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Department of Intensive
Care Medicine, Inselspital,
Bern University Hospital,
Freiburgstrasse 18,
3010Bern, Switzerland.
2
Department of Clinical
Cardiology, Attikon University
Hospital, National and
Kapodistrian University of
Athens, Rimini 1,
12462Athens, Greece.
3
Department of Cardiology
and Pneumology, University
of Gttingen Medical School,
Robert-Koch-Strasse 40,
Gttingen 37075, Germany.
4
Department of Cardiology
and Pneumology, Innovative
Clinical Trials, University of
Gttingen Medical School,
Robert-Koch-Strasse 40,
Gttingen 37075, Germany.
1
Correspondence to S.D.A.
s.anker@cachexia.de
doi:10.1038/nrneph.2016.113
Published online 30 Aug 2016
Abstract | Heart failure (HF) is a major health-care problem and the prognosis of affected patients
is poor. HF often coexists with a number of comorbidities of which declining renal function is of
particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic
kidney disease (CKD), independently predicts mortality and accelerates the overall progression
of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex
bidirectional and interdependent manner in both acute and chronic settings. From a
pathophysiological perspective, cardiac and renal diseases share a number of common pathways,
including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and
(neuro)hormonal responses; metabolic and nutritional changes including bone and mineral
disorder, altered haemodynamic and acidbase or fluid status; and the development of anaemia.
In an effort to better understand the important crosstalk between the two organs, classifications
such as the cardio-renal syndromes were developed. This classification might lead to a more
precise understanding of the complex interdependent pathophysiology of cardiac and renal
diseases. In light of exceptionally high mortality associated with coexisting HF and kidney
disease, this Review describes important crosstalk between the heart and kidney, with a focus on
HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular
pathomechanisms in HF, AKI and CKD are discussed in addition to current and future
therapeutic approaches.
Heart failure (HF) is associated with high morbidity
and mortality, and accounts for more than 1million
primary and about 3,000,000 secondary annual hospital admissions in the USA alone13. It thus poses a
major burden to affected patients and health-care
systems worldwide. HF often coexists with a number
of prognosis-relevant comorbidities and has direct
consequences on other organs, including the kidneys.
Progression of HF or kidney disease can have deleterious effects on patient outcomes through the activation
of vicious cycles that often accelerate cardiac and renal
deterioration. Thus, the heart and kidneys interact in
a complex and interdependent manner in both acute
and chronic conditions, which can lead to dual organ
dysfunction4,5.
Cardiac and renal disease share a number of common bidirectional pathways48 (FIG.1). Here we review
current understanding of this important organ crosstalk, which involves inflammatory and direct cellular
Epidemiology
The use of differing terminology in the HF and nephrology literature remains a major and partly unsolved
issue with important consequences for understanding
the epidemiology of these diseases (BOX1). Improved
understanding of the epidemiology and the under
lying pathomechanisms of HF and kidney dysfunction
will require uniform terminology to be used, to enable
comparisons of different data8,10.
REVIEWS
Key points
Heart failure (HF) interacts with kidney disease via numerous pathophysiological
pathways in both the acute and chronic setting
Mounting data indicate that the complex interplay between the heart and the
kidneys involves haemodynamic, (neuro)homonal and cardiovascular
disease-associated mechanisms
Acceleration of HF or kidney dysfunction is driven by impairment of either the heart
or kidneys via mechanisms including induction of inflammation, activation of the
cellular immune system, metabolic disorders, anaemia and mineral and bone disorder
In an effort to differentiate respective underlying pathologies and to assess acute
and/or chronic organ dysfunction over time, five subtypes of cardio-renal syndromes
were proposed
The absence of a standardized terminology database and the lack of studies specific
to cardio-renal syndrome has hampered efforts to develop novel treatments
Cardio-renal syndromes
Recognition of the bidirectional links between cardiac
and renal function, and the understanding that dysfunction of one organ affects the other, led to coining of
the term cardio-renal syndrome5053. Although use
of cardio-renal syndrome terminology is helpful when
describing the interactions between the heart and kidneys, it is important to realize that the current classification of cardio-renal syndrome encompasses all forms of
bidirectional links and is not specific for HF.
Classification of cardio-renal syndromes
The cardio-renal syndromes are divided into five sub-
categories according to the direction of the effect and
whether the initiating insult is acute or chronic (FIG.2).
Type 5 cardio-renal syndrome can occur in response to
an overwhelming systemic insult, such as severe sepsis
or septic shock, resulting in simultaneous acute cardiac
and renal injury (FIG.2). This classification system aims to
take into account important interactions between the pivotal organ systems (the heart and the kidney). Although
the classification is not widely applied in the clinic, it can
provide a clinically oriented definition as a basis to better
understand the complex interactions between the heart
and kidney; guide future research into the respective
underlying mechanisms; and guide the development of
therapeutic strategies to target the complex bidirectional
pathophysiology46,54. Of note, however, the classification
has not yet been tested in large prospective registries, in
clinical trials or in clinical practice. Furthermore, it is not
always easy to assign a patient to a specific group as a
certain degree of overlap between categories often exists.
Mechanisms of HF and kidney dysfunction
As mentioned, interactions between the heart and kidneys are complex and bidirectional. The direct effect
of kidney dysfunction on HF progression is strikingly
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Haemodynamic mechanisms
Fluid overload and retention of salt and water
Renal and cardiac congestion (renal venous hypertension)
Limited organ perfusion (forward failure)
Vasoconstriction in end organs
(Neuro)hormonal
mechanisms
Activation of the RAAS
Activation of the
sympathetic nervous system
Reninangiotensin
aldosterone system
A complex hormone system
and a key regulator of salt and
water homeostasis in humans.
The reninangiotensin
aldosterone system is
considered to be one of the
key blood pressure regulating
hormonal systems. Activation
of this system in heart failure
and chronic kidney disease
makes it particularly important
in cardio-renal syndrome.
Haemodynamic considerations
HF with reduced LVEF or HF with preserved ejection
fraction can lead to a state of reduced cardiac output
(FIG.3). GFR is dependent on renal plasma flow and
filtration fraction, which are determined by a pressure gradient between the capillaries and the Bowman
space. GFR can be maintained at a constant rate despite
a significant decline in cardiac output through renal
autoregulatory and tubuloglomerular feedback mechanisms, including vasoconstriction and vasodilation of
the afferent and efferent arterioles60. Thus, filtration fraction and renal plasma flow are independent of renal perfusion pressure within the limits of autoregulation60,61.
As the kidneys receive about 25% of cardiac output,
the traditional understanding (the socalled low-flow
theory) was that hypoperfusion of the kidneys followed
by triggering of baroreceptors, juxtaglomerular renin
release, and RAAS activation might lead to renal vasoconstriction affecting both the glomerulus and tubular
apparatus. This interaction between the heart and kidneys is most evident in acute cardio-renal syndrome
(cardio-renal syndrome type1). HF with significant
cardiac-output decline (clinically referred to as forward
failure), can lead to renal tubule hypoxia and acute tubular necrosis, due to the sensitivity of renal tubular cells
to hypoxia. Moreover, tubulointerstitial injury in this
clinical setting might be further aggravated by the presence of comorbidities, such as diabetes mellitus, which
is associated with chronic tubular hypoxia, inflammation, and tubulointerstitial fibrosis6264. In the traditional
understanding of cardio-renal interactions, the process
of forward failure leading to acute tubular necrosis was
regarded the key underlying mechanism contributing to
renal dysfunction in the acute clinical setting.
Data from the ADHERE registry19, which includes
118,465 patients with HF, show that a considerable
number of these patients present with renal dysfunction. Average LVEFs were similar regardless of whether
patients had mild or severe renal dysfunction65. In addition, the ESCAPE trial, which included 433 patients
with advanced HF, did not demonstrate an association
between cardiac index and baseline renal function66. In
this trial, an increase in cardiac index as assessed by
invasive monitoring did not result in improved renal
function or prognosis. However, ESCAPE identified
an association between right atrial pressure and baseline serum creatinine level66. Data from ADHERE and
ESCAPE are supported by findings from other investigations showing that elevations in right atrial pressure,
which correlate with central venous pressure, but not a
decline in cardiac output and/or cardiac index, correlate with declining renal function6772. An investigation
involving 2,557 patients with CVD identified a curvilinear relationship between estimated GFR and central venous pressure, and an independent association
between increased central venous pressure and all-cause
mortality72.
REVIEWS
Forward failure
Term often used by physicians
involved in the care of patients
with acute heart failure to
describe a clinical situation in
which left ventricular output is
substantially reduced leading
to insufficient end-organ and/or
peripheral perfusion and/or
pulmonary oedema.
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REVIEWS
Box 2 | Types of heart failure
Heart failure (HF) is a clinical syndrome that is characterized by typical signs and
symptoms. The causes of HF are structural and/or functional cardiac abnormalities that
ultimately lead to reduced cardiac output and/or elevated intracardiac pressures at rest
or during stress. Left ventricular ejection fraction (LVEF; normal value >55%) is an
important characteristic of left ventricular function. A reduced LVEF (<40%) is the chief
determinant of heart failure with reduced ejection fraction, whereas elevated
intracardiac pressure is the chief determinant of heart failure with preserved ejection
fraction, in which LVEF is >50% by definition. In 2016, the European Society of
Cardiology introduced the term heart failure with mid-range ejection fraction to
describe patients with symptomatic HF and only mildly reduced LVEF. The clinical signs
and symptoms of these main types of HF overlap, and patients with all types of HF
typically present with elevated serum levels of natriuretic peptides, particularly during
phases of decompensation. The term decompensated HF describes rapid worsening of
signs and symptoms of HF in a previously diagnosed patient. This term is used in contrast
to compensated HF in which signs and symptoms are present, but stable over time.
Terminology adapted from elsewhere198.
Cardiac index
Cardiac index (units: l per min
per m2) is a global index of
heart function and a quotient of
cardiac output and body
surface area. This index is
important for the monitoring of
heart function in critically ill
patients in intensive care units.
Renal congestion
Central venous pressure is
typically increased in heart
failure and acts as the back
pressure to venous return,
resulting in diminished efferent
renal blood flow and renal
venous hypertension. Renal
congestion is considered to be
the result of right ventricular
failure, (neuro)hormonal and
sympathetic mechanisms
resulting in hypervolaemia,
inflammation, and reduced
glomerular filtration rate.
(Neuro)hormonal responses
Activation of the RAAS and the sympathetic nervous
system are regarded key characteristics in chronic HF
and CKD. Mounting data show that persistent RAAS
Type 1:
acute cardiorenal syndrome
Acute HF
leading to AKI
Type 2:
chronic cardiorenal syndrome
Chronic HF leading
to progressive and
permanent CKD
Type 3:
acute renocardiac syndrome
AKI causing
acute HF
Type 4:
chronic renocardiac syndrome
CKD leading to
chronic HF and
CKD progression
Type 5:
secondary cardiorenal syndrome
Systemic insult
(e.g. in severe
sepsis and/or
septic shock)
Preload
The effective end-diastolic
volume that stretches the
ventricles of the heart before
contraction. Ventricular end
diastolic volume and/or
pressure is used for
assessment of preload; atrial
pressure might serve as a
surrogate marker.
Altered cardiac
and/or renal
haemodynamics
might be of
particular
importance
Accelerated renal
cell apoptosis
and replacement
brosis might
be of particular
importance
CKD-induced
myopathy might
be of particular
importance in
this setting
Microcirculatory
dysfunction, altered
innate and adaptive
immune responses and
cytokine release, and
other eects result in
simultaneous organ injury
Starling curve
Cardiac function curve showing
the graphical relationship
between cardiac output or
venous return (yaxis) and end
diastolic volume or right atrial
pressure (xaxis). Frank
Starlings law indicates that
cardiac output increases in
response to increased end
diastolic volume (that is, filling)
up to a certain maximum (given
that all other influencing
factors remain constant).
Figure 2 | Definitions of cardio-renal syndromes. Five subtypes of cardio-renal syndrome exist. The subtypes are defined
Nature Reviews | Nephrology
according to the direction of the effect heart to kidney (types 1 and 2), kidney to heart (types 3 and 4) or systemic (type 5)
and whether the initiating insult is acute or chronic. Potential key pathomechanisms that lead to organ failure differ between
these subtypes. In type 5 cardio-renal syndrome, a severe systemic insult, such as severe sepsis or septic shock, can result in
acute and simultaneous organ injury. AKI, acute kidney injury; CKD, chronic kidney disease; HF, heart failure.
REVIEWS
a Traditional hypothesis of cardio-renal interactions
Heart failure
Renal
hypoperfusion
(low ow)
Renal vasoconstriction
Renal tubular hypoxia
CO or CI
(Acute) tubular necrosis
Cardiac congestion
Right arterial pressure
Central venous pressure
Cardiac output
Venous
return
Renal venous
hypertension
( eerent
pressures)
Eective arterial
blood volume
Fluid overload
Salt and water
retention
Intra-abdominal
hypertension
Renal blood ow
Renal congestion
Intraglomerular
hydrostatic pressure
Intraglomerular pressure
Net ltration pressure
Transrenal perfusion
pressure
Fibrogenesis
Loss of renal
function
GFR
Urine output
Sodium
excretion
Water excretion
| The
Figure 3 | Haemodynamic mechanisms in cardio-renalNature
interactions.
Reviews | aNephrology
traditional hypothesis of how renal dysfunction develops in heart failure develop is
that it results from heart failure-induced hypoperfusion of the kidneys (low flow).
Renal hypoperfusion was thought to increase renal vasoconstriction, which resulted
in renal tubular hypoxia and tubular necrosis. b | Renal dysfunction in heart failure is
now also thought to develop as a result of reduced cardiac output, which results in
increased cardiac congestion, increased right atrial pressure and increased central
venous pressure. Thechanges to renal function as a consequence of reduced cardiac
output result inthe development of renal venous hypertension, renal venous
congestion, increased renal fibrogenesis, and eventually the loss of renal function.
Renal venous congestion and finally loss of renal function in combination with
(neuro)hormonal responses and potentially altered intra-abdominal and/or
intrasplanchnic pressures might contribute to fluid overload and increased venous
return in a vicious circle. ANP, atrial natriuretic peptide; BNP, brain natriuretic
peptide; CI, cardiac index; CO, cardiac output; GFR, glomerular filtration rate;
Na, sodium; RAAS, reninangiotensinaldosterone system.
CVD-associated mechanisms
Comorbidities related to both CVD and CKD include
chronic inflammation and associated phenotypic
changes in cellular immunity 108110, malnutrition
inflammationatherosclerosis (MIA) syndrome 111,
cardio-renal anaemia112,113, and other metabolic changes
such as CKDmineral and bone disorder (MBD)114
(FIG.5). These factors are thought to trigger and facilitate the progression of wasting, which usually commences with the loss of skeletal muscle mass and is later
accompanied by loss of fat tissue115,116.
Inflammation. Systemic and chronic low-grade inflammation is considered to be a key trigger of both CKD and
CVD. Mounting data show that chronic inflammation
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Increased venous return
Increased venous return can
almost always be observed in
heart failure and results from
early activation of key
compensatory mechanisms,
including neurohormonal
responses and activation of the
sympathetic nervous system,
resulting in increased
circulating volume.
Sympathetic
(nervous) activity
Cardiac output
Heart
failure
Cardiac remodelling
(brogenesis)
RAAS activity
Altered arginine
vasopressin
ANP
BNP
Ang II
Sodium and
water retention
(uid overload)
Aldosterone
Systemic
vasoconstriction
Venous return
Renal venous
congestion
Galectin-3
Renal remodelling
(brogenesis)
Inammation
Oxidative stress
Eventual loss of
renal function
Nature Reviews | Nephrology
REVIEWS
Cardiac hypertrophy
Fibrosis
Heart
failure
Cardiovascular
disease and
comorbidities
Atherosclerosis
Diabetes mellitus
Arterial hypertension
Wasting and
cachexia
Endothelial dysfunction
Vascular stiness and
calcication
Cardio-renal
anaemia
Anaemia
Haemoglobin
Iron
Fetuin A
EPO
CKD
and AKI
Hyperphosphataemia
PTH
Serum calcium
FGF-23
Renal phosphate
excretion
Vitamin D
Intestinal
calcium absorption
The reduced capacity of the kidney to excrete phosphate results in hyperphosphataemia, which results
in elevated serum levels of parathyroid hormone
(PTH) and fibroblast growth factor 23 (FGF23)152.
Hyperphosphataemia, persistently increased levels
of PTH and FGF23, as well as vitaminD deficiency,
which results in reduced intestinal calcium absorption,
are all associated with cardiovascular toxicity, left ventricular mass153155 and catabolism156. FGF23 maintains
phosphate homeostasis by regulating tubular phosphate
reabsorption, so is of particular interest. Future work
should aim to elucidate whether FGF23 is a marker
or even a mediator of cardio-renal syndrome before
efforts are made to target increased FGF23 levels
therapeutically157.
Although the mechanisms by which hyperphosphataemia, increased PTH, and vitaminD deficiency
contribute to cardiovascular toxicity have not been fully
elucidated151,158, they might at least be partially explained
by vitaminDinduced reduction of RAAS activity and
anti-inflammatory effects, as suggested by murine
data159. Nevertheless, although treatment with the active
vitaminD compound paricalcitol reduced albuminuria
in patients with CKD160, a large randomized, placebocontrolled clinical trial reported that treatment with this
agent did not result in reductions in left ventricular mass
or diastolic dysfunction in patients with CKD stages 3
and 4 (GFR1560ml/min/1.73 m)(REF.161).
Therapeutic considerations
Due to a lack of studies specifically in populations with
cardio-renal syndrome, therapeutic recommendations
for the treatment of HF and/or CKD mainly rely on
the predominant underlying disease. Furthermore, a
limited amount of data are available on patients with
severely reduced kidney function (that is, GFR <30 ml/
min/1.73 m). Overall, therapeutic efforts for patients
with cardio-renal syndromes types 1 and 2 (acute and
chronic HF leading to renal dysfunction), mainly concentrate on the treatment of HF. By contrast treatment of
underlying renal disease might be the focus for patients
with cardio-renal syndromes types 3 and 4 (acute and
chronic renal disease leading to HF). Therapeutic
approaches for type 5 cardio-renal syndrome focus on
treatment of the underlying condition, such as severe
sepsis, septic shock or vasculitis. Of note, however, the
classification of a given patient into a specific cardio-
renal group can be a challenge in daily clinical practice,
and is a limitation of the current classification system. In
all subtypes of cardio-renal syndrome, interdisciplinary
care teams should include the early involvement of both
cardiologists and nephrologists.
Major treatment strategies for cardio-renal syndrome
include preventive measures, which centre around the
avoidance of nephrotoxic drugs, such as contrast media,
certain antibiotics, non-steroidal anti-inflammatory
medications or low-dose dopamine in AKI; lifestyle
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Obesity paradox
Epidemiological data show that
obese patients with chronic
diseases such as heart failure,
coronary artery disease or
chronic kidney disease
requiring dialysis can have
higher survival rates compared
to those of non-obese
individuals.
Orthodema
Key clinical symptoms at rest
for congestion include
orthopnoea and peripheral
oedema. An orthodema
congestion score based on
these symptoms was
previously used to grade
congestion in clinical trials.
REVIEWS
Aquaresis
Excretion of (free) water
without loss of electrolytes via
the renal system. Aquaresis is
of particular interested in
dilutional hyponatraemia.
Vaptans (also referred to as
aquaretics) are a new class of
drugs used to promote
aquaresis.
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Progressive metabolic (that is, renal or lactic) acidosis can
alter protein and enzymatic activities and might directly
affect cardiac function by altering adrenoreceptor
expression and/or function and inducing arrhythmia197.
Conclusions
The care of patients with coexisting HF and kidney disease
is a major medical challenge in both the acute and chronic
settings. This challenge will become even more evident
in the future with the increasing incidence of both disorders. From a pathophysiological perspective, the heart and
the kidneys share a number of pathways that are intrinsically linked to each other. These include altered haemo
dynamics and fluid overload leading to renal venous
congestion, a profound imbalance with regard to hormonal and sympatho-adrenergic status, mechanisms induced
by malnutrition and cachexia, and CVD-associated risk
factors. Respective cardiovascular risk factors include persistent chronic inflammation, anaemia, metabolic changes
including CKDMBD, and other factors that contribute
to acceleration of vascular ageing.
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Author contributions
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