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This textbook provides a practical and board-driven resource to describe and define the emerging field of cardiorenal medicine. Covering all aspects of the topic with depth and relevance, this groundbreaking reference brings together experts at the nexus between cardiovascular and renal medicine to provide an exception reference to educate in this critical area of modern medicine. It describes how the heart and kidneys are inextricably linked via hemodynamic, neural, hormonal and cellular signaling systems and, concentrating on disease-based coverage, goes on to review emerging concepts in epidemiology, pathogenesis, screening, diagnosis and the management of cardiorenal syndromes, all extensively illustrated and containing features to support scholarship in the field.

Textbook of Cardiorenal Medicine provides consistent chapter organization, clear design and engaging text to define the diagnosis, treatment, intervention and surgical aspects of the full range of conditions encountered within this area of medicine. It is therefore an essential resource to all involved in the management of cardiorenal disease.

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of Cardiorenal
Peter A. McCullough
Claudio Ronco


Textbook of Cardiorenal Medicine

Peter A. McCullough • Claudio Ronco

Textbook of Cardiorenal

Peter A. McCullough
Baylor University Medical Center
Texas A&M University
Dallas, TX

Claudio Ronco
Director, Department of Nephrology
Dialysis and Transplantation
International Renal Research Institute
Ospedale San Bortolo Vicenza

ISBN 978-3-030-57459-8    ISBN 978-3-030-57460-4


© Springer Nature Switzerland AG 2021
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way,
and transmission or information storage and retrieval, electronic adaptation, computer software,
or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are
exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in
this book are believed to be true and accurate at the date of publication. Neither the publisher nor
the authors or the editors give a warranty, expressed or implied, with respect to the material
contained herein or for any errors or omissions that may have been made. The publisher remains
neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Dedicated to:
Claudio Ronco, MD, Dir; ector, Department of Nephrology
Dialysis and Transplantation International Renal Research
Institute (IRRIV), Ospedale San Bortolo Vicenza, Vicenza, Italy.
Peter A. McCullough, MD, MPH
Baylor University Medical Center
Texas A&M University
Dallas, TX, USA


Cardiorenal medicine is an emerging multidisciplinary field that spans a wide
spectrum of disease that affects both the cardiovascular and renal systems. It
also uniquely highlights how one organ system can affect the other in both
health and disease. Cardiorenal medicine has a stout scientific foothold in
epidemiology, pathophysiology, diagnosis, prognosis, and management. The
bourgeoning medical literature concerning cardiorenal medicine in these
areas is testament to the growing base of new knowledge in this field.
The inaugural edition of Cardiorenal Medicine is the culmination of a bold
and ambitious project that sought out experts across the globe to put their
thoughts into text, tables, and figures for the reader to learn and gain new
insight into this field of medicine. The term “cardiorenal medicine” harkens
for collaboration and for careful understanding that living organisms are
organized into systems, and that those systems inter-relate and rely on one
another in both health and disease. It also intimates that multisystem disease
such as diabetes mellitus greatly influences both organ systems and those
changes in turn impact the next phases of disease in both organs. Lastly, cardiorenal medicine implies that in vitro diagnostics and therapeutics are very
likely to have clinical implications and, in some cases, direct application to
both organs.
This text is a tribute to each and every contributor who is an expert in his
or her fields. We are indebted to Springer Publications and their assiduous
pursuit of materials for publication with all the sudor of publisher working
through a global pandemic. It also commemorates a lifetime of professional
dedication and tireless effort by Dr. Claudio Ronco of Vicenza and Padua,
Italy. Professor Ronco was the original inspiration for this text and through
his vision we are “carpe diem” or seizing the day of science where cardiologists, nephrologists, intensivists, and primary care physicians can come
together in the best interests of medical science for the benefit of their patients
and generations to come.
Dallas, TX, USA

Peter A. McCullough



1	Implications of Chronic Kidney Disease on the
Epidemiology of Cardiovascular Disease��������������������������������������   1
Peter A. McCullough and Aaron Y. Kluger
2	Prevalence and Progression of Cardiovascular
Calcification in the General Population and
Patients with Chronic Kidney Disease ������������������������������������������   7
Paolo Raggi and Antonio Bellasi
3	Spectrum of Ventricular Dysfunction in
Chronic Kidney Disease������������������������������������������������������������������ 19
Amarinder Bindra and Yong Ji
4	The Myocardium in Renal Failure ������������������������������������������������ 25
Kerstin Amann
5	Impact of Renal Failure on Valvular Heart Disease �������������������� 31
Natalia Rocha and Katherine Panettiere-Kennedy
6	Arrythmias in Chronic Kidney Disease: Working
Towards a Clinical Approach in Atrial Fibrillation���������������������� 47
Justin Ashley and Manish M. Sood
7	Type 1 Cardio-Renal Syndrome ���������������������������������������������������� 59
Youn-Hyun Kim, Weining Xu, Takeshi Kitai,
and W. H. Wilson Tang
8	Type 2 Cardiorenal Syndrome�������������������������������������������������������� 75
Natalia Rocha and Peter A. McCullough
9	Type 3 Cardiorenal Syndrome�������������������������������������������������������� 95
Sandeep Soman and Lindsey Aurora
10	Type-5 Cardiorenal Syndrome ������������������������������������������������������ 111
Luca Di Lullo and Claudio Ronco
11	Post Contrast Acute Kidney Injury������������������������������������������������ 125
Richard Solomon
12	Distinct Cardiorenal Syndromes:
Cardiac Surgery Associated Acute Kidney Injury������������������������ 135
Andrew A. House and Andrea C. J. Cowan


13	Pediatric Cardiorenal Syndromes�������������������������������������������������� 155
Chiara Giorni, Alessandra Rizza, and Zaccaria Ricci
14	Key Concepts of Organ-Crosstalk�������������������������������������������������� 165
Grazia Maria Virzì and Anna Clementi
15	Methods to Assess Intra- and Extravascular
Volume Status in Heart Failure Patients���������������������������������������� 177
Maria Rosa Costanzo
16	Novel Biomarkers of Acute Cardiorenal Disease�������������������������� 207
Michael Haase, Christian Butter, and A. Haase-Fielitz
17	Novel Biomarkers of Chronic
Cardiorenal Disease ������������������������������������������������������������������������ 227
Peter A. McCullough
18	Mechanisms of Kidney and Heart Cross-talk in
Acute Kidney Injury������������������������������������������������������������������������ 235
Negiin Pourafshar and Mark D. Okusa
19	Kidney and the Heart in Multiorgan
System Failure���������������������������������������������������������������������������������� 245
Nevin M. Katz
20	Cardiac Consequences of Renal Artery Stenosis�������������������������� 255
Mohanad Hasan, Jose Tafur-Soto, and Hector Ventura
21	Obesity���������������������������������������������������������������������������������������������� 267
Sohail Abdul Salim, Krishna Keri, and Mohit Agarwal
22	Class Effects of SGLT2 Inhibitors on
Cardiorenal Outcomes�������������������������������������������������������������������� 279
Aaron Y. Kluger
23	Management of Diabetes Mellitus in
Acute and Chronic Cardiorenal Syndromes �������������������������������� 295
Allison J. Hahr and Mark E. Molitch
24	Pharmacoepidemiology in Cardiorenal Medicine������������������������ 315
Kristen M. Tecson and Scott S. Shafiei
25	Anticoagulation for Atrial Fibrillation in Advanced Chronic
Kidney Disease �������������������������������������������������������������������������������� 333
Simonetta Genovesi and Federico Ronco
26	Cardiac Consultative Approach to Hemodialysis
Patients and Cardiovascular Evaluation and
Management of Potential Kidney Transplant Recipients������������ 343
Mengistu A. Simegn and Charles A. Herzog
27	Nephrology Inpatient Consultative Approach in
Patients with Cardiovascular Disease�������������������������������������������� 369
Janani Rangaswami
Index���������������������������������������������������������������������������������������������������������� 383



Implications of Chronic Kidney
Disease on the Epidemiology
of Cardiovascular Disease
Peter A. McCullough and Aaron Y. Kluger



The heart and the kidneys are inextricably linked
via hemodynamic, neural, hormonal, and cellular
signaling systems. The kidneys are the most vascular organ in the body receiving a quarter of cardiac output at rest despite a distal location from
renal arteries branching from the aorta. Thus, follows that kidney disease is strongly associated
with cardiovascular illness and in fact, may be
considered more than a cardiovascular risk factor
and better termed as a cardiovascular risk state.
Additionally, when either organ sustains injury or
begins to fail, there appears to be a consequential
affect on the other organ in either an adaptive or
maladaptive response that we now recognize as a
“cardiorenal syndrome(s)” [1]. This chapter will
review the connections between the heart and the
kidneys from epidemiological, biological, and
clinical perspectives with the aim of gaining
greater appreciation for this important interface
in both acute and chronic care.

P. A. McCullough (*)
Baylor University Medical Center, Texas A&M
University, Dallas, TX, USA
A. Y. Kluger
Baylor Scott and White Research Institute,
Temple, TX, USA


Cardiovascular Risk
in Chronic Kidney Disease

The Chronic Kidney Disease Prognosis
Consortium (CKD-PC) was established in 2009
by Kidney Disease: Improving Global Outcomes
(KDIGO) organization in an attempt to understand the risks of declining renal filtration function represented by the estimated glomerular
filtration rate (eGFR) and the presence of albumin in the urine indexed to the filtered creatinine
concentration (urine albumin:creatinine ratio
[ACR]). In a series of manuscripts, this group
demonstrated in a very large, pooled database
(1,555,332 subjects in 45 cohorts), that the severity of chronic kidney disease (CKD) was related
to the risks of all-cause mortality, cardiovascular
death, acute kidney injury, progressive CKD, and
end-stage renal disease (ESRD) [2]. These relationships can also be shown in a “heat map” of
risk. It is important to understand that when both
eGFR and elevated ACR overlap, there appears to
be magnified risks for all outcomes. Data from
the National Kidney Foundation Kidney Early
Evaluation Program (KEEP) and the National
Health and Nutrition Examination Survey suggest that the majority of individuals with CKD in
the younger age groups are identified by albuminuria while those in the older age strata have
reduced eGFR (<60 mL/min/1.73 m2) as the
CKD marker. Importantly, the overlap between
the two markers is less common than one alone in

© Springer Nature Switzerland AG 2021
P. A. McCullough, C. Ronco (eds.), Textbook of Cardiorenal Medicine,


P. A. McCullough and A. Y. Kluger


these large populations. However, when both
reduced eGFR and albuminuria are present in the
same patient the predicted and observed rates of
cardiovascular events are markedly increased
over a relatively short (<5 years) duration. Thus,
it is critical that in every patient, both the eGFR
be calculated from the age, gender, race, and
serum creatinine using standardized equations
and that the urine ACR be checked on a first
morning voided specimen. Structural kidney disease detected by imaging studies including polycystic kidney disease also are characterized as
CKD in the absence of eGFR and ACR abnormalities. The CKD-PC was limited in terms of
nonfatal cardiovascular outcomes; therefore, we
must turn our attention to other sources of information to understand the connections to coronary
atherosclerosis, myocardial disease, valvular disease and arrhythmias.
The term “reverse epidemiology” has been
applied to patients with ESRD for many risk factors, particularly body weight. What this means is
that in the general population, increased adiposity as expressed with the body mass index is consistently associated with cardiovascular events
and reduced survival. However, in ESRD,
increased BMI confers improved survival. This
suggests that increased adiposity is the inverse of
cachexia. That is, as chronic disease progresses,
cachexia and reduction in weight is along common pathway towards inanition and death. Thus,
retention of adiposity is associated with survival.
Reverse epidemiology has also been observed
with total cholesterol and albumin which are
proxies for nutritional intake and are epidemiologically inversely related to the degree of


Coronary Heart Disease

Data from many studies suggests that the CKD
milieu promotes the early initiation and accelerated course of coronary atherosclerosis. Because
CKD is strongly associated with traditional coronary risk factors including hypertension, diabetes, dyslipidemia, and smoking, the combination
of these factors may be reflected by CKD and

thus its relationship is amplified by positive confounding. However, when adjusting for these factors, CKD has been consistently associated with
nonfatal myocardial infarction and cardiovascular death [3]. A prominent feature of coronary
atherosclerosis in patients with CKD and ESRD
is accentuated calcification which occurs in all
cases of atherosclerosis when reviewed at necropsy. Initially, calcium deposits on cholesterol
crystals in the subendothelial space [4]. However,
the progression of atherosclerosis involves a multitude of local and systemic factors which stimulate vascular smooth muscle cells to undergo
osteoblastic transformation into osteocyte-like
cells which deposit calcium hydroxyapatite crystals into both the subendothelial and medial compartments of blood vessels. Many factors have
been implicated in CKD to accelerate this process including low-density lipoprotein cholesterol, non-high density lipoprotein cholesterol,
vascular calcification factor, osteoprotegerin, and
most notably phosphorus [5]. As eGFR falls,
there is retention of phosphate which can stimulate the Pit-1 receptor on vascular smooth muscle
cells thereby facilitating the osteoblastic transformation [6]. Of note, neither dietary calcium or
the plasma concentration of calcium have been
independently associated with calcific deposits in
the coronary arteries. As CKD progresses, coronary artery disease is commonly identified on a
variety of clinical studies, frequently as longer
lesions and in more proximal vessels [7].
Fortunately more extensive calcification while it
is related to the burden of coronary disease, is
also associated with more stable lesions, thus,
CKD patients often have stable but extensive
CAD leading to episodes of both silent and symptomatic coronary ischemia.
It has been suggested that there are both traditional and non-traditional risk factors that may
contribute to more accelerated atherosclerosis in
persons with CKD. The traditional risk factors
include: elevated LDL-C, hypertension, diabetes
mellitus, smoking, family history of premature
coronary heart disease (first degree relative
female before age 55 and male before age
45 years). Nontraditional risk factors in CKD
have been variously mentioned in the literature


Implications of Chronic Kidney Disease on the Epidemiology of Cardiovascular Disease

and include blood markers of mineral and bone
disorder (hyperphosphatemia, elevated calcium-­
phosphorus product, osteopontin, hyperparathyroidism,
C-reactive protein, uremia, asymmetric dimethylarginine and reduced nitric oxide availability,
anemia, hyperuricemia, increased unbound iron
(catalytic or poorly liganded iron), homocysteine, fibrinogen, and increased coagulation proteins. None of these factors has been sufficiently
tested in prospective studies to be considered a
therapeutic target for prevention in CKD patients
with atherosclerosis.


Heart Failure

Chronic kidney disease promotes the three major
pathophysiologic mechanisms by which the left
ventricle can fail: pressure overload, volume
overload, and cardiomyopathy. Because hypertension is both a determinant and a consequent of
CKD, the vast majority of CKD patients have
longstanding histories of elevated blood pressure
and increased cardiac afterload resulting in left
ventricular hypertrophy and increased left ventricular mass [8]. Salt and water retention result
in chronic volume overload. Nephrotic syndrome
and loss of oncotic forces results in worsened
fluid retention and edema. Uremia and retention
of many substances (indoxyl sulfate and p-­cresol)
results in impaired myocyte function in both systole and diastole. It has become recently understood that production of fibroblast growth
factor-23 from bone in response to CKD phosphate retention, has off-target effects on the left
ventricular myocardium resulting in increased
left ventricular mass and cardiac fibrosis. The
resultant myocardial tissue has a reduced capillary density compared to that of persons with
normal renal function. Considerable evidence is
accumulating that “CKD cardiomyopathy” is
manifest by impaired systole and diastole with
biomarker and imaging evidence of cardiac fibrosis. The observation that galectin-3 levels correlate with type III aminoterminal propeptide of
procollagen, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-1 suggests that


myocardial macrophage infiltration enhances
turnover of extracellular matrix proteins in
patients with CKD [9]. Thus, patients with CKD
are at very high risk for the development of heart
failure associated with markedly impaired cardiorespiratory function and the cardinal features
of fatigue, effort intolerance, edema, and clinical
findings including pulmonary congestion and
elevation of B-type natriuretic peptides (BNP and
NT-proBNP) [10]. When acutely decompensated
heart failure is present, then a viscous cycle of
worsened renal filtration function, venous and
renal congestion, and further retention of salt and
water can occur. This is commonly termed cardiorenal syndrome type 1 [11].
It has become increasingly recognized that
hemodialysis itself may contribut to myocardial
disease through process of “myocardial stunning” where there are transient wall motion
abnormalities that are related to episodes of
hypotension during hemodialysis. The greater the
number of segmental wall motion abnormalities,
the worsened survival over time (Fig. 1.1). Recent
analyses suggest short daily hemodialysis in the
home setting is associated with fewer episodes of
intra-dialytic hypotension, regression of left ventricular hypertrophy, and a 41% lower risk of
heart failure, fluid overload, and cardiomyopathy
[12]. At very low ultrafiltration rates over longer
periods of time, the removal of fluid from the
intravascular space may better match the rate of
plasma refill from the extravascular space, and
thus, avoiding hypotension and myocardial


 alvular Calcific Deposits
and Complications

Accelerated aortic valvular and mitral annular
calcification and fibrosis is common in patients
with CKD and nearly universally present in
patients with ESRD. The murmur of aortic valve
sclerosis is found in the majority of patients while
the mitral annular disease is usually silent and
detected only by echocardiography or other
forms of imaging. The aortic valve sclerosis and
calcification can progress to symptomatic aortic

P. A. McCullough and A. Y. Kluger

Fig. 1.1 Pathophysiologic
rationale for myocardial
stunning in ESRD on

stenosis while the mitral annular disease can
result in very mild functional stenoses or regurgitation by Doppler but rarely requires surgical
attention. Recent studes have linked elevations in
lipoprotein (a) which occur in ESRD to the development of calcific aortic stenosis [13]. Both valvular lesions can be the substrate for acute
infective endocarditis in ESRD patients with
temporary dialysis catheters and occurs at a rate
of 6–8% per year. Staphylococcus aureus is the
main cause (75%) of vascular access-related bacteremia among patients receiving long-term
hemodialysis. When endocarditis occurs in this
setting, the operative mortality rate can be in
excess of 50% [14]. Most patients with CKD
should undergo echocardiography at some point
in their care in order to evaluate not only for the
extent of valve disease but also to assess left ventricular systolic and diastolic function.



Patients with CKD have the myocardial and
hemodynamic determinants of all forms of
arrhythmias. In the United States Renal Data
System database, 62% of cardiac deaths (27% of
all deaths) are attributable to lethal arrhythmias
[15]. Atrial fibrillation occurs at an elevated rate
in patients with CKD and is associated with an
increased risk of cardioembolic stroke compared
to those with normal renal function at all levels of
the CHA2DS2-VASc score. Recent data are supportive of apixaban (either 2.5 mg or 5 mg p.o.

bid) potentially in place of warfarin for CKD
patients with nonvalvular at high risk of stroke or
systemic embolism [16]. Because of accelerated
myocardial fibrosis and the presences of both
macrovascular and microvascular disease, re-­
entrant ventricular tachycardia is believed to be
the prelude to ventricular fibrillation followed by
asystole and sudden death. Increased premature
atrial and ventricular beats when seen on monitoring can be harbingers of atrial fibrillation and
ventricular tachycardia, respectively. Electrolyte
shifts, and particularly changes in potassium concentration that occurs in CKD and is accentuated
with forms of dialysis are also believed to play a
role in ventricular arrhythmias and sudden death,
most likely due to ventricular fibrillation. The
role of implantable cardio defibrillators is controversial at the time of this writing given shortened
survival and the risks of device and lead infection
in ESRD [17]. Each guidelines-based approach
in the population of patients with heart disease
and normal renal function is complicated by
increased adverse events and even iatrogenic
death in patients with CKD and ESRD [18].
Thus, therapy must be individualized and very
frequent monitoring is required.



The connection between kidney and heart disease
can be viewed in four domains: coronary atherosclerosis, myocardial disease, valvular abnormalities, and arrhythmias. Chronic kidney disease


Implications of Chronic Kidney Disease on the Epidemiology of Cardiovascular Disease

plays a role in the epidemiology, pathogenesis,
presentation, outcomes, and management of each
manifestation of CVD. Future research is needed
to better understand the unique mechanisms at
work in patients with CKD that promotes and
worsens CVD outcomes. Practical strategies are
needed to guide clinicians towards most appropriate medical and procedural management of
this high-risk population.




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Aspromonte N, Bagshaw SM, et al. Cardiorenal
syndromes: an executive summary from the consensus conference of the acute dialysis quality initiative
(ADQI). Contrib Nephrol. 2010;165:54–67.
2. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor
BC, Matsushita K, et al. The definition, classification, and prognosis of chronic kidney disease, a
KDIGO controversies conference report. Kidney Int.
3. McCullough PA, Li S, Jurkovitz CT, Stevens LA,
Wang C, Collins AJ, et al. Kidney Early Evaluation
Program Investigators. CKD and cardiovascular disease in screened high-risk volunteer and general populations, the Kidney Early Evaluation Program (KEEP)
and National Health and Nutrition Examination
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Prevalence and Progression
of Cardiovascular Calcification
in the General Population
and Patients with Chronic Kidney
Paolo Raggi and Antonio Bellasi


 oronary Artery Calcium
as a Marker of Atherosclerotic
Vascular Disease in the General

Atherosclerosis development is almost universal
during human life [1] and coronary artery calcium (CAC) has been known for centuries to be
an intrinsic component of the disease. CAC is
accumulated through active processes of calcification resembling hydroxyapatite bone formation and not simple precipitation of crystals [2].
To date, it is still unclear whether CAC is deposited in an attempt to heal the atherosclerotic
plaque, or whether it is part of an ongoing process of inflammation and damage of the subintimal arterial layer. However, it has become very
clear that the presence of CAC is a harbinger of
poor outcome. The demonstration that CAC carries an adverse prognostic value was obtained
with fluoroscopy [3] even before the introduction
of fast computed tomography, but it was only

P. Raggi (*)
Division of Cardiology, Mazankowski Alberta Heart
Institute, University of Alberta,
Edmonton, AB, Canada
A. Bellasi
Reserarch, Innovation and Brand Reputation,
ASST Papa Giovanni XXIII, Bergamo, BG, Italy

with the latter that non-invasive quantification of
CAC became possible [4].
CAC seen on cardiac CT imaging can be
quantified with 3 different scores. The Agatston
score [4] is the product of the area of a calcified
lesion by the peak density within the lesion.
Although this score is exquisitely sensitive to the
calcium content of a plaque, it is poorly reproducible and it is therefore not recommended for
sequential scanning. The volume score [5] is the
sum of all voxels within a calcified plaque with
an attenuation (i.e radiological density) greater
than 130 Hounsfield units. This score was introduced to overcome the limited reproducibility of
the Agatston score and it is recommended for
sequential CT studies. Finally, the mass score [6]
is an actual measure of calcium content in the
plaque, and it requires the positioning of a calcium phantom underneath the patient while
acquiring the CT scans, but it is rarely used.
In the general population the extent of CAC
measured on CT imaging is closely associated
with the burden of atherosclerosis, and it is generally believed that CAC represents 15–20% of
the total plaque burden [7, 8]. CAC can be seen as
the final product of a long time exposure to risk
factors for atherosclerosis [9, 10], and as such it
is loosely correlated with the Framingham risk
score (FRS) [11]. However, a substantial number
of patients at risk of atherosclerotic events have
no CAC on a screening CT [12, 13], and their
event rate is extremely low [13, 14].

© Springer Nature Switzerland AG 2021
P. A. McCullough, C. Ronco (eds.), Textbook of Cardiorenal Medicine,



The impact of risk factors is not equal among
men and women and among subjects of different
ethnic groups [15]. For example black patients
have a lower prevalence and smaller amounts of
CAC compared to white patients [16–19], despite
having more risk factors for atherosclerosis than
Whites [20]. However, black patients with CAC
tend to have a worse prognosis than Whites [16].
The investigators of the Multi Ethnic Study of
Atherosclerosis (MESA) performed CAC
screening in 6814, 45–84 year-old patients of
White, Hispanic, Black and Chinese ethnicity
[21]. The prevalence and magnitude of CAC
were higher in Whites, followed by Chinese,
Hispanic, and black patients [22]. As shown in
several other databases, the prevalence and
extent of CAC were higher in men than in women
of all ethnicities, and a good proportion of
patients had no CAC despite the presence of risk
factors. Women have smaller arteries than men
[23–26], and the volume of atherosclerosis and
CAC that can be accommodated in their arteries
are therefore smaller than that of men.
Additionally, women tend to develop atherosclerosis 10–15-year later than men and this is
reflected in the delayed appearance of CAC on
cardiac CT screening [27].
Nomograms of CAC scores have been used to
describe the age and sex prevalence of subclinical
atherosclerosis in several studies [27–29]. Raggi
et al. [30] demonstrated that CAC nomograms
help to assess risk among patients with a low
absolute CAC score, but a high score relative to
subjects of similar age and sex. In a study of 632
asymptomatic subjects referred for CAC screening and followed for 32 ± 7 months, patients with
high absolute CAC scores had a high risk of myocardial infarction. However, the majority of
patients had a small absolute CAC score, but
investigators noted that the majority of these
patients had a high score percentile. This suggested that they had accumulated a critical burden of atherosclerosis too quickly and too large
for their age.
The utility of CAC as a marker of risk for
future cardiovascular events has been tested in
numerous studies in the general population.
Probably the most representative are 2 large pop-

P. Raggi and A. Bellasi

ulation studies; the MESA -mentioned aboveand the Heinz Nixdorf Recall (HNR) study
conducted in the Ruhr area in western Germany.
Both studies showed that increasing CAC scores
are associated with a progressively increased risk
of cardiovascular events [31, 32], and CAC adds
incrementally to traditional risk factors for atherosclerosis for the prediction of events [32, 33].
The same investigators incorporated CAC scores
in a new risk score algorithm derived from the
MESA and validated with data from the HNR
data and the Dallas Heart Study (DHS) [34].
They showed that incorporating CAC scores into
a prediction model increased its ability to identify patients at risk of events (C-statistics
improvement from 0.75 to 0.80; p < 0.0001),
with excellent discrimination and calibration.
Several other methods to assess extent of CAC
besides the classic methods described above were
shown to be predictive of events. Some of the
reported methods include: number and location
of calcified lesions in the coronary artery tree
[35], distribution of calcified lesions along the
course of the coronary arteries [36], coverage of
the coronary artery length with calcific plaques
[37], and presence of low attenuation (i.e. density) plaques [38]. The latter is of particular interest for the purpose of comparing risk assessment
by means of CAC in the general population and
in patients affected by CKD. For the general population the presence of low attenuation plaques
may be indicative of plaques with a larger lipid
content, hence fragile and more prone to fracture.
In patients with CKD, the pathophysiology of
calcium accumulation in the vasculature is likely
very different and, as discussed later in this chapter, risk increases with increasing plaque density
The utility of CAC screening in the general
population extends to its very high negative predictive value. Among 19,898 patients without
CAC at screening, the 10-year mortality rate was
0.87%, while it rose to 7.8% among the 18,767
with a CAC score > 10 [40]. Esteves et al. showed
that without CAC on a screening chest CT, 99%
of the simultaneously performed nuclear stress
tests were negative for inducible myocardial
ischemia [41]. Based on several other ­publications


Prevalence and Progression of Cardiovascular Calcification in the General Population and Patients…

showing a similar trend, the recent guidelines of
the American Heart Association and American
College of Cardiology on treatment of dyslipidemias added for the first time a consideration for
“de-escalation” of treatment in patients at intermediate risk in the absence of CAC [42]. On the
other hand the presence of CAC should increase
the level of risk and stimulate an intensification
of treatment [42].
In view of its excellent specificity for the presence of atherosclerosis in the arterial wall, some
investigators thought that sequential CAC imaging might be useful to assess effectiveness of
anti-atherosclerotic therapies. Initial observational studies with statins seemed to prove that
these drugs delay progression of CAC [5, 43].
However, further randomized trials disputed
these initial observations [44, 45], and careful
metanalyses even showed an increase in CAC
score in patients treated with lipid lowering
agents [46, 47]. As a consequence, current guidelines discourage use of sequential CAC imaging
in the general population for the mere purpose of
gauging effectiveness of therapeutic interventions. As discussed in more detail in the next section, the situation is different in patients with
CKD likely due to the different pathophysiology
of vascular calcification in those patients.


Cardiovascular Calcification
in Chronic Kidney Disease



Cardiovascular calcification (CVC) is highly
prevalent in patients with CKD [10, 48] and it
involves both arterial conduits and cardiac valves
(Figs. 2.1 and 2.2). As such, it is regarded as an
important marker of CV risk in this fragile population [49].
Accelerated CV senescence has been postulated as one of the mechanisms potentially
responsible for development of CVC and CV risk
in patients with CKD [50]. It is notable that CVC
becomes more prevalent and severe as renal function declines, independent of age [51].
Additionally this marker of vascular damage is


less closely associated with atherosclerotic risk
factors than in the general population [52].
Calcified coronary artery plaques are larger and
atherosclerotic plaques contain more calcium
than in the general population [53].
Although it is unclear if medial calcification
develops in the coronary arteries, considered to
be medium size arterial conduits, a few reports
suggested that in patients with advanced CKD
subintimal and medial calcification may coexist.
The two most likely coexist in larger size arteries
such as the carotid arteries and the aorta [2].
While sub-intimal calcification has been traditionally associated with atherosclerosis, medial
calcification seems connected with non-­
traditional CV risk factors such as inflammation,
oxidative stress, advanced glycation end products
(AGEs) accumulation, derangement of bone and
mineral metabolism, uremic toxins and deficit of
inhibitors of CVC [2, 48, 50].
Several in-vitro and in-vivo data suggest that
abnormalities of calcium and phosphate homeostasis may influence the development of CVC
[54]. In physiologic conditions, inhibitors such as
phyrophosphate, matrix-GLA protein (MGP) or
fetuin-A prevent minerals from aggregating,
forming insoluble crystals of hydroxyapatite that
precipitate in soft tissues including the blood

Fig. 2.1 Axial computed tomography image of the heart
showing heavy calcium deposits in the ascending aorta
(Ao), left main trunk (LM), left anterior descending artery
(LAD), left circumflex artery (LCx) and descending thoracic aorta (DAo)


P. Raggi and A. Bellasi

Fig. 2.2 Positron emission tomography (PET) stress test
in the same patient as above showing a large perfusion
defect after stress involving the entire inferior wall of the
left ventricle (part of the defect is indicated by the asterisks). The perfusion defect is entirely reversible at rest.

Note that the distribution of coronary calcium and areas of
ischemia often do not correspond; therefore it is incorrect
to use distribution of coronary artery calcium to predict
inducibility and location of myocardial ischemia

v­ essel walls [2, 48, 54]. Preclinical data show
that incubation of vascular smooth muscle cells
(VSMCs) with high levels of calcium and phosphate in the media induces an osteochondrogenic
phenotypic switch and VSMCs become capable
of secreting bone matrix in the context of the
arterial wall, triggering deposition and progression of CVC [2]. Some researchers suggested
that passive precipitation of hydroxyapatite nano-

crystals may occur due to chronically elevated
serum concentrations of minerals, promoting
activation of resident macrophages, pro-­
inflammatory cytokine secretion and cellular
apoptosis, in an attempt to eliminate calcium-­
phosphate crystals [48].
CKD is characterized by a state of chronic
subclinical inflammation due to an imbalance of
pro- and anti-inflammatory cytokines [50].


Prevalence and Progression of Cardiovascular Calcification in the General Population and Patients…


expression of pro-inflammatory factors
Finally, vitamin K (an essential cofactor for
such as tumor necrosis factor alpha (TNFα) or MGP carboxylation and activation) and pyrointerleukin 6 (IL-6) reduces the synthesis of anti-­ phosphate (an inhibitor of calcium-phosphate
inflammatory factors. Fetuin-A and alpha-klotho crystals formation) are often deficient in CKD
are among the deficient factors that may be impli- patients further increasing susceptibility to develcated in CVC inception and progression. opment of CVC in these patients [55].
Fetuin-A is essential for calcium-phosphate crystals solubilisation and formation of calciproteins
in plasma. In contrast, alpha-klotho modifies the 2.2.2 Epidemiology and Clinical
Significance of Cardiovascular
binding of fibroblast growth factor 23 (FGF23) to
Calcification in CKD
its receptor in the kidney increasing urinary phosphate wasting [48]. Although the roles of calciproteins and alpha-klotho/FGF23 are not Patients with CKD have an exceptionally high
completely understood, their impact on mineral risk of cardiovascular (CV) events [56]. Although
metabolism may account for some of their pre- there is an incomplete understanding of the reasumed effect on CVC deposition and progression sons behind such risk, epidemiological studies
[48]. Of note, the effect of the altered Klotho/ have repeatedly reported a linear and indepenFGF23 axis on CVC may be independent of dent association between degree of renal function
phosphate homeostasis since Klotho impairment and risk of CV events [56]. One in
modulates other signalling pathways such as two patients with end stage renal disease (ESRD)
FGF-receptor 1 and mTOR [48]. Future efforts receiving dialysis dies from a CV event [56, 57].
are required to establish the contribution of these Risk algorithms validated in the general populafactors in the development of CVC in patients tion to predict major CV events (MACE) underwith CKD due to the conflicting clinical data cur- perform in patients with CK [58], and these
rently available.
patients suffer a poorer outcome after a CV event
Oxidative stress and accumulation of AGEs [56] than subjects with normal renal function.
have also been implicated in the pathogenesis of
In comparison with the general population,
CVC [48]. Besides promoting calcium/phosphate patients with CKD suffer from the impact of non-­
removal from the bone through activation of the traditional risk factors such as derangements of
RANK/RANKL system in osteoblasts, experi- bone and mineral metabolism and the accumulamental data suggest that AGEs may induce tion of uremic toxins. The most frequent cardioVSMC osteogenic differentiation through vascular conditions of patients with CKD are
p38-mitogen-activated protein kinase (MAPK) sudden cardiac death, arrhythmias and congesas well as Wnt/β catenin signalling. Additionally, tive heart failure, while ischemic heart disease is
AEGs may act synergistically with some uremic relatively less common [56].
toxins and induce the synthesis of pro-­ Epidemiological studies showed that CVC is
inflammatory cytokines (IL-1, IL-6, TNFα) associated with adverse outcomes in patients with
linked to endothelial dysfunction and vascular CKD and that the prevalence of CVC increases
calcification [48].
with declining renal function. In a cohort of 572
Uremic toxins that accumulate as renal func- non-dialysis dependent CKD (NND-CKD)
tion declines may also affect vascular health [48]. patients Gorriz and coworkers documented a stepAs an example, indoxyl sulfate triggers the wise age-independent increase in prevalence and
expression of the sodium-phosphate co-­severity of vascular calcification [59]. The authors
transporter Pit-1 that enhances the uptake of cal- assessed CVC by means of simple imaging tools
cium and phosphorus by VSMCs and appears to such as planar X-rays of the abdomen, hips and
mediate their osteogenic differentiation. In addi- hands, and detected calcifications in one or more
tion, indoxyl sulfate suppresses the hepatic syn- territories in 79% of the study participants; in
thesis of Fetuin-A [48].
47% of the patients CVC was graded as severe


[59]. The MESA investigators reported a higher
prevalence and severity of CAC among 1284 subjects with non dialysis dependent-CKD compared
to 5269 subjects with normal renal function
enrolled in the study [51]. In the Dallas Heart
Study, CKD (defined as presence of microalbuminuria and GFR <60 mL/min*1.73 m2) compared to normal renal function, was associated
with an almost threefold increase in risk of extensive CAC (Odds Ratio of CAC greater than
100 AU 2.85; 95% confidence interval, 0.92 to
8.80 in CKD vs. no-CKD subjects) [60].
The prevalence of CVC continues to increase
after initiation of dialysis and up to 80% of
patients on maintenance dialysis exhibit some
degree of CVC [61, 62]. It is also notable that
unlike the general population, white and black
patients, as well as men and women receiving
maintenance hemodialysis show no difference in
markers of vasculopathy (namely thoracic aorta
calcification, CAC and arterial stiffness) despite
differences in baseline clinical characteristics
[52]. These data suggest that renal replacement
therapy (RRT) is toxic for the CV system independent of clinical characteristics that may differentiate patients in the general population.
Whether restoration of renal function and dialysis cessation after kidney transplantation reduce
the risk of CVC is still under scrutiny. Research
data in this direction are limited, and likely confounded by the concomitant use of various immunosuppressants [63].
A large amount of observational data accumulated over the years, demonstrated that CVC is
associated with an adverse outcome in patients
with CKD. Simple imaging modalities such as
vascular ultrasound and planar X-ray to show
presence of CVC in the radial, femoral, iliac
arteries [64–67], abdominal aorta [68, 69], and
CAC on chest CTs [70, 71] have all shown the
power of CVC as a marker of risk in CKD.
The value of CAC as a marker of risk in CKD
patients is also supported by large collaborative
epidemiological studies. In the Chronic Renal
Insufficiency Cohort (CRIC) study, CAC predicted myocardial infarction, congestive heart
failure and all-cause mortality, independent of
baseline CV risk evaluated by traditional risk

P. Raggi and A. Bellasi

score algorithms [72]. In addition, inclusion of
CAC score in a risk algorithm led to a small albeit
significant increase in the accuracy of cardiovascular events prediction [72]. In the MESA study
CAC was associated with and adverse outcome
both in patients with normal and impaired renal
function independent of age, sex, race and comorbid conditions [51]. Additionally, CAC was a better predictor of outcome than markers of arterial
stiffness (ankle-brachial index) and carotid
intima media thickness [51].
Similar findings have been reported in CKD
patients receiving maintenance hemodialysis or
peritoneal dialysis (PD) and after kidney transplantation [10, 63, 73]. Presence or extent of vascular calcification predict unfavorable events
irrespective of baseline risk or comorbidities [10,
63, 73].
In contrast, as seen in the general population,
the absence of CVC is a harbinger of an excellent
prognosis. Block et al. [62] showed that CAC measured within a few weeks of dialysis initiation was
a significant predictor of mortality after adjustment
for age, race, gender, and diabetes mellitus with an
increased mortality proportional to baseline score
(P = 0.002) [71]. However, the absence of CAC
was associated with an excellent prognosis and a
low mortality rate at 5 years (3.3/100 patient years
vs. 14.7/100 patients years for CAC > 400). In a
series of 179 patients receiving PD, subjects without CAC had a significantly lower risk of all-cause
mortality, cardiovascular mortality and cardiovascular events, even after adjustment for demographic
and comorbid factors [73].
Deposition of hydroxyapatite in the arterial
wall is linked with other markers of cardiovascular risk. As with vascular calcification, a stepwise
increase in arterial stiffness with increasing CKD
stage has been documented in non-dialysis
dependent-CKD patients [74, 75]. In a series of
132 patients new to dialysis, Di Iorio et al.
reported a significant association of CAC and
arterial stiffness (assessed via pulse wave velocity) as well as abnormal myocardial repolarization (assessed via QT dispersion on EKG) [76].
Similarly, Raggi and coworkers showed that
patients on maintenance hemodialysis with evidence of valvular, thoracic and abdominal aorta


Prevalence and Progression of Cardiovascular Calcification in the General Population and Patients…

calcification have reduced aortic compliance
[77]. Observational data confirmed the cardiovascular risk inherent with decreasing arterial
compliance [78, 79].
Finally, calcification of the cardiac valves has
been associated with an unfavourable outcome in
CKD. The prevalence of aortic and mitral valve
calcification is higher in CKD subjects than the
general population. Cardiac valve calcification
leads to disturbed leaflet motility, increase transvalvular pressure gradients as well as left ventricular
hypertrophy and, in some cases, left atrium enlargement [80, 81]. All of these factors are predictors of
an adverse prognosis. Of interest, the increased risk
associated with valvular calcification appears independent of its reported association with coronary
artery or aortic calcification [67, 82].
The debate on the pathogenetic and teleological meaning of calcium deposition, repair mechanism vs. promoter or participant in vascular
damage, is still ongoing. However, some data support the notion that plaque mineral content is
associated with an adverse outcome. In a series of
140 consecutive hemodialysis patients, higher
plaque density was independently associated with
increased mortality before and after adjustment
for confounders [39]. In addition, plaque density
mitigated the risk associated with CAC burden
(significant interaction effect) [39]. These results
are in conflict with data reported in subjects with
preserved renal function. In fact, the MESA investigators [38] reported an inverse -rather than
direct- association of plaque density and survival
in subjects from the general population. Reverse
epidemiology is a plausible explanation. Indeed, a
large number of CKD patients expire in the course
of CKD mainly due to CV events. Hence, CKD
subjects receiving dialysis may not be comparable
to individuals with normal renal function albeit
matched for age and sex.


Progression of Cardiovascular
Calcification in CKD

In consideration of the prognostic significance of
both vascular and valvular calcification, a great
effort has been devoted to develop therapies to


delay or reverse CVC in patients with
CKD. Lipophilic statins seem to promote rather
than inhibit calcification progression [83], possibly due to inhibition of vitamin K synthesis [83].
Indeed, vitamin K is an essential factor for MGP
activation that is a potent inhibitor of
CVC. Several ongoing trials are testing the effect
of vitamin K supplementation on CVC progression. In this regard, trials designed to compare
the effects of new direct oral anticoagulants
(DAO) with vitamin K antagonist (warfarin) in
patients with atrial fibrillation are also much
awaited since they will shed light on whether
vitamin K metabolism modulation impacts CVC
progression [84].
The most frequently and best-investigated
therapies to affect CVC so far have been those
involving phosphate binders (Fig. 2.3). Calcium
supplements are associated with CVC progression in the general population [85] as well as
CKD patients [86, 87]. Although calcium supplements are commonly used as phosphate binders
in advanced CKD or dialysis dependent patients,
several studies showed that they can expose
patients to an excess calcium load, positive calcium balance and promote calcium crystal deposition in soft tissue and vessels [88]. In a
randomized controlled study of patients with
moderate to advanced CKD, subjects receiving
calcium acetate showed a trend toward CAC progression compared to placebo or calcium-free
phosphate binders [89]. A considerable amount
of data has been accumulated on the effect of calcium containing vs. calcium free phosphate binders on CVC progression in patients on
maintenance hemodialysis. A recent metanalysis
showed that use of calcium based binders is associated with a significant CAC progression; the
increase in Agatston score was 95 (95% confidence interval: 43–146) units higher among
patients treated with calcium-containing phosphate binders [87]. This was associated with a
significant 22% increased risk of all-cause mortality [87].
Though based on preliminary observations,
the effect of calcium supplements may be modified by the concomitant use of other drugs that
modulate calcium metabolism such as calcimi-

P. Raggi and A. Bellasi




Fig. 2.3 Comparison of axial computed tomography
images of the heart taken 1 year apart, showing progression from 3 (panel a, baseline scan) to 4 calcified lesions

(panel b, follow-up scan) along the length of the left anterior descending artery

metics or vitamin D [90]. In a post-hoc analysis
of the ADVANCE trial [91], patients with evidence of aortic valve calcification at study inception showed a significantly smaller progression
of CAC when treated with cinacalcet and low
doses of vitamin D compared to flexible doses of
vitamin D [92]. In a post-hoc analysis of the
INDEPENDENT study [93], the concomitant use
of calcium-free phosphate binders and cincacalcet was associated with a better survival compared to the combination of calcium based
binders and cinacalcet or vitamin D [94]. Based
on the numerous studies showing the undesirable
effect of calcium based therapies, guidelines on
mineral metabolism management in patients with
CKD recommend the use of limited amounts of
calcium-based phosphate binders in all stages of
renal impairment [95].
Newer compounds designed to slow the progression of vascular calcification are currently
under clinical development and hold promise for
the future. A new inhibitor of CVC, SNF472, has
progressed from phase 1 clinical development
and is being studied in an ongoing phase 2 trial
that will hopefully shed light on its potential inhibition of CAC progression [96]. This compound
shares chemical properties with bisphosphonates
and pyrophosphate and preclinical data suggest
that CVC regression may occur in animals treated
with SNF472 [96]. Other drugs are of potential
interest to reduce vascular calcification deposition and progression. Although we are not aware

of any trial in humans, an increase mineralization
in bone coupled with reduced hydroxyapatite
deposition in the vasculature has been described
in preclinical models treated with sotatercept, an
anti-anemia compound that inhibits the activin-A
receptor. Similarly, it has been shown that bortezomib and everolimus may potentially prevent
CVC progression by increasing Wnt/B-catenin
signalling and Klotho synthesis, respectively.
Finally, sclerostin, and DKK1-secreted frizzled
related proteins (Wnt inhibitor antagonists) are
under preclinical development and future efforts
are needed to establish their role in inhibition of
CVC progression [97].



Only a portion of the exceptional cardiovascular
morbidity in patients with CKD can be explained
by traditional risk factors. During the past several
years, it has become apparent that CVC contribute substantially to the adverse prognosis of
patients with CKD, and that alterations of mineral metabolism and bone turn-over are closely
linked with the development of vascular and
­valvular calcification. However, it is noteworthy
that a proportion of patients, even after years of
advanced CKD and renal replacement therapy,
do not develop CVC and have a remarkably lower
probability of events compared to patients with
CVC. Some interventions directed at limiting


Prevalence and Progression of Cardiovascular Calcification in the General Population and Patients…

exposure to known or purported noxious stimuli
have been shown to slow the development of
CVC and its adverse effects. More research is
undoubtedly necessary to advance this agenda
and continue to expand on the successes of earlier endeavors.

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Spectrum of Ventricular
Dysfunction in Chronic Kidney
Amarinder Bindra and Yong Ji

Chronic kidney disease (CKD) is the presence of
structural and functional abnormalities of the
kidneys with gradual loss of kidney function and
progressive decrease in glomerular filtration rate
(GFR). It is associated with significant number of
comorbidities and cardiovascular diseases where
a significant percentage of patients suffer from
adverse cardiovascular events or mortality before
progressing further into the stages of CKD. The
heart and the kidney are two intricately linked
organs through hemodynamic functions involving various regulatory pathways. These pathways
include the sympathetic nervous system, renin
angiotensin aldosterone system, and other various neuro-hormonal systems which can serve as
a compensatory mechanism but may lead to progressive structural changes to the heart beginning
in the earlier stages of CKD.
As the population begins to age with higher
percentage of people living beyond 60 years old,
the prevalence of hypertension (HTN), diabetes
mellitus (DM), obesity, and other comorbidities
increase causing age related pathological changes
to the kidney and the heart driven primarily by
A. Bindra (*)
Department of Advanced Heart Failure and
Transplant, Baylor Scott and White Heart and
Vascular Hospital, Dallas, TX, USA
Y. Ji
Department of Cardiology, Loma Linda University
Health, Loma Linda, CA, USA

progressive vascular injury. CKD has traditionally been linked with cardiovascular diseases,
particularly sharing a close relationship with
accelerated atherosclerosis. Now with more
advanced diagnostic modalities, evidence of
structural changes to the heart or the process of
cardiac remodeling is becoming more transparent. CKD has been shown to have a strong association with ventricular systolic and diastolic
function through various mechanisms. In this
chapter, we will discuss how CKD has a direct
and indirect contribution to the process of cardiac
remodeling and changes in cardiac geometry and
structure leading to a spectrum of ventricular
With declining kidney function there has been
an increase in the prevalence of heart failure
(HF). In the ARIC Study, Kottgen et al. showed
that the incidence of heart failure (HF) was threefold higher in individuals with eGFR <60 mL/
min [1]. In a prospect cohort study of 433 end
stage renal disease (ESRD) patients who were
followed from start of ESRD therapy to mean of
41 months, 31% of the patients had cardiac failure, 15% had systolic dysfunction, 32% had LV
dilatation, and 74% had left ventricular hypertrophy at the start if therapy [2]. Identifying individuals with CKD and newly diagnosed HF is
important as prognosis is poor in these patients as
the mortality rate three years after diagnosis of
HF in ESRD patients was 83% [3]. Specifically
LV cavity and mass index were independently

© Springer Nature Switzerland AG 2021
P. A. McCullough, C. Ronco (eds.), Textbook of Cardiorenal Medicine,


A. Bindra and Y. Ji


associated with death after two years [2]. The
timing of cardiac dysfunction occurrence in those
with CKD that is independent of other comorbidities is not yet well known; however, the
course has been shown to occur sooner if patient
has significant concurrent comorbidities including HTN and DM.
There is increasing data to support the role of
echocardiography as a noninvasive method in the
evaluation of cardiac function in advanced CKD
patients. Two-dimensional echocardiography
(2D-echo) is an important diagnostic modality
for assessment of RV and LV structure and function by providing measurements of ventricular
diameters and volumes, wall thickness, and ejection fractions. But 2D-echo can also provide useful information regarding atrial and ventricular
filling pressures. Trans-mitral pulsed wave doppler flow in echocardiography is used to measure
diastolic function, particularly by measuring the
E (early diastolic filling phase) velocity which
can be influenced by the load on the left atrium
(LA) and heart rate (HR) [4]. One can also assess
the early diastolic velocity along the longitudinal
myocardial axis (e′) at the level of the mitral
annulus by using the tissue doppler imaging
(TDI). Although there are some pitfalls, the ratio
of E/e’ have been traditionally used to measure
filling pressures and some have used it as a
marker of prognosis in patients with CKD [5].
Increasing stages of renal failure have been
shown to correlate with LA size and Left Ventricle
(LV) systolic and diastolic dimensions.
Interestingly, worsening diastolic function measured by shortening of deceleration time, E wave,
and E/A ratio was noted in more than 50% of
patients in ESRD with formed AV fistula and
their diastolic diameter of the LV improved after
HD (hemodialysis) sessions [6]. Also noted
through echocardiography was increase in LV
muscle mass, interventricular septal thickness in
end diastole and systole, and right ventricle (RV)
diameter with increased stage of CKD. 2D-Echo
has expanded our understanding of the morphological changes associated with CKD and its
physiological consequences.
One of the key cardiac pathophysiological
features in patients with CKD is LVH. Study by

Park et al. showed a strong association of higher
LV mass, increased LVH, and abnormal LV
geometry in those with eGFR <30 mL/min [7].
Specifically‚ higher albuminuria have also been
associated with higher LV mass, and lower eGFR
has been linked with LV size and systolic and
diastolic function [8]. In the general population,
prevalence of LVH is predicted to be approximately 15–21%, but near 50–70% in the intermediate stages of CKD, and 90% in ESRD [9].
Patients who have classic risk factors such as diabetes, hypertension, are at increased risk of
developing renal failure leading to accelerated
atherosclerosis and vascular disease, reninangiotensin- aldosterone (RAAS) activation, and
volume and pressure overloaded state which all
contribute to the development of compensatory
LVH. There are various proposed mechanisms of
the progression and stages of ventricular
Traditionally cardiologists have tried to
describe HF syndrome with purely hemodynamic concepts and targeted therapy towards
correcting hemodynamic derangements—Fig.
3.1. However, explanation of heart failure with
just hemodynamic stressors has been shown to
be inadequate leading to further suggestions and
investigation of alternative mechanisms involved
in the disease process. When often discussing
the pathophysiology of the heart, we discuss the


Increased preload
(volume overload)

LV Dilation

Fig. 3.1 Hemodynamic model

Increased afterload
(pressure overload)

arterial stiffness,
valvular aortic
stenosis, LVH


Spectrum of Ventricular Dysfunction in Chronic Kidney Disease



Angiotensin II

capillary density




Fig. 3.2 Micro vascular model

preload, ­afterload, and measurement of pressure,
volume, and flow. When targeting treatment
options we often think about cardio output, pulmonary capillary wedge pressure, and systemic
vascular resistance.
One of the more popular hypothesis involves
the neuro-hormonal mechanism, where the activation of the sympathetic nervous system and
RAAS produces a harmful effect on the heart by
exacerbating further hemodynamic abnormalities
and has a direct toxic effect on the myocardium.
Activation of these systems leads to systemic
vasoconstriction, stimulates sodium and water
retention, further increasing neuro-hormonal
activity through a vicious cycle by increasing
atrial distension and progresses to secondary
baroreceptor dysfunction. Studies have shown
that elevated nor-epinephrine and angiotensin has
direct deleterious effects on the myocytes which
produces increased LV remodeling and progressive LV dysfunction. As seen by early trials targeting the blockade of RAAS and sympathetic
nervous system with use of ACEI or beta adrenergic blockers, these agents demonstrated favorable effects on disease progression and mortality

However the neuro-hormonal axis pathway is
unlikely to explain the involvement of the pro-­
inflammatory cytokines in patients with heart failure (Fig. 3.2). Plasma levels of TNF-alpha and
IL-6 were elevated in patients as their functional
heart failure classification deteriorated [11].
Chronic inflammation, oxidative stress, and endothelial dysfunction in patients with CKD have
been shown to increase morbidity and mortality in
patients with cardio vascular disease by creating a
milieu that increases their risk. CKD also has
been correlated with both a systemic inflammatory and oxidative stress state which may increase
HF risk.
Patients with CKD are more susceptible to
reduction in capillary density in myocardium
making them vulnerable to ischemia, and fibrosis. In the hypertrophied myocardium, capillary
density is reduced causing an imbalance of oxygen supply and demand leading to exaggerated
extracellular and collagen synthesis [12]. Amann
et al. demonstrated this myocyte capillary mismatch particularly in patients with uremia [13].
The imbalance of exaggerated collagen synthesis
and collagen degradation leads to fibrosis making
patients more susceptible to diastolic dysfunction


[14]. Long term, the increasing pressure load
may promote cardiac remodeling, increasing the
release of myo-fibroblasts leading to the development of interstitial myo-fibrosis.
In the context of hemodynamics, LVH can be
viewed as a compensatory mechanism for the
high cardiac work load secondary to increased
afterload and increased preload. CKD patients
may lead to decreased aortic compliance, arterial
hypertension leading to an increased afterload
state. In conjunction, loss of nephrons and
decrease in GFR leads to further salt retention
and accumulation of fluid leading to increased
preload causing LV dilatation. Both of these
changes contribute to worsening hypertension
and further volume pressure overload. This eventually leads to the upregulation of RAAS activity
which not only increases aldosterone production
and sympathetic pathway but also leads to excess
angiotensin II. Angiotensin II, along with the
release of pro-fibrotic factors such as galectin-3,
TGF-beta, endogenous cardiac steroids, by the
activation of RAAS pathway, promotes myocardial hypertrophy, fibroblast proliferation, and
interstitial accumulation of collagen [15]. This
cycle is further intensified by uremic toxins
which also has been shown to contribute to cardiac fibrosis by producing TGF-beta, tissue
inhibitor of metalloproteinase (TIMP-1), and
alpha-1 collagen which contributes to fibrosis
Other biomarkers such as fibroblastic growth
factors like FGF-23, which plays a key role in
regulation, growth, and differentiation of cardiac
myocytes, have been investigated and linked to
LV remodeling [17]. In the general population,
higher FGF-23 concentrations were associated
with LVH, but this correlation was stronger in
those with CKD [18]. Study by Nerpin et al.
demonstrated pathological hypertrophy in isolated rat cardiomyocytes after FGF receptor-­
dependent activation of the calcineurin-NFAT
signaling pathway, along with increased prevalence of LVH in mice after intra-myocardial and
IV injection of FGF-23 [19]. CKD leads to accumulation of phosphate which leads to increase in
FGF-23 which has phosphaturic properties and is
also involved in blocking vitamin D3 synthesis

A. Bindra and Y. Ji

with prolonged levels leading to cardiac remodeling and LVH.
Secondary hyperparathyroidism and hyperphosphatemia in patients with CKD have also
been shown to contribute to increased LV mass,
LVH, and impaired LV diastolic dysfunction [20,
21]. This was supported with tissue Doppler
imaging, where calcium-phosphate levels were
correlated with diastolic myocardial function in
patients with CKD [22]. Vitamin D deficiency
has been proposed to also contribute to myocardial hypertrophy and extracellular matrix production via increased c-myc protein levels [23].
Patients with CKD have different features of
inter-myocardial fibrosis in which endocardial
and epicardial fibrosis predominate which is distinct from patients with hypertensive heart disease or chronic ischemic heart disease. Study by
Mall et al. showed that uremia was a determinant
of inter-myocardial fibrosis independent of HTN,
DM, anemia, heart weight, and prevalence or
absence of dialysis [24]. Myocardial infiltration
of monocytes and macrophages can lead to diastolic dysfunction. Macrophages produce
Galectin-3 which interacts with extracellular
matrix proteins and binds to cardiac fibroblasts
and increase collagen in myocardium and was
shown to be an independent predictor of mortality in patients with CKD [25]. However, other
studies have shown not shown any correlation of
Galectin-3 with HF, but eGFR <30 mL/min correlated with twofold higher levels.
LVH is associated with both LV systolic and
diastolic dysfunction, but diastolic dysfunction
has been demonstrated to occur in early stages of
CKD where subtle changes in echocardiographic
parameters of LV filling pressures can be seen
[26]. It is estimated that approximately 15% of
patients with CKD starting dialysis therapy have
LV systolic dysfunction while prevalence of diastolic dysfunction is much higher and more
apparent in earlier stages of CKD [27]. In a study
by Franczyk-Skora et al. looking at HF disturbances in CKD, LV EF was the lowest in stage V
CKD and the highest in stage II CKD. However,
there has been varying data in regards to impairment in systolic function in patients with CKD
with up to 15%–28% variance in patients on


Spectrum of Ventricular Dysfunction in Chronic Kidney Disease

­dialysis [6]. LVH, CAD, microvascular abnormalities, neuro-hormonal imbalances, myocardial fibrosis, all contribute to the development of
LV systolic and diastolic dysfunction.
The Acute Dialysis Quality Initiative XI
Workgroup have proposed a new classification of
HF in patients with structural heart disease.
Using this proposed criteria, Hickson et al. evaluated for structural heart disease in patients with
ESRD and concluded that impaired LVEF and
RV dysfunction had a twofold increased risk of
death with RV functioning having the strongest
association with mortality [28]. Among the 567
patients who had structural heart disease, 78%
had grade II or above diastolic dysfunction, 49%
had LVH, 34% had RV systolic dysfunction. RV
dysfunction is believed to be from a chronic volume overload state further exacerbated by arteriovenous fistulas which increases the preload, or
the rate or volume of blood returning to the heart
which can also increase the SV load on the LV
contributing to LVH and diastolic and systolic
dysfunction. HD has been associated with
increased risk of RV dysfunction particularly in
those with brachial AVF [29]. Patient also undergoing HD compared to PD are at higher risk of
RV dysfunction [30]. Momtaz et al. demonstrated
lower RV systolic indices which includes RV
fractional area change, tricuspid plane systolic
excursion, and peak systolic velocity at lateral
tricuspid annulus, were significantly lower in HD
patients [30]. Compared to earlier stages of CKD,
patients with stage V had much greater RV diameter [6]. RV dysfunction leads to impaired LV
diastolic and systolic function, and this interdependence has been demonstrated in various cardiac diseases [28]. Chronic dialysis treatment has
also been associated with increased pulmonary
pressures which was however not significantly
associated with RV or LV dysfunction [30].
As demonstrated in this chapter, the impact
CKD has on cardiac geometry and structure
through cardiac remodeling is multi-dimensional. Activated neuro-hormonal pathways
indirectly contributes to the remodeling process
through a compensatory mechanism caused by
an increased preload and afterload state mean-


while having a direct toxic effect on the myocardium leading to both right ventricular and
left ventricular dysfunction. The pro-inflammatory and oxidative stress state exhibited in CKD
further exacerbates ventricular function by
making the myocardium more vulnerable to
ischemia by causing an imbalance of oxygen
supply. It also exaggerates extracellular and
collagen synthesis leading to fibrosis supported
by the presence of elevated growth factors
linked to ventricular remodeling. As mentioned,
secondary hyperparathyroidism and vitamin D
deficiency in patients with deteriorating kidney
function have also been linked with ventricular
dysfunction. Echocardiography has been
proven to be a valuable noninvasive imaging
modality to confirm the changes in the geometric dimensions in the heart during the remodeling stages including increased LA size, LVH,
LV mass, while being able to assess the diastolic and systolic functions of the ventricles. It
is now well established that chronic kidney disease is not only the consequence of cardiovascular disease, but also the cause of significant
ventricular dysfunction through various pathways and mechanisms.

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The Myocardium in Renal Failure
Kerstin Amann

In patients with chronic kidney disease (CKD),
the exceedingly and disproportionally high prevalence and mortality of cardiovascular (cv) disease are a major clinical problem [1]. In these
patients, cv disease is approximately 20 times
more frequent than in age- and sex-matched segments of the non-renal population and up to 3
times more frequent than in other cv risk groups,
such as diabetes mellitus. However, it is of major
importance that particularly young CKD patients
exhibit up to 1000 times higher risk of cv disease
compared to matched segments of the non-renal
population. In addition to this negative epidemiology, it is important to emphasize that cv disease
in CKD patients, specifically coronary artery disease, myocardial interstitial fibrosis, and myocardial capillary supply, is different in several
aspects from what is seen in non-renal patients.
Therefore, these alterations are much more complex and difficult to treat than in non-renal
patients. Certainly, some treatable CKD-specific
factors such as anemia, hyperphosphatemia and
hypercalcemia, hyperparathyroidism, and others
contribute to the problem, but they are clearly not
sufficient to explain the broad spectrum of cv disease in renal patients. Consequently, it has been

K. Amann (*)
Department of Nephropathology, Institute of
Pathology, University of Erlangen-Nürnberg,
Erlangen, Germany

shown that some therapeutic strategies for cv disease that are extremely effective in non-renal
patients lack comparable efficacy in CKD
patients, i.e., statins [2]. Moreover, traditional
surgical vascular procedures such as angioplastic
or cardiac bypass surgery are associated with
worse outcome and worse prognosis in CKD
patients compared to a non-renal group with otherwise similar additional risk profile [3].
Initially, it was assumed that higher cv morbidity and particularly cardiac death in CKD
patients are due to more frequent and particularly
accelerated atherosclerosis with more pronounced coronary artery sclerosis and higher risk
of myocardial infarction. It has been shown
recently, however, that the majority of cv events,
i.e., up to 60%, is not caused by myocardial
infarction but is due to sudden cardiac death [4]
most likely due to arrhythmias, which may be
explained by a characteristic cv pathology with
specific CKD-associated changes that will be discussed in more detail in the following.
First, in CKD patients there is marked and
early onset left ventricular hypertrophy (LVH)
that is present in approximately 60% of patients
even before the start of dialysis. Second, patients
with CKD suffer from pronounced myocardial
fibrosis that develops early on, is much more
pronounced than in other cardiac diseases, i.e.,
in hypertensive heart disease, and has important
functional consequences in terms of increased
myocardial stiffness and increased arrhythmo-

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P. A. McCullough, C. Ronco (eds.), Textbook of Cardiorenal Medicine,



genicity. Third, myocardial arterial and capillary supply is also altered in CKD, i.e.,
intramyocardial arteries show increased wall
thickening and angioadaptation to increased
heart weight is markedly impaired leading to
lesser capillary supply in the setting of LVH. In
summary, these specific myocardial structural
changes in CKD favor a so-called myocyte-capillary mismatch with increased intercapillary
distances and as a consequence decreased myocardial blood and oxygen supply that renders
the heart more susceptible to ischemic injury
and arrhythmias [5, 6].
Specific animal models have been instrumental in further exploiting the aforementioned structural alterations in CKD, their pathogenesis, and
their functional consequences. Here, particularly
the well-established animal model of the subtotally nephrectomized rat (SNX) which develops
mild to moderate stable and long-lasting renal
failure excellently mimics cv pathology in CKD
patients [7]. Using this model a specific time
course of cv alterations was detected with an
early and specific activation of cardiac interstitial
fibroblasts as soon as 2 weeks after induction of