REVIEWS

Heart failure and kidney dysfunction:

1
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.
Correspondence to S.D.A.
s.anker@cachexia.de
doi:10.1038/nrneph.2016.113
Published online 30 Aug 2016
epidemiology, mechanisms and
management
Joerg C. Schefold1, Gerasimos Filippatos2, Gerd Hasenfuss3, Stefan D. Anker4
and Stephan von Haehling4
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 immune-mediated responses, stress-mediated and
and mortality, and accounts for more than 1million (neuro)hormonal mechanisms, metabolic and nutri-
primary and about 3,000,000 secondary annual hos- tional changes including mineral and bone disorder,
pital admissions in the USA alone13. It thus poses a altered fluid and acidbase status, and anaemia, in both
major burden to affected patients and health-care acute and chronic conditions. The underlying patho-
systems worldwide. HF often coexists with a number mechanisms that contribute to HF with acute kidney
of prognosis-relevant comorbidities and has direct injury (AKI)9, or chronic kidney disease (CKD) are dis-
consequences on other organs, including the kidneys. cussed with a focus on current diagnostic options and
Progression of HF or kidney disease can have deleteri- therapeutic advances.
ous effects on patient outcomes through the activation
of vicious cycles that often accelerate cardiac and renal Epidemiology
deterioration. Thus, the heart and kidneys interact in The use of differing terminology in the HF and neph-
a complex and interdependent manner in both acute rology literature remains a major and partly unsolved
and chronic conditions, which can lead to dual organ issue with important consequences for understanding
dysfunction4,5. the epidemiology of these diseases (BOX1). Improved
Cardiac and renal disease share a number of com- understanding of the epidemiology and the under
mon bidirectional pathways48 (FIG.1). Here we review lying pathomechanisms of HF and kidney dysfunction
current understanding of this important organ cross- will require uniform terminology to be used, to enable
talk, which involves inflammatory and direct cellular comparisons of different data8,10.

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Key points compared to age and sex-matched controls without kidney

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
The risk of HF typically increases with age, and data
show that left ventricular dysfunction (both systolic and
diastolic) and HF is common in community-based aged
populations. Although the prevalence of HF is estimated
to be 59% in individuals over 65years of age3,11,12, HF
of any type (BOX2) is observed in up to 12% of some
populations, depending on age2. Patients with HF have
a high prevalence of comorbid cardiovascular condi-
tions, such as CKD, which contribute to the high mor-
bidity and mortality of HF. Importantly, about 4050%
of patients with HF have coexisting chronic renal dys-
function, defined as persistent glomerular filtration rate
(GFR) <60 ml/min/1.73m (REFS1317). Even slight
reductions in GFR strongly affect all-cause mortality in
patients with HF14. Both HF and CKD also accelerate
comorbidities, such as metabolic disorders. Involuntary
weight loss, or cachexia, can develop in patients with
either condition. In Europe, an estimated 1.2 million
patients with advanced HF and 185,000 patients with
end-stage renal disease (ESRD) are cachectic18.
The Acute Decompensated Heart Failure National
Registry (ADHERE) has shown that approximately 30%
of patients admitted to hospital for acute decompensated
HF have acute or chronic renal insufficiency19. In another
study, only about 17% of outpatients with HF had nor-
mal renal function, defined as GFR >90ml/min/1.73m
(REF.15). Moreover, CKD is a powerful independent risk
factor for the development and progression of cardio-
vascular disease (CVD) and respective cardiovascular
outcomes6,2022. Data from the USA show that >60% of
patients with CKD have CVD, including HF, and that
the degree of CVD correlates closely with CKD severity23.
Development of HF is often observed in patients with
CKD, and the prevalence of HF increases significantly
in cohorts with declining GFR. Compared to patients
with normal kidney function, defined as GFR >90 ml/
min/1.73m, patients with at least moderately reduced
kidney function (that is Kidney Disease Outcomes
Quality Initiative (KDOQI)24 CKD stage 3 or higher, or
GFR <60 ml/min/1.73m), have about a threefold higher
risk of HF25.
The impact of kidney disease on CVD becomes most
evident in patients with ESRD on dialysis26,27, who have a
1030fold higher risk of all-cause cardiovascular mortality
disease28,29. Thus, the risk of death from a cardiac cause
in a 30year-old patient with ESRD would be comparable
to that of an 80year-old individual in the general pop-
ulation30. Moreover, the presence of HF at the initiation
of dialysis is an independent predictor of mortality31,32,
regardless of whether the mode of renal replacement
therapy (RRT) is haemodialysis33 or peritoneal dialysis34.
AKI can also contribute to the progression of
CVD35,36. AKI of varying severity affects about 57%
of all hospitalized patients, 20% of patients hospital-
ized for HF, and about 3040% of patients in intensive
care units (ICUs) in Western populations3740. Since
1998, a constant rise in the incidence of AKI has been
observed4145. Importantly, AKI is now recognized as a
strong independent predictor of both inhospital and
1year mortality, as well as length of hospital stay46,47,
increasing the risk of mortality by 57fold compared to
that of matched controls without AKI37. AKI has direct
adverse effects on nonrenal organs, including the heart48.
However, several studies have shown that an increase
in serum creatinine level in hospitalized patients might
have prognostic value only in those with congestion49.
Cardio-renal syndromes
Recognition of the bidirectional links between cardiac
and renal function, and the understanding that dys-
function 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 kid-
neys, it is important to realize that the current classifica-
tion 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 piv-
otal 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 kid-
neys are complex and bidirectional. The direct effect
of kidney dysfunction on HF progression is strikingly

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Haemodynamic mechanisms as alterations in cell-mediated immunity; metabolic

Fluid overload and retention of salt and water changes such as malnutrition-induced effects; anaemia;
Renal and cardiac congestion (renal venous hypertension) and bone and mineral disorder (BMD)7,51,5459.
Limited organ perfusion (forward failure)
Vasoconstriction in end organs
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 pres-
sure 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 mech-
anisms, including vasoconstriction and vasodilation of
the afferent and efferent arterioles60. Thus, filtration frac-
tion and renal plasma flow are independent of renal per-
fusion pressure within the limits of autoregulation60,61.
Cardiovascular disease-associated mechanisms As the kidneys receive about 25% of cardiac output,
(Neuro)hormonal Chronic inammation and activation of
mechanisms cellular immunity the traditional understanding (the socalled low-flow
Activation of the RAAS Malnutrition, cachexia and wasting theory) was that hypoperfusion of the kidneys followed
Activation of the Bonemineral disorder by triggering of baroreceptors, juxtaglomerular renin
sympathetic nervous system Acidbase metabolism disorder
Anaemia and cardio-renal anaemia release, and RAAS activation might lead to renal vaso-
constriction affecting both the glomerulus and tubular
Figure 1 | Overview of key cardio-renal interactions. Three major mechanisms
Nature Reviews | Nephrology apparatus. This interaction between the heart and kid-
contribute to the development and/or acceleration of cardio-renal dysfunction neys is most evident in acute cardio-renal syndrome
haemodynamic mechanisms, (neuro)hormonal mechanisms and cardiovascular (cardio-renal syndrome type1). HF with significant
disease-associated mechanisms. All three mechanisms are interconnected and can cardiac-output decline (clinically referred to as forward
negatively affect both cardiac and renal function. The main haemodynamic
failure), can lead to renal tubule hypoxia and acute tubu-
mechanisms include salt and water retention leading to fluid overload, which results in
cardiac and renal venous congestion. Renal venous congestion might be key for lar necrosis, due to the sensitivity of renal tubular cells
acceleration of renal dysfunction in this clinical context. (Neuro)hormonal mechanisms to hypoxia. Moreover, tubulointerstitial injury in this
include classic compensatory pathways of heart failure with activation of both the clinical setting might be further aggravated by the pres-
reninangiotensinaldosterone system (RAAS) and the sympathetic nervous system. ence of comorbidities, such as diabetes mellitus, which
Cardiovascular disease-associated mechanisms comprise multiple pathways that is associated with chronic tubular hypoxia, inflamma-
contribute to the development and/or acceleration of cardiovascular disease. These tion, and tubulointerstitial fibrosis6264. In the traditional
pathways include the development of systemic and local inflammatory mechanisms understanding of cardio-renal interactions, the process
with altered innate and adaptive immune responses, bonemineral and acidbase of forward failure leading to acute tubular necrosis was
disorders, anaemia, and cachexia. regarded the key underlying mechanism contributing to
renal dysfunction in the acute clinical setting.
illustrated by studies of kidney transplant recipients. Data from the ADHERE registry19, which includes
Data show that left ventricular hypertrophy is present 118,465 patients with HF, show that a considerable
in about 75% of patients at commencement of dialysis31 number of these patients present with renal dysfunc-
and that uraemia promotes interstitial cardiac fibrosis55. tion. Average LVEFs were similar regardless of whether
In patients with dialysis-dependent CKD stage5 and HF patients had mild or severe renal dysfunction65. In addi-
with reduced left ventricular ejection fraction (LVEF) <40%, tion, the ESCAPE trial, which included 433 patients
Left ventricular ejection
fraction
kidney transplantation can result in a considerable with advanced HF, did not demonstrate an association
The fraction of left increase in mean LVEF, and even normalization of LVEF between cardiac index and baseline renal function66. In
intra-ventricular volume that is in a considerable number of patients56. This improve- this trial, an increase in cardiac index as assessed by
pumped from the left ventricle ment in cardiac function highlights the key role of kid- invasive monitoring did not result in improved renal
per contraction or heartbeat.
ney dysfunction in cardiac remodelling, independent function or prognosis. However, ESCAPE identified
Reninangiotensin of classic CVD risk factors50. an association between right atrial pressure and base-
aldosterone system Three key pathophysiological categories are currently line serum creatinine level66. Data from ADHERE and
A complex hormone system thought to contribute to the development and progres- ESCAPE are supported by findings from other investi-
and a key regulator of salt and sion of cardio-renal and reno-cardiac interactions: hae- gations showing that elevations in right atrial pressure,
water homeostasis in humans.
The reninangiotensin
modynamic alterations due to low cardiac output and/or which correlate with central venous pressure, but not a
aldosterone system is altered venous return; dysregulation of the (neuro) decline in cardiac output and/or cardiac index, corre-
considered to be one of the hormonal axis via sympathetic nerve activation and/or late with declining renal function6772. An investigation
key blood pressure regulating triggering of the reninangiotensinaldosterone system involving 2,557 patients with CVD identified a curvi-
hormonal systems. Activation
(RAAS); and other factors that contribute to the accel- linear relationship between estimated GFR and cen-
of this system in heart failure
and chronic kidney disease
erated progression of HF and CKD (FIG.1). Factors that tral venous pressure, and an independent association
makes it particularly important contribute to the accelerated progression of HF and between increased central venous pressure and all-cause
in cardio-renal syndrome. CKD include local and systemic inflammation such mortality72.

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Forward failure Central venous pressure and/or right atrial pressure,
Term often used by physicians which are typically increased in the setting of HF, consti-
involved in the care of patients tute the lowest pressures in the circulation, as eventually
with acute heart failure to all blood flow goes to the right atrium (except for in the
describe a clinical situation in
which left ventricular output is
thebesian veins). They are considered the back pressure to
substantially reduced leading venous return and cardiac output according to Guytons73
to insufficient end-organ and/or classic physiological model of the circulation74,75. In that
peripheral perfusion and/or sense, central venous pressure and/or right atrial pressure
pulmonary oedema.
also act as the outflow pressure of the blood flow through
the kidney, and elevated central venous pressure is
associated with renal venous hypertension.
The ability of renal venous pressure to reduce renal
blood flow was shown in animal models more than
60years ago76,77. Renal venous hypertension can induce
a decline in GFR via mechanisms that include reduced
Box 1 | Definitions of AKI and worsening renal function in HF
AKI (KDIGO)
Stage 1
Serum creatinine: 1.51.9 fold increase from baseline within 17days or 26.5 mol/l
increase within 48h
Urine output: <0.5 mlkg1/h for 612h
Stage 2
Serum creatinine: 2.02.9 fold increase from baseline
Urine output: <0.5 mlkg1/h for 12 h
Stage 3
Serum creatinine: 3.0 fold increase from baseline or increase >354 mol/l or
initiation of renal replacement therapy
Urine output: <0.3 mlkg1/h for 24 h or anuria 12 h
Worsening renal function (HF literature)
Definitions based on creatinine level
26.5 mol/l increase; 26.5 mol/l and 25% increase; 44 mol/l increase 1.5 in the presence of an adequate number of functionally
times baseline; 25% increase and above 176mol/l
Definitions based on cystatin C
>0.3 mg/l increase
Definitions based on eGFR
20% decrease; 25% decrease; >5 mlmin1 per year decrease
Worsening renal function in chronic HF or AKI in acute HF (suggested definitions)
Worsening renal function in chronic HF*
26.5 mol/l and 25% increase in serum creatinine or 20% decrease in eGFR over
126weeks
Additional criteria: deterioration in HF status but not leading to hospitalization
AKI in acute HF*
Increase 1.51.9 times baseline serum creatinine level within 17days before or
during hospitalization or 26.5 mol/l increase in serum creatinine within 48h or
urine output <0.5 mlkg1/h for 612h
Additional criteria: deterioration in HF status or failure to improve or need for
inotropes, ultrafiltration or renal replacement therapy
For conversion of creatine from mol/l to mg/dl divide by 88.4. AKI, acute kidney injury; eGFR,
estimated glomerular filtration rate; HF, heart failure; KDIGO, Kidney Disease: Improving Global
Outcomes. *Any deterioration in renal function that does not meet these criteria should be
regarded as pseudo-worsening of renal function or pseudo-AKI where there is no evidence of
associated harm with the exception of very large increases in serum creatinine level (doubling
or >88.4 mol/l increase), which should always be a reason to refer for further investigation.
Consider alternative reasons for increases in creatinine or cystatin C or decreases in eGFR other
than worsening renal function or AKI, such as intravascular depletion, dehydration, excessive
diuresis, medication that alters tubular handling of creatinine, and reninangiotensin
aldosterone inhibitors. Or 0.3mg/l increase in cystatin C. Permission obtained from Oxford
University Press Damman,K. et al. Eur. Heart J. 35, 34133416 (2014).
renal blood flow via increased efferent pressures,
decreased transrenal perfusion pressure, increased
intraglomerular hydrostatic pressure, increased intra
tubular pressure, and reduced net filtration pres-
sure67,72,78. Although increases in renal venous pressure
above 15mmHg cause linear increases in both peri
tubular capillary and intratubular pressures, data on the
effects of pressure changes below this level are sparse.
The available data indicate that minor changes in renal
venous pressure (15mmHg) have only little effect on
haemodynamic systems, such as peritubular capillaries
or intratubular pressures. This finding seems of to be
of particular importance as a minor increase in intra
tubular pressure can induce decreased GFR by altering
net ultrafiltration pressure79. Further, in cases of per-
sisting renal venous hypertension, both glomeruli and
tubules are affected, which can induce tubular hypertro-
phy, tubulointerstitial renal fibrosis, and intraglomerular
sclerosis, resulting in progression of kidney disease72,7981.
Interestingly, increased renal parenchymal pressures do
not seem to affect GFR or renal blood flow, but the exact
role of the renal interstitial parenchyma in this particular
clinical setting awaits further clarification.
Importantly, when assessing the complex conse-
quences of renal venous hypertension and/or renal
congestion, the link to sympathetic and/or sympatho
adrenergic activity, renin release, RAAS activation, and
activation of key inflammatory mechanisms becomes
clear82. For example, RAAS-induced sodium and water
retention results in expansion of the intravascular vol-
ume and increased right heart filling pressures. The
resulting pressure natriuresis can only temporarily
compensate for the increase in renal perfusion pressure
active nephrons.
Clinical considerations for haemodynamic alterations
in HF and CKD. Clinically, differentiation of renal
congestion from states of low cardiac output, especially
in the acute-care setting, can primarily be based on
approximating the trend of preload status in respective
patients, for example, using clinical investigation and/or
anamnesis, right atrial pressures and echocardiographic
measures). A Starling curve-based assessment, which can
be used to demonstrate compromised heart function
and includes assessment of cardiac function indices
(for example by a pulmonary artery catheter-based
approach) might then be important. Although assess-
ment of preload and cardiac (especially right ventricu-
lar) function helps to differentiate renal congestion
from low cardiac output clinically, one should always
note that the precise assessment of filling status can be
rather challenging. In the future, assessment of renal
venous profiles using sonography might be interest-
ing, but the usefulness of this approach awaits further
investigation.
A considerable fraction of patients with HF present
with increased intra-abdominal pressure70, which might
affect renal function72. However, the impact of increased
intra-abdominal pressure or intra-splanchnic pressure
on renal function in the setting of cardio-renal syndrome

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Box 2 | Types of heart failure activation exerts deleterious effects on both the heart
and the kidneys7,85 (FIG.4). Angiotensin II (ang II) and
Heart failure (HF) is a clinical syndrome that is characterized by typical signs and aldosteroneinduced sodium and water retention lead
symptoms. The causes of HF are structural and/or functional cardiac abnormalities that to renal and systemic vasoconstriction, increased venous
ultimately lead to reduced cardiac output and/or elevated intracardiac pressures at rest
return and end-diastolic ventricle pressure, augmented
or during stress. Left ventricular ejection fraction (LVEF; normal value >55%) is an
oxidative stress, increased production of proinflamma-
important characteristic of left ventricular function. A reduced LVEF (<40%) is the chief
determinant of heart failure with reduced ejection fraction, whereas elevated tory cytokines, phenotypic changes in cell-mediated
intracardiac pressure is the chief determinant of heart failure with preserved ejection immunity, and acceleration of renal and cardiac
fraction, in which LVEF is >50% by definition. In 2016, the European Society of remodelling via mechanisms that include the promo-
Cardiology introduced the term heart failure with mid-range ejection fraction to tion of fibrosis85,86. Moreover, ang II and aldosterone
describe patients with symptomatic HF and only mildly reduced LVEF. The clinical signs stimulate macrophage-derived galectin3, which pro-
and symptoms of these main types of HF overlap, and patients with all types of HF motes remodelling via induction of cardiac and renal
typically present with elevated serum levels of natriuretic peptides, particularly during fibrosis, resulting in organ degeneration87. In the past
phases of decompensation. The term decompensated HF describes rapid worsening of few years, galectin3 has received considerable interest
signs and symptoms of HF in a previously diagnosed patient. This term is used in contrast
as a diagnostic biomarker in HF with preserved ejection
to compensated HF in which signs and symptoms are present, but stable over time.
fraction, as well as a biomarker of prognosis and disease
Terminology adapted from elsewhere198. progression88. However, the usefulness of galactin3 as a
biomarker is controversial, particularly after adjusting
for natriuretic peptide plasma levels89.
Cardiac index is not fully elucidated. Further investigation could prove The release of ang II and aldosterone also result in
Cardiac index (units: l per min to be especially interesting in light of the fact that both stimulation of the natriuretic peptide system. Two pep-
per m2) is a global index of intra-abdominal pressure and intra-splanchnic pressure tides, atrial natriuretic peptide (ANP) and Btype natriu-
heart function and a quotient of
cardiac output and body
might be considered key players in the pathophysiology retic peptide (BNP), are generated in large quantities9092,
surface area. This index is of hepatorenal decompensation and/or hepatorenal but neither are sufficient to oppose RAAS-induced
important for the monitoring of syndrome83,84. sodium retention. The resulting imbalance between
heart function in critically ill RAAS, ANP and BNP, and the attenuated renal respon-
patients in intensive care units.
(Neuro)hormonal responses siveness to ANP further characterizes HF as a state
Renal congestion Activation of the RAAS and the sympathetic nervous of (neuro)hormonal imbalance85. The pro-hormones of
Central venous pressure is system are regarded key characteristics in chronic HF ANP and BNP serve as reliable markers of HF severity
typically increased in heart and CKD. Mounting data show that persistent RAAS and prognosis9395. In the context of (neuro)hormonal
failure and acts as the back
pressure to venous return,
resulting in diminished efferent
renal blood flow and renal
Type 1: Type 2: Type 3: Type 4: Type 5:
acute cardio- chronic cardio- acute reno- chronic reno- secondary cardio-
venous hypertension. Renal
renal syndrome renal syndrome cardiac syndrome cardiac syndrome renal syndrome
congestion is considered to be
the result of right ventricular Acute HF Chronic HF leading AKI causing CKD leading to
leading to AKI to progressive and acute HF chronic HF and
failure, (neuro)hormonal and
permanent CKD CKD progression
sympathetic mechanisms
resulting in hypervolaemia, Systemic insult
inflammation, and reduced (e.g. in severe
glomerular filtration rate. sepsis and/or
septic shock)
Preload
The effective end-diastolic
volume that stretches the
ventricles of the heart before
contraction. Ventricular end Altered cardiac Accelerated renal Salt and water Microcirculatory
diastolic volume and/or CKD-induced dysfunction, altered
and/or renal cell apoptosis imbalance, uraemia-
myopathy might innate and adaptive
pressure is used for haemodynamics and replacement induced eects and
be of particular immune responses and
assessment of preload; atrial might be of brosis might neuro-hormonal
importance in cytokine release, and
pressure might serve as a particular be of particular dysregulation might
this setting other eects result in
surrogate marker. importance importance be key in this setting
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
Figure 2 | Definitions of cardio-renal syndromes. Five subtypes of cardio-renal syndrome exist. The subtypes are defined
response to increased end Nature Reviews | Nephrology
diastolic volume (that is, filling) 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)
up to a certain maximum (given and whether the initiating insult is acute or chronic. Potential key pathomechanisms that lead to organ failure differ between
that all other influencing these subtypes. In type 5 cardio-renal syndrome, a severe systemic insult, such as severe sepsis or septic shock, can result in
factors remain constant). acute and simultaneous organ injury. AKI, acute kidney injury; CKD, chronic kidney disease; HF, heart failure.

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a Traditional hypothesis of cardio-renal interactions stimulation due to increased plasma osmolarity or

Heart failure via stimulation of blood pressure sensitive arterial
Renal
hypoperfusion baroreceptors. Arginine vasopressin augments vaso
(low ow) constriction and inhibits free water clearance by altering
the expression of aquaporin2 channels; clinically these
Renal vasoconstriction alterations can result in dilutional hyponatraemia97.
Activation of the sympathetic nervous system
Renal tubular hypoxia occurs early in HF98 and predicts survival in patients
CO or CI with ESRD99. Key afferences are located in the carotid
(Acute) tubular necrosis sinus and aortic arch and respond to stretching of vessel
walls. Over time, persistent elevations in sympathetic
activity and adrenergic tone can result in systemic down
regulation of overall adrenergic receptor density and sen-
b
Cardiac congestion sitivity to their respective signals. Sympathetic activation
Right arterial pressure also affects renal sympathetic nerve activity, especially
Central venous pressure in patients with HF and reduced ejection fraction100102.
Moreover, impaired clearance of catecholamines due to
Cardiac output
reduced renal function can be observed. Increased renal
sympathetic activity can result in renal vasoconstric-
tion103, triggering of RAAS activity augmenting sodium
Eective arterial retention and fluid overload, and spillover of catecho-
Venous blood volume Intra-abdominal lamines100102. Induction of renal sympathetic activity is
Fluid overload hypertension thought to occur as an effect of diminished inhibitory
return Renal blood ow
Salt and water reflexes as well as an increased sensitivity towards excit-
retention
atory reflexes. As this system can only be investigated
by indirect means in humans, the exact mechanisms
(Neuro)hormonal and inammatory response involved remain controversial102. Moreover, activation
Sympathetic nervous system activity of the RAAS and sympathetic activity can result in asym-
Renal venous RAAS metric dimethylarginine (ADMA) accumulation due to
hypertension Altered arginine vasopressin
Altered ANP and BNP its impaired renal clearance, which might accelerate
( eerent
pressures) Inammation and immune cell activation overall progression of CKD and CVD104. The resulting
decrease in nitric oxide levels might have an important
role in the progression of cardio-renal syndrome105,106.
Renal congestion Loss of renal
Intraglomerular function Clinical considerations in (neuro)hormonal responses.
hydrostatic pressure GFR Levels of the vasoconstrictor adenosine are significantly
Intraglomerular pressure Fibrogenesis Urine output
Net ltration pressure Sodium elevated in patients with acute HF, and data from small
Transrenal perfusion excretion studies indicate that the 1 adenosine receptor antagonist,
pressure Water excretion
rolofyllin, increases diuresis and improves renal function.
The randomized, double-blind phaseIII PROTECT
Figure 3 | Haemodynamic mechanisms in cardio-renalNature interactions. | The trial107 assessed whether rolofyllin would improve renal
Reviews | aNephrology
traditional hypothesis of how renal dysfunction develops in heart failure develop is function and/or clinical outcomes in patients with acute
that it results from heart failure-induced hypoperfusion of the kidneys (low flow). HF, but no significant effects on the primary compos-
Renal hypoperfusion was thought to increase renal vasoconstriction, which resulted ite end point of persistent renal impairment, hospital
in renal tubular hypoxia and tubular necrosis. b | Renal dysfunction in heart failure is readmission, or 60day mortality were noted107.
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 CVD-associated mechanisms
venous pressure. Thechanges to renal function as a consequence of reduced cardiac Comorbidities related to both CVD and CKD include
output result inthe development of renal venous hypertension, renal venous chronic inflammation and associated phenotypic
congestion, increased renal fibrogenesis, and eventually the loss of renal function.
changes in cellular immunity 108110, malnutrition
Renal venous congestion and finally loss of renal function in combination with
(neuro)hormonal responses and potentially altered intra-abdominal and/or inflammationatherosclerosis (MIA) syndrome 111,
intrasplanchnic pressures might contribute to fluid overload and increased venous cardio-renal anaemia112,113, and other metabolic changes
return in a vicious circle. ANP, atrial natriuretic peptide; BNP, brain natriuretic such as CKDmineral and bone disorder (MBD)114
peptide; CI, cardiac index; CO, cardiac output; GFR, glomerular filtration rate; (FIG.5). These factors are thought to trigger and facil-
Na, sodium; RAAS, reninangiotensinaldosterone system. itate the progression of wasting, which usually com-
mences with the loss of skeletal muscle mass and is later
accompanied by loss of fat tissue115,116.
imbalance in HF, the antidiuretic hormone arginine
vasopressin and its precursor copeptin must also be Inflammation. Systemic and chronic low-grade inflam-
considered96. Arginine vasopressin is released from the mation is considered to be a key trigger of both CKD and
posterior hypothalamus following either osmoreceptor CVD. Mounting data show that chronic inflammation

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Increased venous return strongly contributes to a high general cardiovascular risk such as dendritic cells and monocytes or macrophages,
Increased venous return can and increased infection in patients with CKD and CVD. are recruited124,125. Thus, inflammatory mechanisms have
almost always be observed in Inflammation-induced CVD is recognized as a leading a key role in driving vasculopathy and tissue remodelling
heart failure and results from cause of death in respective patient cohorts117. in the heart and in the kidneys, and might contribute to
early activation of key
compensatory mechanisms,
In addition, the degree of chronic inflammation in accelerated organ dysfunction.
including neurohormonal CKD and HF predicts cardiovascular and all-cause mor- Chronic inflammation is a major factor that drives
responses and activation of the tality109,117,118 and contributes to premature vascular age- progression of wasting in HF and CKD126 and also has
sympathetic nervous system, ing119,120. Various factors contribute to chronic low-grade detrimental effects on nutritional and body composition
resulting in increased
inflammation in CKD and HF, including fluid retention status127131. In addition, elevated levels of ang II lead to
circulating volume.
and/or expansion leading to visceral oedema, sympa- enhanced oxidative injury by increasing levels of reactive
thetic nerve activity and other stress-induced (neuro)hor- oxygen species via NADH and NADPH oxidase, which
monal effects, uraemic toxins, chronic activation of the might promote oxidative injury and subsequent endothe-
adaptive immune system, endothelial activation, oxida- lial dysfunction132135. Mounting evidence, therefore, sug-
tive stress, dialysis-related factors, inflammation-driven gests that persistent chronic inflammation and associated
catabolism of amino acids such as tryptophan121, obesity, changes in cellular immunity are key factors that pro-
smoking, dietary and lifestyle factors, environmental mote and accelerate HF and CKD, and that these factors
factors, comorbidities, the microbiome122, and genetic contribute to the progression of organ dysfunction.
factors109,123. Circulating biomarkers of inflammation
such as Creactive protein, pentraxin3, IL10, and the Anaemia. Normochromic normocytic anaemia is typ-
ratio of IL6 to IL10 increase with declining renal func- ically observed in patients with severely reduced GFR
tion109,117. In addition to humoral factors, a number of owing to an inability of the kidney to synthesize suff-
investigations have focused on the role of the innate and ient erythropoietin (EPO). In adults, >90% of EPO is
adaptive immune system in the interplay between HF produced by peritubular cells through oxygen sens-
and CKD. Following their activation via the innate immune ing mechanisms involving hypoxia-inducible factors
system, T lymphocytes and antigen-presenting cells, (HIFs)136. In addition to the decreased production of
EPO in CKD, chronic inflammation associated with
CKD might inhibit binding of EPO to EPO receptors
through cytokine-induced effects, and by decreasing
Sympathetic
Cardiac output (nervous) activity overall iron availability through impaired iron absorp-
Heart tion, transport, and turnover. In patients on dialysis these
Cardiac remodelling
failure effects are augmented by procedural blood loss in both
(brogenesis) RAAS activity acute137 and chronic conditions138. Anaemia also affects
a considerable proportion of patients with HF139141, as
demonstrated by the OPTIMIZEHF study142. Moreover,
Altered arginine ANP anaemia independently predicts length of hospital stay,
Ang II
vasopressin BNP
readmission rates, and prognosis of patients with anae-
mia and HF 142144. In patients with HF who do not have
Sodium and marked CKD, erythropoiesis-stimulating agents (ESAs)
Aldosterone Systemic
water retention vasoconstriction can improve overall quality of life, exercise capacity and
(uid overload) risk of hospitalization, but do not provide a mortality
benefit145. Intravenous iron administration has also
Galectin-3 shown convincing beneficial effects on exercise capacity
Venous return
in patients with stable chronic HF146,147, and a large-scale
trial that aims to investigate the effects of repleting iron
Renal venous Renal remodelling stores on mortality reduction is currently underway148.
congestion (brogenesis)
Anaemia in cardio-renal syndrome, sometimes
Inammation
Oxidative stress
referred to as cardio-renal anaemia, can be especially
relevant112. Both HF and CKD accelerate anaemia, and
Eventual loss of
renal function loss of haemoglobin might not only be a marker, but also
an indirect contributor to the progression of cardio-renal
Nature Reviews | Nephrology
syndrome. Data show that persistent anaemia is related
Figure 4 | (Neuro)hormonal mechanisms in cardio-renal interactions. The to left ventricular hypertrophy and dilatation149 and that
regulation of cardiac and renal function involves a complex interplay between EPO might have direct anti-apoptotic effects on cardio-
(neuro)hormones, sympathetic nervous activity, and filling status. Key mediators myocytes150. Cardio-renal anaemia therefore contributes
that promote a (neuro)hormonal imbalance include increased activation of the
to a decreased quality of life, increased hospitalization
reninangiotensinaldosterone system (RAAS), which results in increases in
angiotensin II (ang II) and aldosterone and a reduction in renal salt and water
rates and most likely progression of HF and CKD, as well
excretion. Increased sympathetic nervous activity can further enhance as increased mortality.
RAASmediated fluid overload and increase systemic vasoconstriction.
Compensatory mechanisms result in increased renal and cardiac fibrogenesis and Bone and mineral disorder. CKDBMD develops in
eventually in dysfunction of both the heart and the kidneys. ANP, atrial natriuretic most patients with CKD stage 3 or higher and is an impor-
peptide; BNP, brain natriuretic peptide. tant player in the context of cardio-renal syndrome151.

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Cardiac hypertrophy
Fibrosis
Heart
failure Endothelial dysfunction
Vascular stiness and
calcication

Cardiovascular
disease and Cardio-renal
comorbidities anaemia
Atherosclerosis Anaemia Mineral bone disorder
Diabetes mellitus Haemoglobin PTH Serum calcium
Arterial hypertension Iron
Wasting and Fetuin A
cachexia EPO Hyperphosphataemia FGF-23

Renal phosphate
excretion
CKD
and AKI Vitamin D Intestinal
calcium absorption

Inammation and (neuro)hormonal activation

Figure 5 | Cardiovascular disease-associated mechanisms leading to the progression ofNature heartReviews

failure, |chronic
Nephrology
kidney disease (CKD), and/or acute kidney injury (AKI). Cardiovascular disease and its comorbidities, such as systemic
atherosclerosis, diabetes mellitus, arterial hypertension, wasting and cachexia, contribute to the development and/or
acceleration of cardiac and/or renal dysfunction. Cardiac and renal dysfunction can be further accelerated by the presence
of cardio-renal anaemia, which can be triggered by reductions in haemoglobin, iron, fetuin A and renal erythropoietin
(EPO), and/or bone and mineral disorder, which can be triggered by conditions associated with CKD and AKI, such as
hyperphosphataemia. In a set of complex dynamic control systems, hyperphosphataemia can result in both the increased
production of parathyroid hormone (PTH) and/or fibroblast growth factor 23 (FGF-23). In combination with systemic
inflammatory and/or (neuro)hormonal mechanisms the increase in PTH and FGF-23 can augment chronic or acute kidney
injury and/or cardiac disease via remodelling and/or fibrogenesis and through the consecutive loss of organ function.

The reduced capacity of the kidney to excrete phos- Therapeutic considerations

phate 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 ven-
tricular 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 hyperphos-
phataemia, 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, placebo-
controlled 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).
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 con-
centrate 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.
changes including smoking cessation, control of blood
pressure, lipid status and intensified glucose manage-
ment; medical treatment of haemodynamic and fluid
status; treatment with modulators of (neuro)hormonal
and stress responses; and eventually treatment of anae-
mia or malnutrition, control of CKDMBD, cardiac
resynchronization or defibrillator therapy in indicated
cases162, mechanical circulatory support or transplan-
tation in patients with end-stage HF or ESRD, optimal
RRT, and other specific therapies for CVD, CKD or
HF6,5358,109,114,151,163.
Preventive measures and nutrition
Severely obese patients with BMI >35 kg/m2 who also
have HF and/or CKD, can benefit from lifestyle changes
that result in weight reduction. The same benefits are
not shared by less obese patients. This difference is
referred to as the obesity paradox in patients with CKD
and/or HF164,165. Nutritional aspects should, however, be
considered for patients with HF and/or CKD128, includ-
ing treatment of anorexia with appetite stimulants, pre-
scription of a high-calorie diet for patients with any
type of tissue wasting166, and administration of essen-
tial amino acids, micronutrients and/or trace elements
for patients with muscle wasting167,168. The evidence
with regard to the benefits of restricting salt intake
remains controversial in HF, and no recommendation
is made in the current version of the European Society
of Cardiology (ESC) HF guidelines12. This controversy
is highlighted by the retraction of a large meta-analysis
of six randomized trials that compared low sodium diets
(1.8 g per day) with normal sodium diets (2.8 g per day)
in more than 2,700 patients with chronic HF169,170. In
patients with acute HF, however, sodium intake is com-
monly restricted to <2 g per day although the evidence
base for these recommendations is rather thin12. The
blood pressure in CKD clinical practice guideline171 rec-
ommends that patients reduce their salt intake to <2 g
(corresponding to 5 g of sodium chloride) per day
unless contraindicated. This limit is recommended
because lowering salt intake reduces blood pressure in
the general population, and in patients with reduced
GFR salt retention is associated with increased blood
pressure171. However, the evidence in patients with
CKD is not robust and derives from small, short-term
randomized controlled trials171.
Medical and extracorporeal treatment
Current ESC treatment guidelines for patients with
chronic HF and reduced ejection fraction recommend
the use of blockers, angiotensin-converting-enzyme
(ACE) inhibitors, mineralocorticoid-receptor antag-
onists and diuretics12. In select patients, use of the
heart-rate-lowering agents ivabradine and digitalis can
also be indicated, and angiotensin-receptor blockers
(ARBs) can be used instead of ACE inhibitors. The new-
est addition to the treatment portfolio for chronic HF is
the combination angiotensin receptorneprilysin inhibi-
tor sacubitrilvalsartan. Data from the PARADIGMHF
trial, which included 8,442 patients with HF and reduced
ejection fraction, demonstrated convincing additional
reductions in cardiovascular and all-cause mortality with
this agent172. Although findings from PARADIGMHF
are promising, long-term followup data focusing on
renal function and renal-related outcomes are needed.
Nevertheless, sacubitrilv alsartan will potentially
change the way we treat patients with HF in the future,
underlining the importance of natriuretic peptides in
this context.
Diuretics are of special importance in patients with
HF and/or CKD but should be considered a double-edged
sword, particularly in patients with severely reduced kid-
ney function (GFR <30 ml/min/1.73m2). The limita-
tions of diuretics in patients with severely reduced renal
function are partly due to the fact that a combination
of loop diuretics with metolazone or thiazide diuretics
can activate the RAAS or induce volume depletion, lead-
ing to pre-renal AKI173. Nevertheless, in certain clinical
states, diuretics can reduce renal congestion and/or renal
venous hypertension, so might improve renal function.
From a clinical perspective, it is worth noting that in
situations of worsening renal failure and/or advanced
renal dysfunction, switching of diuretics, for example
from classical thiazide diuretics to metolazone, indap-
amid or xipamid should be considered in an effort to
increase diuretic efficiency.
Diuretic-resistant states, which are mostly observed
in patients with severely reduced kidney dysfunction
(KDOQI stages 4), are defined clinically as an ina-
bility to obtain a negative fluid balance, despite the
use of high-dose intravenous loop diuretics, sequential
nephron blockade in pre-terminal renal conditions,
additional use of mineralocorticoid-receptor antago-
nists (if tolerated with regard to potassium levels), and
adequate fluid and/or sodium restriction174. In such
diuretic-resistant clinical states, extracorporeal meas-
ures such as ultrafiltration and/or dialysis should be
considered. Studies of patients with HF that have used
extracorporeal ultrafiltration measures do not, however,
generally indicate improved clinical outcomes175. Data
from two studies of acute decompensated HF, the DOSE-
AHF176 and CARESSHF trials177, show that the use of
such decongestive measures for a limited period of time
is not straightforward; the therapies often fail to relieve
orthodema or prevent recurrence of congestion after dis-
charge and do not affect prognosis178. Nevertheless, such
approaches can be beneficial in selected patients with
refractory congestion179. Long term ultrafiltration using
both extracorporeal and intracorporeal measures might
also serve as a palliation therapy, particularly for patients
with chronic cardio-renal syndrome.
The aforementioned studies investigated simple
fluid removal by means of extracorporeal ultrafiltration.
The role of RRTs employing dialysis and/or filtration
techniques in cardio-renal or reno-cardiac interactions
remains somewhat unclear. In critically ill patients in the
ICU, progressive AKI can lead to uraemia and fluid over-
load, which necessitates RRT. However, in patients with
secondary cardio-renal syndrome, for example in those
with severe sepsis or septic shock, questions remain
as to the optimal RRT modality180182, timing183,184 and
dose185. Nevertheless, general consensus suggests that

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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.
RRT should be administered early to critically ill patients
in the ICU186, which might be of particular importance
in those with cardio-renal syndrome type 3.
An interesting future approach to increase aquaresis
is the use of arginine vasopressin receptor antagonists,
also known as vaptans. Although the role of vaptans such
as tolvaptan in HF or cardio-renal syndrome is unclear,
they are thought to increase aquaresis, but not natriu-
resis, and correct hypervolaemic or even euvolaemic
hyponatraemia187,188. As dilutional hyponatraemia is a
common complication of advanced HF, the use of tol-
vaptan might theoretically provide benefits. In patients
with decompensated HF in the EVEREST trial, however,
the use of oral tolvaptan had no effect on long-term
mortality or HFrelated morbidity189, although data
from hypertensive rats showed beneficial effects on
both progression of left ventricular dysfunction and on
renal injury190. The conflicting results from animal and
human studies might partially be explained by the fact
that, as stated above, tolvaptan does not induce natriu-
resis, which night be necessary to achieve sustained
decongestion in patients with acute HF.
Once GFR worsens in patients with HF, a number of
important aspects should be considered. Importantly, thi-
azide diuretics might be less effective in patients with a
very low GFR, and certain renally excreted drugs, such as
digoxin, insulin and low molecular-weight heparin, can
accumulate in patients with renal impairment12. From a
clinical perspective, the accumulation and altered effec-
tiveness of various drugs is of major importance espe-
cially in non-steady-state conditions, such as acute HF,
AKI, and/or acute cardio-renal syndrome subtypes.
RAAS inhibitors such as ACE inhibitors, ARBs and
mineralocorticoidreceptor antagonists, frequently
induce a decline in GFR, although any reduction in
GFR is usually small and should not lead to treatment
discontinuation12. In patients with CKD, RAAS inhibi-
tors reduce left ventricular hypertrophy and cardiac and
renal fibrosis independently of a blood pressure effect191.
Thus, RAAS inhibitors might be of particular impor-
tance in chronic reno-cardiac syndrome (type4)50,57,81.
Despite the fact that a clear pathophysiological ration-
ale exists for the treatment of patients with acute
reno-cardiac interactions (that is, type3 cardio-renal
syndrome) with ACE inhibitiors, these agents should be
used with caution in the acute-care setting due to the risk
of progression of AKI and the potential development of
hyperkalaemia. These adverse effects are of particular
importance in haemodynamically unstable, critically ill
patients with progressive AKI and multiple organ failure.
Investigation of nesiritide, a recombinant form of the
human Btype natriuretic peptide, in patients with acute
decompensated HF in the ASCENDHF trial showed
that this agent led to increased rates of hypotension
without inducing renal dysfunction, but did not decrease
mortality or rehospitalization192. Contradictory results
were initially reported with regard to the renal effects
of nesiritide in patients with acute HF; however, data
from ASCENDHF demonstrated that serum creati-
nine level and blood urea nitrogen levels were similar
between nesiritide and placebo-treated patients, and that
the frequency of worsening renal function was similar in
both treatment groups. Thus, nesiritide does not seem to
affect renal function193, although data for patients with
low GFR are currently unavailable.
Serelaxin is a recombinant form of human relaxin2
that binds to the Gprotein-coupled receptor relaxin
receptor 1, which is expressed in both the heart and the
kidneys, and acts as a primary vasodilator. Data indicate
that treatment of patients with HF with serelaxin results
in increased calcium sensitivity in the myocardium,
antifibrotic effects, and increased creatinine clearance
as a result of increased renal blood flow194. The 2013
placebo-controlled multicentric phaseIII RELAX-AHF
trial195, which included 1,161 patients with acute HF,
showed that serelaxin significantly improved dyspnoea,
shortened the length of the hospital stay, and signifi-
cantly reduced cardiovascular death and all-cause mor-
tality at 180days compared to placebo195. Interestingly,
serelaxin might reduce serum creatinine and cystatinC
levels, indicating improvement in renal function196.
As stated above, increased FGF23 levels are associated
with increased cardiovascular toxicity and cardiac hyper-
trophy153155. Cinacalcet, a calcimimetic that is used to
treat CKD-induced secondary hyperparathyroidism, sig-
nificantly reduced FGF23 levels in the EVOLVE trial, and
this reduction was associated with lower cardiovascular
mortality and fewer CVD events157. Although these data
are promising, the effect of cinacalet on cardio-renal or
reno-cardiac interactions remains unclear.
A number of novel agents are currently undergoing
testing in clinical trials, including the natriuretic pep-
tides ularitide and cenderitide, the short-acting calcium
channel blocker clevidipine, the potassium-channel acti-
vator nicorandil, nitroxyl donors and guanylate cyclase
modulators. Whether these therapeutical approaches
translate into improved outcomes for patients with
cardio-renal or reno-cardiac interactions remains to be
elucidated.
Treatment of anaemia, CKDMBD and acidbase
disorders. Treatment of cardio-renal anaemia and
CKDMBD should follow established guidelines114,163.
Overtreatment for anaemia in HF and/or CKD should
most likely be avoided, and the degree of iron deficiency
should be taken into account when making treatment
decisions. A large-scale study of the effects of repleting
iron stores on mortality reduction in patients with HF is
currently planned148. Nevertheless, whether anaemia is
simply a marker of HF and/or kidney disease or whether
it also mediates progression of cardio-renal syndrome is
unclear. Additional clinical studies on anaemia in larger
cohorts of patients with cardio-renal syndrome, with
longer followup periods, are required to fully under-
stand the complex interactions between anaemia and
cardio-renal syndrome. Acidbase disorders including
renal acidosis caused by diminished proton excretion
can typically be observed in patients with advanced
stages of CKD and in patients with AKI. Acidosis as well
as acidosisinduced hyperkalaemia are key triggers for
RRT initiation in the ICU, and might be particularly
relevant in patients with type 3 cardio-renal syndrome.

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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 disor-
ders. From a pathophysiological perspective, the heart and
the kidneys share a number of pathways that are intrin-
sically linked to each other. These include altered haemo
dynamics and fluid overload leading to renal venous
congestion, a profound imbalance with regard to hormo-
nal and sympatho-adrenergic status, mechanisms induced
by malnutrition and cachexia, and CVD-associated risk
factors. Respective cardiovascular risk factors include per-
sistent chronic inflammation, anaemia, metabolic changes
including CKDMBD, and other factors that contribute
to acceleration of vascular ageing.
Importantly, in the specific context of cardio-renal
and reno-cardiac interactions, strong clinical evidence
of appropriate treatment approaches is absent. This
absence is the result of a limited number of clinical
trials specific to cardio-renal syndrome and the use of
different terminologies related to renal dysfunction in
the cardiology and nephrology literature. Moreover,
the lack of evidence-based treatments underlines the
paramount importance of preventive and early diag-
nostic measures, and highlights the need for thorough
studies investigating the underlying mechanisms
involved in the development of acute or chronic
cardio-renal syndromes with a focus on treatments.
Until further data are available, patients with HF and
renal dysfunction should be treated early by multi-
disciplinary teams involving specialists in cardiol-
ogy and nephrology. This interdisciplinary approach
demands bidirectional professional interactions
between respective specialties and the formation of
new collaborations, which is in line with the spirit
of this article.

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Author contributions
J.C.S. and S.v.H. wrote the article. All authors contributed to
discussion and researching of the content and to review and/
or editing of the manuscript before submission.
Competing interests statement
The Department of Intensive Care Medicine, Bern University
Hospital, Switzerland (J.C.S.) has received research and
developm ent and/or consulting contracts from Orion
Corporation, Abbott Nutrition International, B. Braun Medical
AG, CSEM SA, Edwards Lifesciences Services GmbH, Kenta
Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical
Research AG, Edwards Lifesciences SA, and Nestl, for which no
personal financial gain was received; educational grants from
Fresenius Kabi; GSK; MSD; Lilly; Baxter; Astellas; AstraZeneca;
B. Braun Medical AG, CSL Behring, Maquet, Novartis, Covidien,
Nycomed, Pierre Fabre Pharma (Roba Pharma); Pfizer, Orion
Pharma; J.C.S has received research funding, (travel) grants, or
Bionanalysis GmbH/ Cube DX GesmbH, and Nestl. G.F. is a
member of committees of heart failure trials and registries
sponsored by Novartis, Servier, Cardiorentis, Medtronic and
Novartis, CircuLite, and DC Devices and received honoraria
from CVRx, Impulse Dynamics, AstraZeneca, Bayer, and Orion.
S.D.A. has consulted or received honoraria from Vifor, Novartis,
Cardiorentis, Brahms, Bayer, Relypsa, ZS Pharma and Stealth
Peptides. S.v.H. has received consultant honoraria, travel sup-
port, and/or speakers fees from Vifor, Thermo Fisher Scientific,
Respicardia, Sorin, Novartis, Chugai Pharma, AstraZeneca,
Pfizer, Professional Dietetics and Solartium Dietetics.

14 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneph

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