Coll Cardiol 2012; 60:

PT
1956-1965

RI
66. Collister D, Komenda P, Hiebert B, et al. The effect of erythropoietin –stimulating agents
on health-related quality of life in anemia of CKD: a systematic review and meta-analysis. Ann

SC
Intern Med 2016; 164: 472-478
67. Cannizzaro LA, Piccini J, Patel UD, Hernandez AF. Device therapy in HF patients with CKD.

NU
J Am Coll Cardiol 2011; 58: 889-896
68. Hawwa N, Shrestha K, Hammadah M, et al. Reverse remodeling and prognosis following
MA
kidney transplantation in contemporary patients with cardiac dysfunction. J Am Coll Cardiol
2015; 66: 1779-1787
D

69. Vali RK, Wang GS, Gottlieb SS, et al. Effect of kidney transplantation on left ventricular
TE

systolic dysfunction and congestive HF. J Am Coll Cardiol 2005; 45: 1051-1060
70. Hasin T, Topilsky Y, Schirger JA, et al. Changes in renal function after implantation of
P

continuous –flow left ventricular assist devices. J Am Coll Cardiol 2012; 59: 26-36
CE

71. Li G, Gersh BJ, Greene EL, et al. Renal function and mortality following cardiac
resynchronization therapy. Eur Heart J 2011; 32: 184-190
AC

72. Molnar MZ, Kalantar-Zadeh k, Lott EH, et al. Angiotensin –converting enzyme inhibitor,
angiotensin receptor blocker use, and mortality in patients with CKD. J Am Coll Cardiol 2014;
63: 650-658
73. Matsumoto Y, Mori Y, Arihana K, et al. Spironolactone reduces cardiovascular and
cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol 2014; 63:
528-536
74. Evans M, Carrero JJ, Szummer K, et al. Angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers in myocardial infarction patients with renal dysfunction. J Am
Col Cardiol 2016; 67: 1687-1697

25
 ACCEPTED MANUSCRIPT

75. Bardve SV, Roberts MA, Hawley CM, et al. Effect of beta- adrenergic antagonists in
patients with CKD. J Am Coll Cardiol 2911; 58: 1152-1161
76. Ghali JK, Wikstrand j, Van Valdaisen DJ, et al.MERIT-HS Study Group. The influence of
renal function on clinical outcome and response to beta-blockade in systolic HF: insights

PT
from Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT -HF). J Cardiol

RI
Fail 2009; 15: 310-318
77. Damman K, Tang WH, Felker MG, et al. Current evidence of treatment of patients with

SC
chronic systolic HF and renal insufficiency. J Am Coll Cardiol 2014; 63: 853-871
78. Magri P, Rao E, Cangianiello S, et al. Early improvement of renal hemodynamic reserve in

NU
patients with asymptomatic HF in restored angiotensin II antagonism. Circulation 1998; 98:
2849-2854
MA
79. Erickson KF, Japa S, Owens DK, et al. Cost-effectiveness of statins for primary
cardiovascular prevention in CKD. J Am Coll Cardiol 2013; 61: 1250-1258
D

80. Upadhyay A, Earley A, Lamont JL, et al. Lipid-lowering therapy in persons with CKD: a
TE

systematic review and meta-analysis. Ann Intern Med 2012; 157: 251-262
81. Jun M, Zhu B, Tonelli M, et al. Effects of fibrates in kidney disease: a systematic review
P

and meta-analysis. J Am Coll Cardiol 2012; 60: 2061-2071

CE

82. Hou W, Lv J, Perkovic V, et al. Effect of statin therapy on cardiovascular and renal
outcomes in patients with CKD: a systematic review and meta-analysis. Eur Heart J 2013; 34:
AC

1807-18
83. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus
undergoing hemodialysis. N Engl J Med 2005; 353: 238-248
84. Silbernagel G, Fauler G, Genser B, et al. Intestinal cholesterol absorption, treatment with
atorvastatin, and cardiovascular risk in hemodialysis patients. J Am Coll Cardiol 2015; 65:
2291-2298
85. Yamamoto S, Yancey PG, Ikizler A, et al. Dysfunctional high-density lipoprotein in
patients on chronic hemodialysis. J Am Coll Cardiol 2012; 60: 2372-2379

26
 ACCEPTED MANUSCRIPT

86. Go AS, Bansal N, Chandra M, et al. CKD and risk for presenting with acute myocardial
infarction versus stable exertional angina in adults with coronary heart disease. J Am Coll
Cardiol 2011; 58: 1600-1607
87. Baber U, Mehram R, Kitrane AJ, et al. Prevalence and impact of high platelet reactivity in

PT
CKD. Circulation: Cardiovascular Interventions 2015; 8: e001683

RI
88. Tsai TT, Messenger JC, Brennan M, et al. Safety and efficacy of drug-eluting stents in
older patients with CKD. J Am Coll Cardiol 2011; 58: 1859-1869

SC
89. Bangalore S, Guo Y, Samadashvili Z, et al. Revascularization in patients with multivessel
coronary artery disease and CKD. J Am Coll Cardiol 2015; 66: 1209-1220

NU
90. Otsuka Y, Ishiwata S, Inada T, et al. Comparison of haemodialysis patients and non-
haemodialysis patients with respect to clinical characteristics and 3-year clinical outcomes
MA
after sirolimus-eluting stent implantation: insights from the Japan multi-center post-
marketing surveillance registry. Eur Heart J 2011; 32: 829-837
D

91. Shroff GR, Solid CA, Herzog CA. Long-term survival and repeat coronary revascularization
TE

in dialysis patients after surgical and percutaneous coronary revascularization with drug-
eluting and bare metal stents in the United States. Circulation 2013; 127: 1861-1869
P

92. Barsa SS, Tsai P, Lakkis NM. Safety and efficacy of antiplatelet and antithrombotic
CE

therapy in acute coronary syndrome patients with CKD. J Am Col Cardiol 2011; 58: 2263-2268
93. Galis ZS, Black JB, Skarlatos SI. National Heart, Lung, and Blood Instituteand the
AC

translation of cardiovascular discoveries into therapeutic approaches. Circulation Res 2013;

112: 1212-1218

27
 ACCEPTED MANUSCRIPT

Figure Legends

Figure 1. Cardiovascular disorders and diseases often affect the kidney; renal disorders and
diseases often affect the cardiovascular system. Further, certain systemic disorders and

PT
diseases may affect both organs. Dysfunction of one organ results in dysfunction of the
other organ leading to a vicious cycle (arrows) [from reference 3].

RI
Figure 2. Homeostatic mechanisms in response to an increase or a decrease in atrial pressure
and stretch (A) or to a decrease in renal perfusion (B). ANP=atrial natriuretic peptide,

SC
RAAS=renin, angiotensin and aldosterone system, SNS= sympathetic nervous system.
Figure 3. Neurohumoral homeostasis on the cardiovascular system and the kidneys.

NU
ANP=atrial natriuretic peptide; GFR=glomerular filtration rate; LA=left atrium [modified from
reference 4].
MA
Figure 4. Neurohumoral activity present in heart failure may also affect kidney function;
inflammatory process present in heart failure is also shown. SNS=sympathetic nervous
D

system.
TE

Figure 5. The mechanisms underlying the development of renal dysfunction in chronic heart
failure are age dependent. Direct cardiorenal interactions due to hemodynamic changes and
P

neurohumoral activation prevail in younger patients (e. g. <40 years old) with non-ischemic
CE

dilated cardiomyopathy, whereas atherosclerosis and increased aortic/arterial stiffness as a

result of the aging process play important role in the elderly patients who constitute the
AC

vast majority of the heart failure population, especially patients with heart failure and
preserved ejection fraction.
Figure 6. Multiple metabolic and neurohumoral abnormalities present in chronic kidney
disease may affect the entire cardiovascular system. RAAS=renin, angiotensin and
aldosterone system
Figure 7. Long-term effects of coexisting common risk factors, especially in the elderly, may
affect both the heart and the kidney. Moreover, stiff aorta that occurs with aging regardless
of other risk factors may initiate or precipitate cardiac and kidney disease. Interrelationships
between heart and kidney disease are shown.

28
 ACCEPTED MANUSCRIPT

Figure 8. Multiple morbid conditions and interactions in heart failure (from ref. 40) (A) and
chronic kidney disease (modified from ref. 3) (B) are shown. The present definition of the
cardiorenal syndrome is a simplistic definition to a complex problem [from reference 38].

PT
RI
SC
NU
MA
D
P TE
CE
AC

29
 ACCEPTED MANUSCRIPT

PT
RI
SC
NU
MA
D
TE
P
CE
AC

30
 ACCEPTED MANUSCRIPT

PT
RI
SC
NU
MA
D
TE
P
CE
AC

31
 ACCEPTED MANUSCRIPT

PT
RI
SC
NU
MA
D
TE
P
CE
AC

32
 ACCEPTED MANUSCRIPT

PT
RI
SC
NU
MA
D
TE
P
CE
AC

33
 ACCEPTED MANUSCRIPT

PT
RI
SC
NU
MA
D
TE
P
CE
AC

34
 ACCEPTED MANUSCRIPT

PT
RI
SC
NU
MA
D
TE
P
CE
AC

35
 ACCEPTED MANUSCRIPT

PT
RI
SC
NU
MA
D
TE
P
CE
AC

36
 ACCEPTED MANUSCRIPT

PT
RI
SC
NU
MA
D
TE
P
CE
AC

37