You are on page 1of 14

REVIEWS

Heart failure and kidney dysfunction:


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
1
Department of Intensive
pathomechanisms in HF, AKI and CKD are discussed in addition to current and future
Care Medicine, Inselspital, therapeutic approaches.
Bern University Hospital,
Freiburgstrasse 18,
3010Bern, Switzerland. Heart failure (HF) is associated with high morbidity immune-mediated responses, stress-mediated and
2
Department of Clinical and mortality, and accounts for more than 1million (neuro)hormonal mechanisms, metabolic and nutri-
Cardiology, Attikon University
Hospital, National and
primary and about 3,000,000 secondary annual hos- tional changes including mineral and bone disorder,
Kapodistrian University of pital admissions in the USA alone13. It thus poses a altered fluid and acidbase status, and anaemia, in both
Athens, Rimini 1, major burden to affected patients and health-care acute and chronic conditions. The underlying patho-
12462Athens, Greece. systems worldwide. HF often coexists with a number mechanisms that contribute to HF with acute kidney
3
Department of Cardiology
of prognosis-relevant comorbidities and has direct injury (AKI)9, or chronic kidney disease (CKD) are dis-
and Pneumology, University
of Gttingen Medical School, consequences on other organs, including the kidneys. cussed with a focus on current diagnostic options and
Robert-Koch-Strasse 40, Progression of HF or kidney disease can have deleteri- therapeutic advances.
Gttingen 37075, Germany. ous effects on patient outcomes through the activation
4
Department of Cardiology of vicious cycles that often accelerate cardiac and renal Epidemiology
and Pneumology, Innovative
Clinical Trials, University of
deterioration. Thus, the heart and kidneys interact in The use of differing terminology in the HF and neph-
Gttingen Medical School, a complex and interdependent manner in both acute rology literature remains a major and partly unsolved
Robert-Koch-Strasse 40, and chronic conditions, which can lead to dual organ issue with important consequences for understanding
Gttingen 37075, Germany. dysfunction4,5. the epidemiology of these diseases (BOX1). Improved
Correspondence to S.D.A. Cardiac and renal disease share a number of com- understanding of the epidemiology and the under
s.anker@cachexia.de mon bidirectional pathways48 (FIG.1). Here we review lying pathomechanisms of HF and kidney dysfunction
doi:10.1038/nrneph.2016.113 current understanding of this important organ cross- will require uniform terminology to be used, to enable
Published online 30 Aug 2016 talk, which involves inflammatory and direct cellular comparisons of different data8,10.

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 1



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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


disease28,29. Thus, the risk of death from a cardiac cause
Heart failure (HF) interacts with kidney disease via numerous pathophysiological in a 30year-old patient with ESRD would be comparable
pathways in both the acute and chronic setting to that of an 80year-old individual in the general pop-
Mounting data indicate that the complex interplay between the heart and the ulation30. Moreover, the presence of HF at the initiation
kidneys involves haemodynamic, (neuro)homonal and cardiovascular of dialysis is an independent predictor of mortality31,32,
disease-associated mechanisms regardless of whether the mode of renal replacement
Acceleration of HF or kidney dysfunction is driven by impairment of either the heart therapy (RRT) is haemodialysis33 or peritoneal dialysis34.
or kidneys via mechanisms including induction of inflammation, activation of the AKI can also contribute to the progression of
cellular immune system, metabolic disorders, anaemia and mineral and bone disorder
CVD35,36. AKI of varying severity affects about 57%
In an effort to differentiate respective underlying pathologies and to assess acute of all hospitalized patients, 20% of patients hospital-
and/or chronic organ dysfunction over time, five subtypes of cardio-renal syndromes
ized for HF, and about 3040% of patients in intensive
were proposed
care units (ICUs) in Western populations3740. Since
The absence of a standardized terminology database and the lack of studies specific
1998, a constant rise in the incidence of AKI has been
to cardio-renal syndrome has hampered efforts to develop novel treatments
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,
The risk of HF typically increases with age, and data increasing the risk of mortality by 57fold compared to
show that left ventricular dysfunction (both systolic and that of matched controls without AKI37. AKI has direct
diastolic) and HF is common in community-based aged adverse effects on nonrenal organs, including the heart48.
populations. Although the prevalence of HF is estimated However, several studies have shown that an increase
to be 59% in individuals over 65years of age3,11,12, HF in serum creatinine level in hospitalized patients might
of any type (BOX2) is observed in up to 12% of some have prognostic value only in those with congestion49.
populations, depending on age2. Patients with HF have
a high prevalence of comorbid cardiovascular condi- Cardio-renal syndromes
tions, such as CKD, which contribute to the high mor- Recognition of the bidirectional links between cardiac
bidity and mortality of HF. Importantly, about 4050% and renal function, and the understanding that dys-
of patients with HF have coexisting chronic renal dys- function of one organ affects the other, led to coining of
function, defined as persistent glomerular filtration rate the term cardio-renal syndrome5053. Although use
(GFR) <60 ml/min/1.73m (REFS1317). Even slight of cardio-renal syndrome terminology is helpful when
reductions in GFR strongly affect all-cause mortality in describing the interactions between the heart and kid-
patients with HF14. Both HF and CKD also accelerate neys, it is important to realize that the current classifica-
comorbidities, such as metabolic disorders. Involuntary tion of cardio-renal syndrome encompasses all forms of
weight loss, or cachexia, can develop in patients with bidirectional links and is not specific for HF.
either condition. In Europe, an estimated 1.2 million
patients with advanced HF and 185,000 patients with Classification of cardio-renal syndromes
end-stage renal disease (ESRD) are cachectic18. The cardio-renal syndromes are divided into five sub-
The Acute Decompensated Heart Failure National categories according to the direction of the effect and
Registry (ADHERE) has shown that approximately 30% whether the initiating insult is acute or chronic (FIG.2).
of patients admitted to hospital for acute decompensated Type 5 cardio-renal syndrome can occur in response to
HF have acute or chronic renal insufficiency19. In another an overwhelming systemic insult, such as severe sepsis
study, only about 17% of outpatients with HF had nor- or septic shock, resulting in simultaneous acute cardiac
mal renal function, defined as GFR >90ml/min/1.73m and renal injury (FIG.2). This classification system aims to
(REF.15). Moreover, CKD is a powerful independent risk take into account important interactions between the piv-
factor for the development and progression of cardio- otal organ systems (the heart and the kidney). Although
vascular disease (CVD) and respective cardiovascular the classification is not widely applied in the clinic, it can
outcomes6,2022. Data from the USA show that >60% of provide a clinically oriented definition as a basis to better
patients with CKD have CVD, including HF, and that understand the complex interactions between the heart
the degree of CVD correlates closely with CKD severity23. and kidney; guide future research into the respective
Development of HF is often observed in patients with underlying mechanisms; and guide the development of
CKD, and the prevalence of HF increases significantly therapeutic strategies to target the complex bidirectional
in cohorts with declining GFR. Compared to patients pathophysiology46,54. Of note, however, the classification
with normal kidney function, defined as GFR >90 ml/ has not yet been tested in large prospective registries, in
min/1.73m, patients with at least moderately reduced clinical trials or in clinical practice. Furthermore, it is not
kidney function (that is Kidney Disease Outcomes always easy to assign a patient to a specific group as a
Quality Initiative (KDOQI)24 CKD stage 3 or higher, or certain degree of overlap between categories often exists.
GFR <60 ml/min/1.73m), have about a threefold higher
risk of HF25. Mechanisms of HF and kidney dysfunction
The impact of kidney disease on CVD becomes most As mentioned, interactions between the heart and kid-
evident in patients with ESRD on dialysis26,27, who have a neys are complex and bidirectional. The direct effect
1030fold higher risk of all-cause cardiovascular mortality of kidney dysfunction on HF progression is strikingly

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



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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.

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 3



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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

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



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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.

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 5



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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

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



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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.

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 7



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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 Due to a lack of studies specifically in populations with
in elevated serum levels of parathyroid hormone cardio-renal syndrome, therapeutic recommendations
(PTH) and fibroblast growth factor 23 (FGF23)152. for the treatment of HF and/or CKD mainly rely on
Hyperphosphataemia, persistently increased levels the predominant underlying disease. Furthermore, a
of PTH and FGF23, as well as vitaminD deficiency, limited amount of data are available on patients with
which results in reduced intestinal calcium absorption, severely reduced kidney function (that is, GFR <30 ml/
are all associated with cardiovascular toxicity, left ven- min/1.73 m). Overall, therapeutic efforts for patients
tricular mass153155 and catabolism156. FGF23 maintains with cardio-renal syndromes types 1 and 2 (acute and
phosphate homeostasis by regulating tubular phosphate chronic HF leading to renal dysfunction), mainly con-
reabsorption, so is of particular interest. Future work centrate on the treatment of HF. By contrast treatment of
should aim to elucidate whether FGF23 is a marker underlying renal disease might be the focus for patients
or even a mediator of cardio-renal syndrome before with cardio-renal syndromes types 3 and 4 (acute and
efforts are made to target increased FGF23 levels chronic renal disease leading to HF). Therapeutic
therapeutically157. approaches for type 5 cardio-renal syndrome focus on
Although the mechanisms by which hyperphos- treatment of the underlying condition, such as severe
phataemia, increased PTH, and vitaminD deficiency sepsis, septic shock or vasculitis. Of note, however, the
contribute to cardiovascular toxicity have not been fully classification of a given patient into a specific cardio-
elucidated151,158, they might at least be partially explained renal group can be a challenge in daily clinical practice,
by vitaminDinduced reduction of RAAS activity and and is a limitation of the current classification system. In
anti-inflammatory effects, as suggested by murine all subtypes of cardio-renal syndrome, interdisciplinary
data159. Nevertheless, although treatment with the active care teams should include the early involvement of both
vitaminD compound paricalcitol reduced albuminuria cardiologists and nephrologists.
in patients with CKD160, a large randomized, placebo- Major treatment strategies for cardio-renal syndrome
controlled clinical trial reported that treatment with this include preventive measures, which centre around the
agent did not result in reductions in left ventricular mass avoidance of nephrotoxic drugs, such as contrast media,
or diastolic dysfunction in patients with CKD stages 3 certain antibiotics, non-steroidal anti-inflammatory
and 4 (GFR1560ml/min/1.73 m)(REF.161). medications or low-dose dopamine in AKI; lifestyle

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



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 9



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

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

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



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

Progressive metabolic (that is, renal or lactic) acidosis can Importantly, in the specific context of cardio-renal
alter protein and enzymatic activities and might directly and reno-cardiac interactions, strong clinical evidence
affect cardiac function by altering adrenoreceptor of appropriate treatment approaches is absent. This
expression and/or function and inducing arrhythmia197. absence is the result of a limited number of clinical
trials specific to cardio-renal syndrome and the use of
Conclusions different terminologies related to renal dysfunction in
The care of patients with coexisting HF and kidney disease the cardiology and nephrology literature. Moreover,
is a major medical challenge in both the acute and chronic the lack of evidence-based treatments underlines the
settings. This challenge will become even more evident paramount importance of preventive and early diag-
in the future with the increasing incidence of both disor- nostic measures, and highlights the need for thorough
ders. From a pathophysiological perspective, the heart and studies investigating the underlying mechanisms
the kidneys share a number of pathways that are intrin- involved in the development of acute or chronic
sically linked to each other. These include altered haemo cardio-renal syndromes with a focus on treatments.
dynamics and fluid overload leading to renal venous Until further data are available, patients with HF and
congestion, a profound imbalance with regard to hormo- renal dysfunction should be treated early by multi-
nal and sympatho-adrenergic status, mechanisms induced disciplinary teams involving specialists in cardiol-
by malnutrition and cachexia, and CVD-associated risk ogy and nephrology. This interdisciplinary approach
factors. Respective cardiovascular risk factors include per- demands bidirectional professional interactions
sistent chronic inflammation, anaemia, metabolic changes between respective specialties and the formation of
including CKDMBD, and other factors that contribute new collaborations, which is in line with the spirit
to acceleration of vascular ageing. of this article.

1. Schocken,D.D. etal. Prevention of heart failure: 14. Hillege,H.L. etal. Renal function as a predictor of 28. Johnson,D.W., Craven,A.M. & Isbel,N.M.
ascientific statement from the American Heart outcome in a broad spectrum of patients with heart Modification of cardiovascular risk in hemodialysis
Association Councils on Epidemiology and Prevention, failure. Circulation 113, 671678 (2006). patients: an evidence-based review. Hemodial. Int. 11,
Clinical Cardiology, Cardiovascular Nursing, and High 15. McAlister,F.A., Ezekowitz,J., Tonelli,M. & 114 (2007).
Blood Pressure Research; Quality of Care and Armstrong,P.W. Renal insufficiency and heart failure: 29. Go,A.S., Chertow,G.M., Fan,D., McCulloch,C.E. &
Outcomes Research Interdisciplinary Working Group; prognostic and therapeutic implications from a Hsu,C.Y. Chronic kidney disease and the risks of
and Functional Genomics and Translational Biology prospective cohort study. Circulation 109, death, cardiovascular events, and hospitalization. New
Interdisciplinary Working Group. Circulation 117, 10041009 (2004). Engl. J.Med. 351, 12961305 (2004).
25442565 (2008). 16. McClellan,W.M., Langston,R.D. & Presley,R. 30. Foley,R.N., Parfrey,P.S. & Sarnak,M.J. Clinical
2. van Riet,E.E. etal. Epidemiology of heart failure: the Medicare patients with cardiovascular disease have a epidemiology of cardiovascular disease in chronic
prevalence of heart failure and ventricular dysfunction high prevalence of chronic kidney disease and a high renal disease. Am. J. Kidney Dis. 32 (Suppl. 3),
in older adults over time. A systematic review. Eur. J. rate of progression to end-stage renal disease. J.Am. S112S119 (1998).
Heart Fail. 18, 242252 (2016). Soc. Nephrol. 15, 19121919 (2004). 31. Foley,R.N. etal. Clinical and echocardiographic
3. Redfield,M.M.etal. Burden of systolic and diastolic 17. van Deursen,V.M. etal. Comorbidities in patients disease in patients starting end-stage renal disease
ventricular dysfunction in the community: appreciating with heart failure: an analysis of the European Heart therapy. Kidney Int. 47, 186192 (1995).
the scope of the heart failure epidemic. JAMA 289, Failure Pilot Survey. Eur. J.Heart Fail. 16, 103111 32. Soucie,J.M. & McClellan,W.M. Early death in
194202 (2003). (2014). dialysis patients: risk factors and impact on incidence
4. Bagshaw,S.M. etal. Epidemiology of cardio-renal 18. Morley,J.E., Anker,S.D. & von Haehling,S. and mortality rates. J.Am. Soc. Nephrol. 7,
syndromes: workgroup statements from the 7th ADQI Prevalence, incidence, and clinical impact of 21692175 (1996).
Consensus Conference. Nephrol. Dial. Transplant. 25, sarcopenia: facts, numbers, and epidemiology-update 33. Harnett,J.D. etal. Congestive heart failure in dialysis
14061416 (2010). 2014. J.Cachexia Sarcopenia Muscle 5, 253259 patients: prevalence, incidence, prognosis and risk
5. House,A.A. etal. Definition and classification of (2014). factors. Kidney Int. 47, 884890 (1995).
cardio-renal syndromes: workgroup statements from 19. Adams,K.F. etal. Characteristics and outcomes of 34. Wang,A.Y. etal. Heart failure in long-term peritoneal
the 7th ADQI Consensus Conference. Nephrol. Dial. patients hospitalized for heart failure in the United dialysis patients: a 4year prospective analysis. Clin.
Transplant. 25, 14161420 (2010). States: rationale, design, and preliminary observations J.Am. Soc. Nephrol. 6, 805812 (2011).
6. Segall,L., Nistor,I. & Covic,A. Heart failure in patients from the first 100,000 cases in the Acute 35. Basile,D.P., Anderson,M.D. & Sutton,T.A.
with chronic kidney disease: a systematic integrative Decompensated Heart Failure National Registry Pathophysiology of acute kidney injury. Comprehensive
review. BioMed Res. Int. 2014, 937398 (2014). (ADHERE). Am. Heart J. 149, 209216 (2005). Physiol. 2, 13031353 (2012).
7. Mentz,R.J., OConnor,C.M. Pathophysiology and 20. Tonelli,M. etal. Chronic kidney disease and mortality 36. Berl,T. & Henrich,W. Kidney-heart interactions:
clinical evaluation of acute heart failure. Nat. Rev. risk: a systematic review. J.Am. Soc. Nephrol. 17, epidemiology, pathogenesis, and treatment. Clin.
Cardiol. 13, 2835 (2016). 20342047 (2006). J.Am. Soc. Nephrol. 1, 818 (2006).
8. Filippatos,G., Farmakis,D. & Parissis,J. Renal 21. Sud,M., Tangri,N., Pintilie,M., Levey,A.S. & 37. Chertow,G.M., Burdick,E., Honour,M.,
dysfunction and heart failure: things are seldom what Naimark,D. Risk of end-stage renal disease and death Bonventre,J.V. & Bates,D.W. Acute kidney injury,
they seem. Eur. Heart J. 35, 416418 (2014). after cardiovascular events in chronic kidney disease. mortality, length of stay, and costs in hospitalized
9. Mehta,R. L. etal. Acute Kidney Injury Network. Circulation 130, 458465 (2014). patients. J.Am. Soc. Nephrol. 16, 33653370 (2005).
Report of an initiative to improve outcomes in acute 22. Gansevoort,R.T. etal. Chronic kidney disease and 38. Nash,K., Hafeez,A. & Hou,S. Hospital-acquired renal
kidney injury. Crit. Care 11, R31 (2007). cardiovascular risk: epidemiology, mechanisms, and insufficiency. Am. J.Kidney Dis. 39, 930936 (2002).
10. Damman,K., Tang,W.H., Testani,J.M. & prevention. Lancet 382, 339352 (2013). 39. Uchino,S. etal. Acute renal failure in critically ill
McMurray,J.J. Terminology and definition of changes 23. United States Renal Data System. Chronic kidney patients: a multinational, multicenter study. JAMA
renal function in heart failure. Eur. Heart J. 35, disease in the adult NHANES population. USRDS 294, 813818 (2005).
34133416 (2014). annual report data http://www.usrds.org/2009/pdf/ 40. Bagshaw,S.M., George,C., Dinu,I. & Bellomo,R. A
11. Hogg,K., Swedberg,K. & McMurray,J. Heart failure V1_01_09.pdf (2009). multi-centre evaluation of the RIFLE criteria for early
with preserved left ventricular systolic function; 24. Levey,A.S. etal. The definition, classification, and acute kidney injury in critically ill patients. Nephrol.
epidemiology, clinical characteristics, and prognosis. prognosis of chronic kidney disease: a KDIGO Dial. Transplant. 23, 12031210 (2008).
J.Am. College Cardiol. 43, 317327 (2004). Controversies Conference report. Kidney Int. 80, 41. Hsu,C.Y. etal. Community-based incidence of acute
12. McMurray,J.J. etal. ESC Guidelines for the diagnosis 1728 (2011). renal failure. Kidney Int. 72, 208212 (2007).
and treatment of acute and chronic heart failure 25. Kottgen,A. etal. Reduced kidney function as a risk 42. Waikar,S.S., Curhan,G.C., Wald,R., McCarthy,E.P.
2012: the Task Force for the Diagnosis and Treatment factor for incident heart failure: the atherosclerosis & Chertow,G.M. Declining mortality in patients with
of Acute and Chronic Heart Failure 2012 of the risk in communities (ARIC) study. J.Am. Soc. Nephrol. acute renal failure, 1988 to 2002. J.Am. Soc.
European Society of Cardiology. Developed in 18, 13071315 (2007). Nephrol. 17, 11431150 (2006).
collaboration with the Heart Failure Association (HFA) 26. Sud,M., Tangri,N., Pintilie,M., Levey,A.S. & 43. Kolhe,N.V., Muirhead,A.W., Wilkes,S.R., Fluck,R.J.
of the ESC. Eur. Heart J. 33, 17871847 (2012). Naimark,D.M. ESRD and death after heart failure in & Taal,M.W. The epidemiology of hospitalised acute
13. Ezekowitz,J. etal. The association among renal CKD. J.Am. Soc. Nephrol. 26, 715722 (2015). kidney injury not requiring dialysis in England from
insufficiency, pharmacotherapy, and outcomes in 6,427 27. Tsuruya, K., Eriguchi, M., Yamada, S., Hirakata, H. & 1998 to 2013: retrospective analysis of hospital
patients with heart failure and coronary artery disease. Kitazono, T. Cardio-renal syndrome in end-stage episode statistics. Int. J. Clin. Practice 70, 330339
J.Am. College Cardiol. 44, 15871592 (2004). kidney disease. Blood Purif. 40, 337343 (2015). (2016).

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 11



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

44. Martensson,J. & Bellomo,R. Sepsis-induced acute patients with heart failure. J.Cardiac Fail. 14, 94. Gegenhuber, A. etal. Midregional pro-A-type
kidney injury. Crit. Care Clin. 31, 649660 (2015). 824830 (2008). natriuretic peptide measurements for diagnosis of
45. Rossaint,J. & Zarbock,A. Acute kidney injury: 70. Mullens,W. etal. Elevated intra-abdominal pressure acute destabilized heart failure in short-of-breath
definition, diagnosis and epidemiology. Minerva Urol. in acute decompensated heart failure: a potential patients: comparison with B-type natriuretic peptide
Nefrol. 68, 4957 (2015). contributor to worsening renal function? J.Am. (BNP) and amino-terminal proBNP. Clin. Chem. 52,
46. Damman,K. etal. Renal impairment, worsening renal College Cardiol. 51, 300306 (2008). 827831 (2006).
function, and outcome in patients with heart failure: 71. Chen,K.P. etal. Peripheral edema, central venous 95. Moertl,D. etal. Comparison of midregional pro-atrial
an updated meta-analysis. Eur. Heart J. 35, 455469 pressure, and risk of AKI in critical illness. Clin. J. Am. and Btype natriuretic peptides in chronic heart
(2014). Soc. Nephrol. 11, 602608 (2016). failure: influencing factors, detection of left ventricular
47. Davison,B.A. etal. Worsening heart failure following 72. Damman,K. etal. Increased central venous pressure systolic dysfunction, and prediction of death. J.Am.
admission for acute heart failure: a pooled analysis of is associated with impaired renal function and College Cardiol. 53, 17831790 (2009).
the PROTECT and RELAX-AHF Studies. JACC Heart mortality in a broad spectrum of patients with 96. Voors,A.A. etal. Cterminal provasopressin
Fail. 3, 395403 (2015). cardiovascular disease. J.Am. College Cardiol. 53, (copeptin) is a strong prognostic marker in patients
48. Grams,M.E. & Rabb,H. The distant organ effects of 582588 (2009). with heart failure after an acute myocardial
acute kidney injury. Kidney Int. 81, 942948 (2012). 73. Guyton,A.C. Determination of cardiac output by infarction: results from the OPTIMAAL study. Eur.
49. Metra,M. etal. Is worsening renal function an equating venous return curves with cardiac response Heart J. 30, 11871194 (2009).
ominous prognostic sign in patients with acute heart curves. Physiol. Rev. 35, 123129 (1955). 97. Farmakis,D., Filippatos,G., Kremastinos,D.T. &
failure? The role of congestion and its interaction with 74. Uemura,K. etal. A novel framework of circulatory Gheorghiade,M. Vasopressin and vasopressin
renal function. Circul. Heart Fail. 5, 5462 (2012). equilibrium. Am. J.Physiol. Heart Circulatory Physiol. antagonists in heart failure and hyponatremia. Curr.
50. Whitman,I.R., Feldman,H.I. & Deo,R. CKD and 286, H23762385 (2004). Heart Fail. Rep. 5, 9196 (2008).
sudden cardiac death: epidemiology, mechanisms, and 75. Magder,S. Point: the classical Guyton view that mean 98. Grassi,G. etal. Early sympathetic activation in the
therapeutic approaches. J.Am. Soc. Nephrol. 23, systemic pressure, right atrial pressure, and venous initial clinical stages of chronic renal failure.
19291939 (2012). resistance govern venous return is/is not correct. Hypertension 57, 846851 (2011).
51. Ronco,C., Haapio,M., House,A.A., Anavekar,N. & J.Appl. Physiol. 101, 15231525 (2006). 99. Zoccali,C. etal. Plasma norepinephrine predicts
Bellomo,R. Cardio-renal syndrome. J.Am. College 76. Winton,F.R. The influence of venous pressure on the survival and incident cardiovascular events in patients
Cardiol. 52, 15271539 (2008). isolated mammalian kidney. J.Physiol. 72, 4961 with end-stage renal disease. Circulation 105,
52. McCullough,P.A. etal. Pathophysiology of the cardio- (1931). 13541359 (2002).
renal syndromes: executive summary from the 77. Gottschalk,C.W. & Mylle,M. Micropuncture study of 100. Dibona,G.F., Jones,S.Y. & Sawin,L.L. Reflex
eleventh consensus conference of the Acute Dialysis pressures in proximal tubules and peritubular influences on renal nerve activity characteristics in
Quality Initiative (ADQI). Contrib. Nephrol. 182, capillaries of the rat kidney and their relation to nephrosis and heart failure. J.Am. Soc. Nephrol. 8,
8298 (2013). ureteral and renal venous pressures. Am. J.Physiol. 12321239 (1997).
53. Hadjiphilippou,S. & Kon,S.P. Cardio-renal syndrome: 185, 430439 (1956). 101. DiBona,G.F. & Kopp,U.C. Neural control of renal
review of our current understanding. J.R.Soc. Med. 78. Doty,J.M. etal. Effect of increased renal venous function. Physiol. Rev. 77, 75197 (1997).
109, 1217 (2016). pressure on renal function. J.Trauma 47, 10001003 102. Ramchandra,R. & Barrett,C.J. Regulation of the
54. Tsuruya,K. & Eriguchi,M. Cardio-renal syndrome in (1999). renal sympathetic nerves in heart failure. Frontiers
chronic kidney disease. Curr. Opin. Nephrol. 79. Braam,B., Joles,J.A., Danishwar,A.H. & Physiol. 6, 238 (2015).
Hypertension 24, 154162 (2015). Gaillard,C.A. Cardio-renal syndrome current 103. Krum,H. etal. Catheter-based renal sympathetic
55. Mall,G., Huther,W., Schneider,J., Lundin,P. & understanding and future perspectives. Nat. Rev. denervation for resistant hypertension: a multicentre
Ritz,E. Diffuse intermyocardiocytic fibrosis in Nephrol. 10, 4855 (2014). safety and proofofprinciple cohort study. Lancet 373,
uraemic patients. Nephrol. Dial. Transplant. 5, 80. Ronco,C. etal. Cardio-renal syndromes: report from 12751281 (2009).
3944 (1990). the consensus conference of the acute dialysis quality 104. Schepers,E. etal. Symmetric dimethylarginine as a
56. Wali,R.K. etal. Effect of kidney transplantation on left initiative. Eur. Heart J. 31, 703711 (2010). proinflammatory agent in chronic kidney disease.
ventricular systolic dysfunction and congestive heart 81. Damman,K., Voors,A.A., Navis,G., van Clin.J.Am. Soc. Nephrol. 6, 23742383 (2011).
failure in patients with end-stage renal disease. J.Am. Veldhuisen,D.J. & Hillege,H.L. The cardio-renal 105. Bongartz,L.G. etal. Transient nitric oxide reduction
College Cardiol. 45, 10511060 (2005). syndrome in heart failure. Prog. Cardiovasc. Dis. 54, induces permanent cardiac systolic dysfunction and
57. Bock,J.S. & Gottlieb,S.S. Cardio-renal syndrome: 144153 (2011). worsens kidney damage in rats with chronic kidney
new perspectives. Circulation 121, 25922600 82. Afsar,B. etal. Focus on renal congestion in heart disease. Am. J.Physiol. Regul. Integr. Comp. Physiol.
(2010). failure. Clin. Kidney J. 9, 3947 (2016). 298, R815R823 (2010).
58. Waldum,B. & Os,I. The cardio-renal syndrome: what 83. Erly,B. etal. Hepatorenal syndrome: a review of 106. Bongartz,L.G. etal. Subtotal nephrectomy plus
the cardiologist needs to know. Cardiology 126, pathophysiology and current treatment options. coronary ligation leads to more pronounced damage
175186 (2013). Semin. Intervent. Radiol. 32, 445454 (2015). in both organs than either nephrectomy or coronary
59. Graziani,G. etal. Renal dysfunction in acute 84. Verbrugge,F.H. etal. Abdominal contributions to ligation. Am. J.Physiol. Heart Circulatory Physiol.
congestive heart failure: a common problem for cardio-renal dysfunction in congestive heart failure. 302, H845H854
cardiologists and nephrologists. Heart Fail. Rev. 19, J.Am. College Cardiol. 62, 485495 (2013). 107. Voors,A.A. etal. Effects of the adenosine A1 receptor
699708 (2014). 85. Volpe,M., Carnovali,M. & Mastromarino,V. The antagonist rolofylline on renal function in patients with
60. Carlstrom,M., Wilcox,C.S. & Arendshorst,W.J. natriuretic peptides system in the pathophysiology of acute heart failure and renal dysfunction: results from
Renal autoregulation in health and disease. Physiol. heart failure: from molecular basis to treatment. Clin. PROTECT (Placebo-Controlled Randomized Study of
Rev. 95, 405511 (2015). Sci. 130, 5777 (2016). the selective adenosine A1 receptor antagonist
61. Ljungman,S., Laragh,J.H. & Cody,R.J. Role of the 86. Ruiz-Ortega,M. etal. Angiotensin II regulates the rolofylline for patients hospitalized with acute
kidney in congestive heart failure. Relationship of synthesis of proinflammatory cytokines and chemokines decompensated heart failure and volume overload to
cardiac index to kidney function. Drugs 39 (Suppl. 4), in the kidney. Kidney Int. Suppl. 82, S12S22 (2002). assess treatment effect on congestion and renal
1021(1990). 87. Sharma,U.C. etal. Galectin3 marks activated function). J.Am. College Cardiol. 57, 18991907
62. Singh,D.K., Winocour,P. & Farrington,K. macrophages in failure-prone hypertrophied hearts (2011).
Mechanisms of disease: the hypoxic tubular and contributes to cardiac dysfunction. Circulation 108. Kato,S. etal. Aspects of immune dysfunction in end-
hypothesis of diabetic nephropathy. Nat. Clin. Practice 110, 31213128 (2004). stage renal disease. Clin. J.Am. Soc. Nephrol. 3,
Nephrol. 4, 216226 (2008). 88. de Boer,R.A. etal. Galectin3 in heart failure with 15261533 (2008).
63. Manotham,K. etal. Transdifferentiation of cultured preserved ejection fraction. Eur. J.Heart Fail. 15, 109. Machowska,A., Carrero,J.J., Lindholm,B. &
tubular cells induced by hypoxia. Kidney Int. 65, 10951101 (2013). Stenvinkel,P. Therapeutics targeting persistent
871880 (2004). 89. AbouEzzeddine, O.F. etal. Galectin3 in heart failure inflammation in chronic kidney disease. Translat. Res.
64. Norman,J.T., Clark,I.M. & Garcia,P.L. Hypoxia with preserved ejection fraction. A RELAX trial 167, 204213 (2016).
promotes fibrogenesis in human renal fibroblasts. substudy (phosphodiesterase5 inhibition to improve 110. von Haehling,S. etal. Leukocyte redistribution: effects
Kidney Int. 58, 23512366 (2000). clinical status and exercise capacity in diastolic heart of beta blockers in patients with chronic heart failure.
65. Heywood,J.T. etal. High prevalence of renal failure). JACC Heart Fail. 3, 245252 (2015). PLoS ONE 4, e6411 (2009).
dysfunction and its impact on outcome in 118,465 90. Shenker,Y., Sider,R.S., Ostafin,E.A. & Grekin,R.J. 111. Stenvinkel, P., Heimburger, O., Lindholm, B.,
patients hospitalized with acute decompensated heart Plasma levels of immunoreactive atrial natriuretic Kaysen,G.A. & Bergstrom, J. Are there two types of
failure: a report from the ADHERE database. factor in healthy subjects and in patients with edema. malnutrition in chronic renal failure? Evidence for
J.Cardiac Fail. 13, 422430 (2007). J.Clin. Invest. 76, 16841687 (1985). relationships between malnutrition, inflammation
66. Nohria, A. etal. Cardio-renal interactions: insights 91. Trimarco,B. etal. Blunted sympathetic response to and atherosclerosis (MIA syndrome). Nephrol. Dial.
from the ESCAPE trial. J.Am. College Cardiol. 51, cardiopulmonary receptor unloading in hypertensive Transplant. 15, 953960 (2000).
12681274 (2008). patients with left ventricular hypertrophy. A possible 112. Silverberg,D.S., Wexler,D., Blum,M. & Iaina,A. The
67. Mullens,W. etal. Importance of venous congestion for compensatory role of atrial natriuretic factor. cardio renal anemia syndrome: correcting anemia in
worsening of renal function in advanced Circulation 80, 883892 (1989). patients with resistant congestive heart failure can
decompensated heart failure. J.Am. College Cardiol. 92. Volpe,M. etal. Carotid baroreceptor unloading improve both cardiac and renal function and reduce
53, 589596 (2009). decreases plasma atrial natriuretic factor in hospitalizations. Clin. Nephrol. 60 (Suppl. 1),
68. Drazner,M.H., Rame,J.E., Stevenson,L.W. & hypertensive patients. J.Hypertension 4, S519S522 S93S102(2003).
Dries,D.L. Prognostic importance of elevated jugular (1986). 113. Silverberg,D.S. etal. The effect of correction of
venous pressure and a third heart sound in patients 93. von Haehling,S. etal. Comparison of midregional pro- anaemia in diabetics and non-diabetics with severe
with heart failure. New Engl. J.Med. 345, 574581 atrial natriuretic peptide with Nterminal proBtype resistant congestive heart failure and chronic renal
(2001). natriuretic peptide in predicting survival in patients failure by subcutaneous erythropoietin and
69. Maeder,M.T., Holst,D.P. & Kaye,D.M. Tricuspid with chronic heart failure. J.Am. College Cardiol. 50, intravenous iron. Nephrol. Dial. Transplant. 18,
regurgitation contributes to renal dysfunction in 19731980 (2007). 141146 (2003).

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



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

114. Kidney disease: improving global outcomes (KDIGO) 137. Pschowski,R. etal. Effects of dialysis modality on 160. de Zeeuw,D. etal. Selective vitaminD receptor
CKD-MBD Work Group. KDIGO clinical practice blood loss, bleeding complications and transfusion activation with paricalcitol for reduction of albuminuria
guideline for the diagnosis, evaluation, prevention, and requirements in critically ill patients with dialysis- in patients with type2 diabetes (VITAL study): a
treatment of Chronic Kidney Disease-Mineral and Bone dependent acute renal failure. Anaesth. Intensive Care randomised controlled trial. Lancet 376, 15431551
Disorder (CKD-MBD). Kidney Int.113, S1S130 (2009). 43, 764770 (2015). (2010).
115. Mangner,N. etal. Skeletal muscle alterations in 138. Lin,C.L. etal. Increased blood loss from access 161. Thadhani,R. etal. VitaminD therapy and cardiac
chronic heart failure: differential effects on quadriceps cannulation site during hemodialysis is associated with structure and function in patients with chronic kidney
and diaphragm. J.Cachexia Sarcopenia Muscle 6, anemia and arteriovenous graft use. Ther. Apher. Dial. disease: the PRIMO randomized controlled trial.
381390 (2015). 18, 5156 (2014). JAMA 307, 674684 (2012).
116. Josiak,K., Jankowska,E.A., Piepoli,M.F., 139. Groenveld,H.F. etal. Anemia and mortality in heart 162. Garg,N. etal. Cardiac resynchronization therapy in
Banasiak,W. & Ponikowski,P. Skeletal myopathy in failure patients a systematic review and meta- CKD: a systematic review. Clin. J.Am. Soc. Nephrol. 8,
patients with chronic heart failure: significance of analysis. J.Am. College Cardiol. 52, 818827 12931303 (2013).
anabolic-androgenic hormones. J.Cachexia, (2008). 163. Kidney disease: improving global outcomes (KDIGO)
Sarcopenia Muscle 5, 287296 (2014). 140. Maggioni,A.P. etal. Anemia in patients with heart CKD-MBD Work Group. KDIGO clinical practice
117. von Haehling,S., Schefold,J.C., Lainscak,M., failure: prevalence and prognostic role in a controlled guideline for anemia in chronic kidney disease. Kidney
Doehner,W. & Anker,S.D. Inflammatory biomarkers trial and in clinical practice. J.Cardiac Fail. 11, 9198 Int. 2, 9335 (2012).
in heart failure revisited: much more than innocent (2005). 164. Gastelurrutia,P. etal. Body mass index, body fat,
bystanders. Heart Fail. Clin. 5, 549560 (2009). 141. Kawashiro,N. etal. Clinical characteristics and and nutritional status of patients with heart failure:
118. Colombo,P.C. etal. Inflammatory activation: cardiac, outcome of hospitalized patients with congestive heart The PLICA study. Clin. Nutr. 34, 12331238 (2015).
renal, and cardio-renal interactions in patients with failure: results of the HIJCHF registry. Circul. J. 72, 165. Khalid,U. etal. Pre-morbid body mass index and
the cardio-renal syndrome. Heart Fail. Rev. 17, 20152020 (2008). mortality after incident heart failure: the ARIC study.
177190 (2012). 142. Young,J.B. etal. Relation of low hemoglobin and J.Am. College Cardiol. 64, 27432749 (2014).
119. Stenvinkel,P. & Larsson,T.E. Chronic kidney disease. anemia to morbidity and mortality in patients 166. Rozentryt,P. etal. The effects of a high-caloric protein-
a clinical model of premature aging. Am. J.Kidney hospitalized with heart failure (insight from the rich oral nutritional supplement in patients with
Diseases 62, 339351 (2013). OPTIMIZEHF registry). Am. J.Cardiol. 101, 223230 chronic heart failure and cachexia on quality of life,
120. Kooman,J.P., Kotanko,P., Schols,A.M., Shiels,P.G. (2008). body composition, and inflammation markers: a
& Stenvinkel,P. Chronic kidney disease and premature 143. von Haehling,S. etal. Anaemia is an independent randomized, double-blind pilot study. J.Cachexia
ageing. Nat. Rev. Nephrol. 10, 732742 (2014). predictor of death in patients hospitalized for acute Sarcopenia Muscle 1, 3542 (2010).
121. Schefold, J.P. etal. Increased Indoleamine heart failure. Clin. Res. Cardiol. 99, 107113 167. Witte,K.K. etal. The effect of micronutrient
2,3Dioxygenase (IDO) activity and elevated serum (2010). supplementation on quality-oflife and left ventricular
levels of tryptophan catabolites in patients with 144. von Haehling,S. etal. Anaemia among patients with function in elderly patients with chronic heart failure.
chronic kidney disease: a possible link between heart failure and preserved or reduced ejection Eur. Heart J. 26, 22382244 (2005).
chronic inflammation and uraemic symptoms. Nephrol. fraction: results from the SENIORS study. Eur. J.Heart 168. Valentova,M. etal. Intestinal congestion and right
Dial. Transplant. 24, 19011908 (2009). Fail. 13, 656663 (2011). ventricular dysfunction: a link with appetite loss,
122. Kitai,T., Kirsop,J. & Tang,W.H. Exploring the 145. van der Meer,P., Groenveld,H.F. & Januzzi,J.L.Jr., inflammation, and cachexia in chronic heart failure.
Microbiome in Heart Failure. Curr. Heart Fail. Rep. 13, van Veldhuisen,D.J. Erythropoietin treatment in Eur. Heart J. 37, 16841691 (2016).
103109 (2016). patients with chronic heart failure: a meta-analysis. 169. [No authors listed] Retraction. Low sodium versus
123. Barreto,D.V. etal. Plasma interleukin6 is Heart 95, 13091314 (2009). normal sodium diets in systolic heart failure: systematic
independently associated with mortality in both 146. Anker,S.D. etal. Ferric carboxymaltose in patients review and meta-analysis. Heart 99, 820 (2013).
hemodialysis and pre-dialysis patients with chronic with heart failure and iron deficiency. New Engl. 170. DiNicolantonio,J.J., Di Pasquale,P., Taylor,R.S. &
kidney disease. Kidney Int. 77, 550556 (2010). J.Med. 361, 24362448 (2009). Hackam,D.G. Low sodium versus normal sodium
124. Ismahil,M.A. etal. Remodeling of the mononuclear 147. Ponikowski,P. etal. Beneficial effects of long-term diets in systolic heart failure: systematic review and
phagocyte network underlies chronic inflammation intravenous iron therapy with ferric carboxymaltose meta-analysis. Heart http://dx.doi.org/10.1136/
and disease progression in heart failure: critical in patients with symptomatic heart failure and iron heartjnl-2012-302337 (2013).
importance of the cardiosplenic axis. Circul. Res. 114, deficiencydagger. Eur. Heart J. 36, 657668 171. Kidney disease: improving global outcomes (KDIGO)
266282 (2014). (2015). Blood Pressure Work Group. KDIGO clinical practice
125. Hoffmann,J. etal. Myocardial ischemia and 148. von Haehling,S., Jankowska,E.A., van guideline for the management of blood pressure in
reperfusion leads to transient CD8 immune deficiency Veldhuisen,D.J., Ponikowski,P. & Anker,S.D. Iron chronic kidney disease. Kidney Int. 2, 337414 (2012).
and accelerated immunosenescence in CMV- deficiency and cardiovascular disease. Nat. Rev. 172. McMurray,J.J. etal. Angiotensin-neprilysin inhibition
seropositive patients. Circul. Res. 116, 8798 (2015). Cardiol. 12, 659669 (2015). versus enalapril in heart failure. New Engl. J.Med.
126. von Haehling,S. The wasting continuum in heart 149. Levin,A. etal. Left ventricular mass index increase in 371, 9931004 (2014).
failure: from sarcopenia to cachexia. Proc. Nutr. Soc. early renal disease: impact of decline in hemoglobin. 173. Eshaghian,S., Horwich,T.B. & Fonarow,G.C. Relation
74, 367377 (2015). Am. J.Kidney Dis. 34, 125134 (1999). of loop diuretic dose to mortality in advanced heart
127. Ebner,N., Elsner,S., Springer,J. & von Haehling,S. 150. Calvillo,L. etal. Recombinant human erythropoietin failure. Am. J.Cardiol. 97, 17591764 (2006).
Molecular mechanisms and treatment targets of protects the myocardium from ischemia-reperfusion 174. ter Maaten,J.M. etal. Diuretic response in acute
muscle wasting and cachexia in heart failure: an injury and promotes beneficial remodeling. Proc. Natl heart failure-pathophysiology, evaluation, and therapy.
overview. Curr. Opin. Supportive Palliative Care 8, Acad. Sci. USA 100, 48024806 (2003). Nat. Rev. Cardiol. 12, 184192 (2015).
1524 (2014). 151. Charytan,D.M., Fishbane,S., Malyszko,J., 175. Costanzo,M.R., Fonarow,G.C. & Filippatos,G.S.
128. Ebner,N. etal. Mechanism and novel therapeutic McCullough,P.A. & Goldsmith,D. Cardio-renal Ultrafiltration in heart failure with cardio-renal
approaches to wasting in chronic disease. Maturitas syndrome and the role of the bone-mineral axis and syndrome. New Engl. J.Med. 368, 11581159 (2013).
75, 199206 (2013). anemia. Am. J.Kidney Dis. 66, 196205 (2015). 176. US National Library of Medicine.ClinicalTrials.gov
129. von Haehling,S., Lainscak,M., Springer,J. & 152. Kovesdy,C.P. & Quarles,L.D. The role of fibroblast [online], https://clinicaltrials.gov/ct2/show/
Anker,S.D. Cardiac cachexia: a systematic overview. growth factor23 in cardio-renal syndrome. Nephron NCT00577135?term=NCT00577135&rank=1
Pharmacol. Ther. 121, 227252 (2009). Clin. Pract. 123, 194201 (2013). (2016).
130. von Haehling,S., Steinbeck,L., Doehner,W., 153. Achinger,S.G. & Ayus,J.C. Left ventricular 177. US National Library of Medicine.ClinicalTrials.gov
Springer,J. & Anker,S.D. Muscle wasting in heart hypertrophy: is hyperphosphatemia among dialysis [online], https://clinicaltrials.gov/ct2/show/
failure: an overview. Int. J.Biochem. Cell Biol. 45, patients a risk factor? J. Am. Soc. Nephrol. 17 NCT01921829?term=NCT01921829&rank=1
22572265 (2013). S255S261 (2006). (2016).
131. Pecoits-Filho, R., Lindholm, B. & Stenvinkel, P. The 154. Fujii,H., Kim,J.I., Abe,T., Umezu,M. & Fukagawa,M. 178. Lala,A. etal. Relief and recurrence of congestion
malnutrition, inflammation, and atherosclerosis (MIA) Relationship between parathyroid hormone and during and after hospitalization for acute heart failure:
syndrome the heart of the matter. Nephrol. Dial. cardiac abnormalities in chronic dialysis patients. insights from diuretic optimization strategy evaluation
Transpl. 17 (Suppl. 11), 2831(2002). Internal Med. 46, 15071512 (2007). in acute decompensated heart failure (DOSE-AHF) and
132. Griendling,K.K., Minieri,C.A., Ollerenshaw,J.D. & 155. Scialla,J.J. & Wolf,M. Roles of phosphate and cardio-renal rescue study in acute decompensated
Alexander,R.W. Angiotensin II stimulates NADH and fibroblast growth factor 23 in cardiovascular disease. heart failure (CARESSHF). Circul. Heart Fail. 8,
NADPH oxidase activity in cultured vascular smooth Nat. Rev. Nephrol. 10, 268278 (2014). 741748 (2015).
muscle cells. Circul. Res. 74, 11411148 (1994). 156. Rozentryt,P. etal. Higher serum phosphorus is 179. Yancy,C.W. etal. 2013 ACCF/AHA guideline for the
133. Heymes,C. etal. Increased myocardial NADPH associated with catabolic/anabolic imbalance in heart management of heart failure: executive summary:
oxidase activity in human heart failure. J.Am. College failure. J.Cachexia Sarcopenia Muscle 6, 325334 areport of the American College of Cardiology
Cardiol. 41, 21642171 (2003). (2015). Foundation/American Heart Association Task Force on
134. Vaziri,N.D., Dicus,M., Ho,N.D., Boroujerdi-Rad,L. 157. Moe,S.M. etal. Cinacalcet, Fibroblast growth practice guidelines. Circulation 128, 18101852
& Sindhu,R.K. Oxidative stress and dysregulation of factor23, and cardiovascular disease in hemodialysis: (2013).
superoxide dismutase and NADPH oxidase in renal the Evaluation of Cinacalcet HCl Therapy to Lower 180. Lins,R. L. etal. Intermittent versus continuous renal
insufficiency. Kidney Int. 63, 179185 (2003). Cardiovascular Events (EVOLVE) trial. Circulation 132, replacement therapy for acute kidney injury patients
135. Munzel,T., Gori,T. & Keaney,J.F.Jr., Maack,C. 2739 (2015). admitted to the intensive care unit: results of a
& Daiber,A. Pathophysiological role of oxidative 158. Wang,A.Y. etal. Serum 25hydroxyvitaminD status randomized clinical trial. Nephrol. Dial. Transplant.
stress in systolic and diastolic heart failure and its and cardiovascular outcomes in chronic peritoneal 24, 512518 (2009).
therapeutic implications. Eur. Heart J. 36, dialysis patients: a 3y prospective cohort study. Am. 181. Schefold, J.C. etal. The effect of continuous versus
25552564 (2015). J.Clin. Nutr. 87, 16311638 (2008). intermittent renal replacement therapy on the
136. Ratcliffe,P.J. From erythropoietin to oxygen: hypoxia- 159. Panizo,S. etal. VitaminD receptor activation, left outcome of critically ill patients with acute renal failure
inducible factor hydroxylases and the hypoxia signal ventricular hypertrophy and myocardial fibrosis. (CONVINT): a prospective randomized controlled trial.
pathway. Blood Purif. 20, 445450 (2002). Nephrol. Dial. Transplant. 28, 27352744 (2013). Crit. Care 18, R11 (2014).

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 13



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
REVIEWS

182. Vinsonneau,C. etal. Continuous venovenous 191. Cannella,G. etal. Prolonged therapy with ACE inhibitors contribution of the Heart Failure Association (HFA) of
haemodiafiltration versus intermittent haemodialysis induces a regression of left ventricular hypertrophy of the ESC. Eur. Heart J. 27, 2129200 (2016).
for acute renal failure in patients with multiple-organ dialyzed uremic patients independently from hypotensive
dysfunction syndrome: a multicentre randomised trial. effects. Am. J.Kidney Dis. 30, 659664 (1997). Author contributions
Lancet 368, 379385 (2006). 192. OConnor,C.M. etal. Effect of nesiritide in patients J.C.S. and S.v.H. wrote the article. All authors contributed to
183. Zarbock,A. etal. Randomized Clinical Trial. JAMA 20, with acute decompensated heart failure. New Engl. discussion and researching of the content and to review and/
21902199 (2016). J.Med. 365, 3243 (2011). or editing of the manuscript before submission.
184. Seabra,V.F. etal. Timing of renal replacement therapy 193. van Deursen,V.M. etal. Nesiritide, renal function,
initiation in acute renal failure: a meta-analysis. Am. and associated outcomes during hospitalization for Competing interests statement
J.Kidney Dis. 52, 272284 (2008). acute decompensated heart failure: results from the The Department of Intensive Care Medicine, Bern University
185. Kellum,J.A. & Ronco,C. Dialysis: results of RENAL Acute Study of Clinical Effectiveness of Nesiritide and Hospital, Switzerland (J.C.S.) has received research and
what is the optimal CRRT target dose? Nat. Rev. Decompensated Heart Failure (ASCENDHF). developm ent and/or consulting contracts from Orion
Nephrol. 6, 191192 (2010). Circulation 130, 958965 (2014). Corporation, Abbott Nutrition International, B. Braun Medical
186. Kidney disease: improving global outcomes (KDIGO). 194. Singh,A., Laribi,S., Teerlink,J.R. & Mebazaa,A. AG, CSEM SA, Edwards Lifesciences Services GmbH, Kenta
KDIGO clinical practice guideline for acute kidney Agents with vasodilator properties in acute heart Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical
injury. Kidney Int. 2, 1138 (2012). failure. Eur. Heart J. http://dx.doi.org/10.1093/ Research AG, Edwards Lifesciences SA, and Nestl, for which no
187. Lin,T.E., Adams,K.F.Jr. & Patterson, J.H. Potential eurheartj/ehv755 (2013). personal financial gain was received; educational grants from
roles of vaptans in heart failure: experience from 195. Teerlink,J.R. etal. Serelaxin, recombinant human Fresenius Kabi; GSK; MSD; Lilly; Baxter; Astellas; AstraZeneca;
clinical trials and considerations for optimizing therapy relaxin2, for treatment of acute heart failure (RELAX- B. Braun Medical AG, CSL Behring, Maquet, Novartis, Covidien,
in target patients. Heart Fail. Clin. 10, 607620 AHF): a randomised, placebo-controlled trial. Lancet Nycomed, Pierre Fabre Pharma (Roba Pharma); Pfizer, Orion
(2014). 381, 2939 (2013). Pharma; J.C.S has received research funding, (travel) grants, or
188. Lehrich,R.W., Ortiz-Melo,D.I., Patel,M.B. & 196. Metra,M. etal. Effect of serelaxin on cardiac, renal, and speaker fees from Bayer AG/Schering AG, Eli Lilly, Anagnostics
Greenberg,A. Role of vaptans in the management of hepatic biomarkers in the Relaxin in Acute Heart Failure Bionanalysis GmbH/ Cube DX GesmbH, and Nestl. G.F. is a
hyponatremia. Am. J.Kidney Dis. 62, 364376 (RELAX-AHF) development program: correlation with member of committees of heart failure trials and registries
(2013). outcomes. J.Am. College Cardiol. 61, 196206 (2013). sponsored by Novartis, Servier, Cardiorentis, Medtronic and
189. Konstam,M.A. etal. Effects of oral tolvaptan in 197. Nimmo,A.J., Than,N., Orchard,C.H. & Vifor. G.H. has consulted for Servier, Impulse Dynamics,
patients hospitalized for worsening heart failure: Whitaker,E.M. The effect of acidosis on -adrenergic Novartis, CircuLite, and DC Devices and received honoraria
theEVEREST outcome trial. JAMA 297, 13191331 receptors in ferret cardiac muscle. Exp. Physiol. 78, from CVRx, Impulse Dynamics, AstraZeneca, Bayer, and Orion.
(2007). 95103 (1993). S.D.A. has consulted or received honoraria from Vifor, Novartis,
190. Morooka,H. etal. Chronic administration of oral 198. Ponikowski,P. etal. 2016 ESC Guidelines for the Cardiorentis, Brahms, Bayer, Relypsa, ZS Pharma and Stealth
vasopressin type2 receptor antagonist tolvaptan diagnosis and treatment of acute and chronic heart Peptides. S.v.H. has received consultant honoraria, travel sup-
exerts both myocardial and renal protective effects in failure: The Task Force for the diagnosis and treatment port, and/or speakers fees from Vifor, Thermo Fisher Scientific,
rats with hypertensive heart failure. Circul. Heart Fail. of acute and chronic heart failure of the European Respicardia, Sorin, Novartis, Chugai Pharma, AstraZeneca,
5, 484492 (2012). Society of Cardiology (ESC). Developed with the special Pfizer, Professional Dietetics and Solartium Dietetics.

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



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
,
p
a
r
t
o
f
S
p
r
i
n
g
e
r
N
a
t
u
r
e
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.