This document discusses anemia in patients with heart failure and kidney disease (cardiorenal anemia). It notes that anemia is common in these patients and associated with higher mortality and costs. The pathophysiology of cardiorenal disease and anemia are both multifactorial, involving interactions between cardiac function, renal dysfunction, inflammation, and other factors. The document outlines five subtypes of cardiorenal syndrome based on whether heart or kidney dysfunction is acute or chronic. It emphasizes that a multidisciplinary approach is needed to manage cardiorenal anemia given its complex causes.

1. Editorial
Staying in the Pink of Health
for Patients with Cardiorenal
Anemia Requires
a Multidisciplinary Approach
Ragavendra R. Baliga, MD, MBA James B. Young, MD
Consulting Editors
Anemia in heart failure is not only debilitating but
also associated with higher morbidity, mortality,
and greater total health care costs1
in an ever-
aging population. It is common in patients who
have heart failure, with a prevalence ranging from
4% to 55%.2
Most studies indicate that the preva-
lence of anemia is higher in patients with heart
failure who are more symptomatic or have comor-
bid conditions, such as kidney disease, diabetes
mellitus, and advanced age, when compared
with ambulatory and less-symptomatic patients.3,4
The relative risk of death increases by a factor of
1.6 in anemic patients with heart failure who also
have chronic kidney disease.
The pathophysiology of cardiorenal failure is
multifactorial.5
A recent consensus conference
on cardiorenal syndromes6
described 5 subtypes
with distinct pathophysiologies (Fig. 1),7
preven-
tion, and management strategies (Fig. 2):
Type 1, or acute cardiorenal syndrome, is acute
worsening of heart function leading to kidney
injury or dysfunction. Approximately 27% to
40% of the patients with acute decompensated
heart failure seem to develop acute kidney
injury. This type is associated with the poorest
prognosis.
Type 2, or chronic cardiorenal syndrome,
includes patients with chronic abnormalities in
heart function leading to kidney injury or
dysfunction. This has been reported in 63% of
patients hospitalized with congestive heart
failure. In this subset, serum creatinine may
not entirely reflect underlying renal function.
Type 3, or acute renocardiac syndrome, is
acute worsening of kidney function, leading to
heart injury or dysfunction. The effects on heart
function are due to factors in addition to volume
overload (eg, acute kidney injury, glomerulone-
phritis, and renal ischemia).
Type 4, or chronic renocardiac syndrome, is
a situation in which chronic kidney disease
leads to heart injury, disease, or dysfunction
(eg, chronic glomerulonephritis).
Type 5, or secondary cardiorenal syndrome,
includes systemic conditions leading to injury
or dysfunction of heart and kidney (eg, diabetes
mellitus, sepsis, systemic lupus erythematosus,
or amyloidosis).
Patients may move from one subtype to another
depending on the nature of primary insult. The
recognition of these 5 distinct subtypes of cardi-
orenal failure should facilitate better under-
standing not only of these conditions but also of
accompanying comorbidities, such as anemia.
The etiology and pathophysiology of anemia in
heart failure is also multifactorial8
and is due to
a complex interaction9
between cardiac function,
renal dysfunction, neurohormonal and inflammatory
Heart Failure Clin 6 (2010) xi–xvi
doi:10.1016/j.hfc.2010.05.001
1551-7136/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
Anemia and Heart Failure

2. Editorialxii

3. Fig. 1. Subtypes of cardiorenal syndrome. (From Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus conference of the acute
dialysis quality initiative. Eur Heart J 2010;31(6):703–11; with permission.)
Editorialxiii

4. Syndromes Acute cardio-renal (type 1) Chronic cardio-renal (type 2) Acute reno-cardiac (type 3) Chronic reno-cardiac (type 4) Secondary CRS (type 5)
Organ failure
sequence
Definition
Acute worsening of heart
function (AHF–ACS)
leading to kidney injury
and/or dysfunction
Chronic abnormalities in heart
function (CHF-CHD) leading
to kidney injury or
dysfunction
Acute worsening of kidney
function (AKI) leading to heart
injury and/or dysfunction
Chronic kidney disease (CKD)
leading to heart injury, disease
and/or dysfunction
Systemic conditions leading
to simultaneous injury
and/or dysfunction of
heart and kidney
Primary
events
Acute heart failure (AHF) or
acute coronary syndrome
(ACS) or cardiogenic
shock
Chronic heart disease (LV
remodelling and
dysfunction, diastolic
dysfunction, chronic
abnormalities in cardiac
function, cardiomyopathy)
DKCIKA
Systemic disease (sepsis,
amyloidosis, etc.)
Criteria for
primary
events
ESC, AHA/ACC ESC, AHA/ACC RIFLE–AKI airetirccificeps-esaesiDIQODKN
Secondary
events
kcohs,saimhtyhrra,SCA,FHADKCIKA
CHD (LV remodelling and
dysfunction, diastolic
dysfunction, abnormalities in
cardiac function), AHF, ACS
AHF, ACS, AKI, CHD, CKD
Criteria for
secondary
events
CCA/AHA,CSECCA/AHA,CSEIQODKNIKA–ELFIR
ESC, AHA/ACC,
RIFLE/AKIN ESC,
AHA/ACC KDOQI
Cardiac
biomarkers
Troponin, CK-MB, BNP, NT-
proBNP, MPO, IMA
BNP, NT-proBNP, C-reactive
protein
BNP, NT-proBNP
BNP, NT-proBNP, C-reactive
protein
C-reactive protein,
procalcitonin, BNP
Renal
biomarkers
Serum cystatine C,
creatinine, NGAL. Urinary
KIM-1, IL-18, NGAL, NAG
Serum creatinine, cystatin C,
urea, uric acid, C-reactive
protein, decreased GFR
Serum creatinine, cystatin C,
NGAL. Urinary KIM-1, IL-18,
NGAL, NAG
Serum creatinine, cystatin C, urea,
uric acid, decreased GFR
Creatinine, NGAL, IL-18,
KIM-1, NAG
Prevention
strategies
Acutely decompensated
heart failure and acute
coronary syndromes are
A common pathophysiology
(neurohumoral,
inflammatory, oxidative
Acute sodium and volume
overload are part of the
pathogenesis.
The chronic processes of cardiac
and renal fibrosis, left
ventricular hypertrophy,
Potential systemic factors
negatively impact
function of both organs
Editorialxiv

5. Syndromes Acute cardio-renal (type 1) Chronic cardio-renal (type 2) Acute reno-cardiac (type 3) Chronic reno-cardiac (type 4) Secondary CRS (type 5)
most common scenarios
Inciting event may be acute
coronary ischaemia,
poorly controlled blood
pressure, and
noncompliance with
medication and dietary
sodium intake
Randomized trials improving
compliance with heart
failure care management
have reduced rates of
hospitalization and
mortality, and a reduction
in the rates of acute
cardio-renal syndrome
(type 1) can be inferred
injury) could be at work to
create organ dysfunction.
Drugs that block the renin–
angiotensin system reduce
the progression of both
heart failure and CKD
It is unknown whether other
classes of drugs can
prevent chronic cardio-renal
syndrome (type 2)
It is unknown whether sodium and
volume overload is prevented
with different forms of renal
replacement therapy and if this
will result in lower rates of
cardiac decompensation
vascular stiffness, chronic Na
and volume overload, and
other factors (neurohumoral,
inflammatory, oxidative injury)
could be at work to create
organ dysfunction
A reduction in the decline of renal
function and albuminuria has
been associated with a
reduction in cardiovascular
events
The role of chronic uraemia,
anaemia, and changes in
CKD-mineral and bone
disorder on the cardiovascular
system is known in chronic
reno-cardiac syndrome
acutely.
It is uncertain if
reduction/elimination of
the key factors (immune,
inflammatory, oxidative
stress, thrombosis) will
prevent both cardiac and
renal decline.
Management
strategies
Specific—depends on
precipitating factors
General supportive—
oxygenate, relieve pain
pulmonary congestion,
treat arrhythmias
appropriately, differentiate
left from right heart
failure, treat low cardiac
output or congestion
according to ESC
guidelines
(a)
; avoid
nephrotoxins, closely
monitor kidney function.
Treat CHF according to ESC
guidelines
a
, exclude
precipitating pre-renal AKI
factors (hypovolaemia
and/or hypotension), adjust
therapy accordingly and
avoid nephrotoxins, while
monitoring renal function
and electrolytes.
Extracorporeal ultrafiltration
Follow ESC guidelines for acute
CHF
a
specific management
may depend on underlying
aetiology, may need to
exclude renovascular disease
and consider early renal
support, if diuretic resistant
Follow KDOQI guidelines for CKD
management, exclude
precipitating causes (cardiac
tamponade). Treat heart failure
according to ESC guidelinesa
,
consider early renal
replacement support
Specific—according to
etiology.
General—see CRS
management as advised
by ESC guidelines* 2008
Fig. 2. Cardiorenal syndromes: classification, definitions, and work group statements. ACC, American College of Cardiology; ACS, acute coronary syndrome; ADHF, acute
de-compensated heart failure; ADQI, Acute Dialysis Quality Initiative; AHA, American Heart Association; AHF, acute heart failure; AKI, acute kidney injury; AKIN, Acute
Kidney Injury Network; CHF, chronic heart failure; CKD, chronic kidney disease; KDOQI, Kidney Disease Outcome Quality Initiative; KIM-1, kidney injury molecule-1; MPO,
myeloperoxidase; NAG, N-acetyl-b-(D)glucosaminidase; NGAL, neutrophil gelatinase-associated lipocalin; NKF, National Kidney Foundation; RIFLE, risk, injury, failure, loss
of kidney function, and end-stage kidney disease; WRF, worsening renal function. a
As advised by European Society of Cardiology guidelines 2008. (From Ronco C, McCul-
lough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010;31(6):703–11; with
permission.)
Editorialxv

6. responses, hemodilution, iron deficiency, impaired
ability to use available iron stores,10
bone marrow
suppression due to cytokines (eg, tumor necrosis
factor a [TNF-a], interleukin [IL]-1, IL-6, and
C-reactive protein), blunted bone marrow respon-
siveness to erythropoietin, impaired iron mobiliza-
tion, and effects of medications. Aspirin and
angiotensin-converting enzyme inhibitors11
contribute to the anemia potentially through the
actions of hematopoesis inhibitor, N-acetyl-seryl-
aspartyl-lysyl-proline.12
IL-6 stimulates the
production of hepcidin in the hepatic cells, which
blocks absorption of iron in duodenum and
down-regulates ferroprotein expression, which in
turn prevents release of iron from total body
stores.13
In contrast, TNF-a and IL-6 inhibit eryth-
ropoietin production in the kidney by activating the
GATA-binding protein, GATA2, and nuclear factor
kB and also inhibits proliferation of bone marrow
erythroid progenitor cells.3,4,13
Some have used
erythropoietin receptor–stimulating agents or
intravenous iron to correct the anemia of heart
failure, but concern has arisen about the true
effectiveness of this approach and morbidity asso-
ciated with the therapy. The Reduction of Events
with Darbopoeitin Alfa in Heart Failure is a large-
scale, phase III, placebo-controlled, randomized,
morbidity and mortality clinical trial designed to
clarify these issues and will likely be finished
recruiting in 18 months.14
To unravel these complex interactions in cardi-
orenal anemia, Anil Agarwal, MD, Stuart Katz,
MD, and Ajay Singh, MD, have assembled a multi-
disciplinary team of experts in this field. In our
opinion, their multidisciplinary approach is essen-
tial to ensure that patients with cardiorenal anemia
stay in the pink of health.
Ragavendra R. Baliga, MD, MBA
Division of Cardiovascular Medicine
The Ohio State University
Columbus, OH, USA
James B. Young, MD
Division of Medicine and Lerner
College of Medicine, Cleveland Clinic
Cleveland, OH, USA
E-mail addresses:
Ragavendra.Baliga@osumc.edu (R.R. Baliga)
YOUNGJ@ccf.org (J.B. Young)
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renal syndromes: report from the consensus confer-
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795–801.
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