Open Journal of Nephrology, 2012, 2, 23-28
http://dx.doi.org/10.4236/ojneph.2012.23004 Published Online September 2012 (http://www.SciRP.org/journal/ojneph)
Erythropoiesis Stimulating Agents (ESAs) in the Treatment
of Cardio-Renal Syndrome Anaemia
Ioannis Koulouridis, Efstathios Koulouridis
Department of Nephrology, General Hospital of Corfu, Corfu, Greece
Received April 23, 2012; revised June 17, 2012; accepted July 3, 2012
ABSTRACT
Coexistence of chronic kidney disease (CKD) and chronic heart failure (CHF) define a recently recognized clinical en-
tity known as cardio-renal syndrome. Sufficient evidence suggests that the two pathological conditions share common
pathogenic etiology which is not yet fully defined. Superimposed anaemia is a common finding among patients suffer-
ing from cardio-renal syndrome. The combination of CKD, CHF and anaemia increase the probability of death by 6
times compared to normal individuals. Early attempts to restore anaemia either by iron supplementation, erythropoiesis
stimulating agents (ESAs) or combination of the two have reported to improve quality of life, morbidity and mortality
especially among patients treated by cardiologists. Recent publications of well controlled epidemiological studies failed
to prove convincing beneficial effect of the above mentioned therapy moreover skepticism has raised concerning the
safety of restoring anaemia among patients with cardio-renal syndrome as well as used medications. There are still un-
resolved problems concerning the definition of anaemia, by means of hemoglobin level among these patients, the target
hemoglobin level and the therapeutic regimen of ESAs administration and iron supplementation. We need much more
evidence in order to define an effective and safe treatment strategy correcting anaemia among patients with cardio-renal
syndrome.
Keywords: Cardio-Renal Syndrome; Anaemia; Erythropoiesis Stimulating Agents; Adverse Outcomes
1. Introduction
The term cardio-renal syndrome refers to the condition of
cardiac and renal failure coexistence when the deteriora-
tion of cardiac function implies deterioration of renal
function and vice versa. It should not be considered as
simple coexistence of two separate pathological condi-
tions but, as a coupled damage of the two organs many of
the leading factors are still unknown [1]. According to
the consensus conference on cardio-renal syndromes
(CRS) held in Venice Italy, 2008 five subtypes of cardio-
renal syndromes were recognized [2]. The type 1 or acute
cardio-renal syndrome refers to the condition of acute
cardiac function worsening which leads to renal injury or
dysfunction. The type 2 or chronic cardio-renal syndro-
me defines the situations of chronic cardiac abnormalities
which are coupled with chronic renal dysfunction. The
type 3 or acute reno-cardiac syndrome refers to the pres-
ence of acute kidney injury which leads to heart injury or
dysfunction. The type 4 or chronic reno-cardiac syndrome
refers to the presence of chronic kidney disease which
leads to chronic cardiac damage or dysfunction and the
type 5 or secondary cardio-renal syndrome refers to the
presence of systemic pathological conditions affecting
simultaneously the two organs such as sepsis, collagen
disease, diabetes mellitus, amyloidosis etc. In the present
review we shall focus our interest mainly upon the type 2
and type 4 CRS and the effect of anaemia correction
upon cardiac and renal function as well as upon patient’s
final outcome concerning morbidity and mortality.
It is known from the literature that the frequency of
kidney disease among patients older than 65 years of age
hospitalized for acute decompensated congestive heart
failure has been estimated to be 21% where as 41% of
them exhibit creatinine levels greater than 1.5 mg/dL [3].
Emergence of acute kidney injury (increment of create-
nine levels greater than 0.3 mg/dL) during therapeutic
manipulation of hospitalized patients suffering from
congestive heart failure is estimated to be 27% - 45%
even though they exhibited normal creatinine levels at
the admission to the hospital [4]. The presence of cardiac
failure among patients suffering from chronic kidney
disease (CKD) has been estimated in a large epidemiol-
ogical survey based upon the data of Medicare system
and showed that 39.9% of patients exhibited cardiac fail-
ure from the first visit and an additional 30.7% devel-
oped cardiac failure during the next year [5]. Data from
the Acute Decompensated Heart Failure National Regis-
try (ADHERE) study showed that increase of creatinine
C
opyright © 2012 SciRes. OJNeph

I. KOULOURIDIS, E. KOULOURIDIS
24
and blood urea nitrogen levels were the most powerful
independent risk factors affecting in-hospital mortality
[6]. The detailed effect of kidney injury upon mortality
of hospitalized and non-hospitalized patients suffering
from congestive heart failure was shown from a meta-
analysis of sixteen RCTs including 80,018 patients. This
study showed a positive correlation between deteriora-
tion of renal function and mortality, moreover each 0.5
mg/dL increment of creatinine exhibited a 15% incre-
ment of mortality where as for each 10 ml/min reduction
of eGFR observed a 7% increase in mortality [7]. The
etiology of increased mortality among patients suffering
from cardio-renal syndrome is probably due to increased
activity of RAS system, increased sympathetic activity,
increased concentration of pro-inflammatory cytokines,
deterioration of anaemia, deterioration of left ventricular
hypertrophy and myocardial contractility, deranged regu-
lation of extra-cellular volume and final exhaust of the
cardiac pump which leads to death [7].
2. Anaemia in Cardio-Renal Syndrome
The frequency of anaemia in cardio-renal syndrome is
difficult to be estimated because of lack of universal cri-
teria in defining anaemia among patients with cardiac
failure. Most authors accept hemoglobin levels lower
than 12 - 12.5 g/dl in order to characterize patients with
cardiac failure as anemic [8].
Data from the Organized Program to Initiate Lifesav-
ing Treatment in Hospitalized Patients with Heart Failure
((OPTIMIZE-HF) which included 48,612 patients, showed
that 51.2% of them exhibited hemoglobin levels lower
than 12.1 g/dL whereas 25% of them exhibited hemoglo-
bin levels between 5 g/dL and 10.7 g/dL. Moreover it was
shown that decrease of hemoglobin level by 1 g/dL pro-
duced an increase in the likelihood of death by 20% [8].
It is widely accepted that among patients with CKD
hemoglobin levels lower than 12 g/dL are compatible
with anaemia. According to this definition McClellan et
al. [9] showed that among 5222 patients with CKD
anaemia was present in 47.7% of them. It was shown
also that anaemia was inversely correlated with GFR, so
patients with GFR levels greater than 60 ml/min/1.73 m2
exhibited anaemia in a percentage of 26.7% whereas pa-
tients with GFR levels lower than 15 ml/min/1.73 m2
exhibited anaemia in a percentage of 75.5%. The coexis-
tence of cardiac failure, chronic kidney disease and anae-
mia increases the probability of death by six times com-
pared to healthy individuals [10].
Etiology of anaemia among patients with cardiac fail-
ure is attributed to fluid retention and concomitant edema
which produce blood dilution as well as to aspirin and
antiplatelet drugs which produce chronic occult blood
loss. Other causes are reduced absorption of iron, folic
acid and vitamin B12 by intestine due to mucosal edema,
increased production of inflammatory cytokines such as
interleukin 1 or 6 and 18 as well as TNF-α which sup-
press erythropoiesis and produce cachexia. Another im-
portant causative factor of anaemia among these patients
is the prescription of angiotensin converting enzyme in-
hibitors as it is known that Ang-II promotes erythropoi-
esis in bone marrow. Moreover it is known that convert-
ing enzyme is the main catabolic enzyme of the tetra
peptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) which is a
known powerful inhibitor of erythropoiesis so that con-
verting enzyme inhibition leads to increased concentra-
tion of AcSDKP with a resultant suppression of effective
erythropoiesis [8,10-12].
It has been speculated that patients suffering from car-
diorenal syndrome are not deficient of endogenous
erythropoietin production. Van der Meer et al. [12] sho-
wed in a small number of anemic patients, suffering from
cardiac failure and CKD, that 29% of them exhibited
levels of endogenous erythropoietin greater than expected
as well as that these patients exhibited greater mortality
rate compared to patients with expected or lower than
expected levels of endogenous erythropoietin. This find-
ing suggests that a considerable proportion of patients
with cardio-renal anaemia exhibit endogenous erythro-
poietin resistance.
The most important causative factor of anaemia among
patients with CKD is the lack of endogenous erythropoi-
etin, absolute or relative, because it is known that about
40% of patients with CKD exhibit increased levels of
bioactive endogenous erythropoietin but reduced respon-
se to the hormone action [13]. Other causes of anaemia in
CKD patients are the reduced time life of red blood cells,
the chronic blood loss from gastrointestinal tract, fre-
quent blood tests, iron deficiency, folate and B12 defi-
ciency, secondary hyperparathyroidism, hypothyroidism,
acute or chronic inflammation, aluminum toxicity and
hemoglobinopathies [12-14].
3. Restoration of Cardiorenal Anaemia
The exogenous administration of erythropoietin and iron,
either solely or in combination, is capable to restore
anaemia of cardio-renal syndrome and several earlier
publications suggest that improve quality of life, left
ventricular ejection fraction and morbidity of these pa-
tients but newer randomized controlled trials (RCTs)
failed to confirm preliminary enthusiasm, on the contrary
it is possible that vigorous attempt to anaemia correction
increase all cause mortality, cardiovascular mortality and
fatal and nonfatal stroke events [15].
The first disappointing results concerning the correc-
tion of anaemia in CKD patients came in 2006 published
in the same issue of New England Journal of Medicine

I. KOULOURIDIS, E. KOULOURIDIS 25
and included the Cardiovascular Risk Reduction by early
Treatment with Epoetin beta (CREATE) [16] study and
the Correction of Hemoglobin and Outcomes in Renal
Insufficiency (CHOIR) [17] study.
The CREATE study included 603 patients with CKD
stage III-IV (eGFR: 15 - 35 ml/min/1.73 m2) and mild
anaemia (Hb: 11 - 12.5 g/dL), patients randomized in two
groups, in group I (n = 301) administered erythropoietin
(epoetin beta, NeoRecormone, F. Hoffman-La Roche)
with target hemoglobin 13.0 - 15 g/dL, in group II (n =
302) administered erythropoietin only when hemoglobin
levels fell below 10.5 g/dL with target hemoglobin lower
than 11.5 g/dL. After a three years observation period no
difference in cardiovascular events, deterioration of renal
function or left ventricular mass index was noted be-
tween groups, in contrast more patients from group I than
group II reached end stage renal disease (127 vs 111, p =
0.03), general condition and physical activity was im-
proved, as expected, in group I (p = 0.003 and p < 0.001
respectively).
The CHOIR study included 1432 patients with CKD
stage III-IV (eGFR: 27.0 ± 8.7 ml/min/1.73 m2), patients
randomized in two groups, in group I (n = 715) adminis-
tered epoetin alfa with target hemoglobin 13.5 g/dL and
in group II (n = 717) administered epoetin alfa with tar-
get hemoglobin 11.3 g/dL. After 16 months Data and
Safety Monitoring Board discontinued study because of
unfavorable outcomes. The end points of the study were
all cause of death, myocardial infarction, hospitalization
for decompensated heart failure and stoke. A total of 222
events were recorded, 125 of them in group I (high he-
moglobin) and 97 in group II (low hemoglobin) [HR =
1.34 (95% CI 1.03 - 1.74) p = 0.03]. The recorded events
were 65 deaths (29.3%), 101 hospitalizations for decom-
pensated heart failure (45.5%), 25 myocardial infarctions
(11.3%), and 23 strokes (10.4%) no difference in the
improvement of quality of life was justified between
groups.
The above mentioned studies prompted the need to
contact double blind placebo controlled trials in order to
elucidate the effect of anaemia correction in the evolution
of kidney disease and cardiac disease among cardio-renal
syndrome patients and so emerged the Study of Anemia
in Heart Failure Trial (STAMINA-HeFT) and the Trial to
Reduce Cardiovascular Events with Aranesp Therapy
(TREAT) study.
The STAMINA-HeFT [18] included 319 patients with
symptomatic heart failure (EF < 40%) and eGFR < 60
ml/min/1.73 m2. Patients randomized in two groups in
group I (n = 157) administered placebo in order to keep
hemoglobin levels about 11.3 g/dL and in group II (n =
162) administered darbepoetin alfa subcutaneously every
two weeks for one year with target hemoglobin 14.0 ±
1.0 g/dL. No statistically significant difference in exer-
cise duration and in heart failure severity according to
NYHA criteria was noted between the two groups, al-
though a trend toward a reduction of all cause mortality
and hospitalization for acute decompensated heart failure
was noted in darbepoetin group.
The TREAT [19] study included 4038 patients with
CKD stage III-IV (eGFR: 20 - 60 ml/min/1.73 m2) and
diabetes mellitus. Patients randomized in two groups, the
darbepoetin alfa group (n = 2012) and the placebo group
(n = 2026). Target hemoglobin for the darbepoetin group
was 12 g/dL and for the placebo group 9 g/dL, whenever
hemoglobin level fell below 9 g/dL in placebo group
administered darbepoetin or transfusions but not exceed-
ing hemoglobin level of 11 g/dL. The end points of the
study were all cause mortality, non fatal myocardial in-
farction, congestive heart failure, stroke, hospitalization
for myocardial ischemia and end-stage renal disease
(ESRD). Death or cardiovascular events occurred in 632
patients of darbepoetin group and in 602 patients in pla-
cebo group [HR = 1.06 (95% CI 0.94 - 1.17) p = 0.41],
death or ESRD occurred in 652 patients of darbepoetin
group and in 618 patients of the placebo group [HR =
1.06 (95% CI 0.95 - 1.19) p = 0.29]. Fatal or nonfatal
stroke occurred in 101 patients of the darbepoetin group
and in 53 patients of the placebo group [HR = 1.92 (95%
CI 1.38 - 2.68) p < 0.001]. Blood transfusions needed
297 patients of the darbepoetin group and 496 patients of
the placebo group (p < 0.001). Only a subtle difference in
fatigue was noted among darbepoetin group in relation to
the placebo group.
In a later post hoc analysis of the TREAT study Solo-
mon et al. [20] compared the outcomes of participants
according to their initial response to darbepoetin. The
analysis included 1872 patients from the darbepoetin
group authors separated 471 patients who after a two
weight-based doses of darbepoetin, in a two-week regi-
men, failed to increase their hemoglobin levels higher
than 2% of the initial level. These patients characterized
as “poor initial responders” and although they received
the higher doses of darbepoetin (median dose 232 μg vs
167 μg, p < 0.001) they exhibited the lower levels of
hemoglobin throughout the study. Moreover poor initial
responders exhibited greater frequency of cardiovascular
events [HR = 1.31 (95% CI 1.09 - 1.59)], greater freque-
ncy of all-cause mortality [HR = 1.41 (95% CI 1.12 -
1.72)] and greater frequency of stokes [HR = 1.26 (95%
CI 0.78 - 2.02)].
More recently published data indicate that erythropoi-
etin dose rather than hemoglobin level is the cause of
inverse outcomes among dialysis and non-dialysis pa-
tients. Zhang Y et al. [21] in an observational study in-
cluded 35,593 elderly patients of Medicare system, un-
dergoing dialysis (19,034 of them were diabetics) the
authors showed that the adjusted 9-month mortality risk

I. KOULOURIDIS, E. KOULOURIDIS
26
for erythropoietin dose between 15,000 U/week and
45,000 U/week was 13% among diabetics (95% CI: 10%
- 16%) and 5% among non-diabetics [(95% CI: 2% - 9%)
p-value = 0.002]. Koulouridis I et al. [22] in a Meta-Re-
gression analysis of 31 RCTs included 12,956 dialysis
and non-dialysis patients showed that an increase of
ESAs dose (erythropoietina equivalent 10,000 U/week
increment) was associated with a higher rate of all cause
mortality, Incidence Rate Ratio [IRR = 1.42 (95% CI:
1.10 - 1.83)] but not cardiovascular mortality, [IRR =
1.09 (95% CI: 1.02 - 1.18)].
4. The Holistic Concept of Cardiorenal
Patient
In every day clinical practice a controversy exist between
cardiologists and nephrologists concerning the correction
of anemia among cardiorenal patients. The controversy is
primarily relied upon three unresolved items: Firstly
what hemoglobin level characterizes a patient with car-
diac failure as anemic, secondly what is the target hemo-
globin among these patients, thirdly what is the proper
therapeutic regimen (dose and frequency of drug admini-
stration).
Reports concerning cardiac failure patients suggest
that the ideal hemoglobin levels must be at 13 g/dL and
preferably between 13.5 g/dL and 14 g/dL but on the
other hand, according to KDOQI guidelines [23], ideal
hemoglobin levels for CKD patients must be between 11
g/dL and 12 g/dL and under no circumstance should they
exceed 13 g/dL because of an increased hazard concern-
ing side effects due to the increased level of hemoglobin
or to erythropoiesis stimulating agents by themselves.
Most of the studies concerning cardiac failure patients
are observational studies from various centers with a
relatively small number of patients and the validation
criteria include improvement of exercise duration, heart
failure according to NYHA classification, left ventricular
ejection fraction and quality of life which confine the
efficacy and not the safety of the drags used. On the
other hand it has been proved that among CKD patient’s
hemoglobin levels greater than 12 g/dL are harmful con-
cerning progression of renal disease suggesting that
anaemia is a “defense mechanism” which protects glom-
erulus from further damage and it is possible that these
patients are benefited in a narrow limit of hemoglobin
level variation [15].
It seems likely that adverse events of anaemia correc-
tion are coupled with platelet function and blood viscosity.
It has been proven in experimental as well as in clinical
studies that hematocrit level greater than 30% leads to
increased platelet aggregation and blood viscosity with
deleterious effects upon glomerulus blood supply and
acceleration of glomerulosclerosis by a concomitant in-
crease of the likelihood of systemic thromboembolic
events. Apart from ESAs the correction of anaemia needs
to be administered intravenous iron supplementation and
it is known that the transferrin-iron complex is filtered
through the glomerulus and in the acidic pH of urine
dissociates to transferrin and divalent iron ions which via
the Fenton reaction produce hydroxyl radicals with re-
sultant oxidative stress and tissue damage [15].
The deleterious effect of full anaemia correction is not
restricted only upon the kidney, but also encompasses the
rest of the cardio-vascular system because increased
blood viscosity is coupled with increased peripheral vas-
cular resistance and increased cardiac after-load whereas
the decline of renal function increases extracellular vol-
ume and blood pressure with resultant congestive heart
failure and left ventricular hypertrophy [15].
The uncertainty of ESAs beneficial effect upon cardio-
renal anaemia is much more complicated from the ob-
servations of van der Meer et al. [12] who investigated
74 anemic patients with congestive heart failure (NYHA
class II-IV) and CKD (stage II-III) and found that 29
(39%) of them exhibited endogenous erythropoietin lev-
els lower than expected, 23 (31%) as expected and 22
(29%) higher than expected. Patients with lower levels of
endogenous erythropoietin exhibited the lower levels of
eGFR which is relevant to reduced erythropoietin pro-
duction from diseased kidneys on the other hand patients
with higher than expected levels of endogenous erythro-
poietin exhibited increased mortality (log rank: p =
0.024). The multifactorial analysis showed that the ratio
O/P (Observed/Predicted) of endogenous erythropoietin
emerged as the most powerful independent risk factor of
increased mortality even if adjusted to variables such as
age, gender, hemoglobin levels, NT-pro-BNP levels and
eGFR [HR = 1020 (95% CI 1.004 - 1.036) p = 0.012].
These results suggest that patients with endogenous
erythropoietin resistance exhibit higher mortality rate. On
the other hand the results of TREAT study showed that
patients with exogenous erythropoietin resistance (non-
responders) exhibited higher mortality rate than the re-
sponders. Taken together these findings suggest the pos-
sibility that increasing the dose of erythropoietin in any
patient who doesn’t respond adequately to the hormone
action may aggravate the possibility of inverse outcomes.
Although it is only a suggestion because endogenous
erythropoietin levels did not estimated in TREAT study
it is wise to accept Sandhu A.’s et al. [10] opinion that
“ESA resistance should not be treated with increase in
ESA dose alone”.
According to present knowledge there are no con-
vinceing answers to the above mentioned items so it is
necessary to conduct prospective controlled trials in order
to solve the confliction concerning the beneficial effect
of restoring anaemia in patients with cardiorenal syn-
drome as well as the safety of erythropoietic agents. The

I. KOULOURIDIS, E. KOULOURIDIS 27
Reduction of Events with Darbepoetin alfa in Heart Fail-
ure (RED-HF) [24] trial and EPOCARES study [25] are
now in progress and we are waiting with great interest
the results to be published. The eligibility criteria in
RED-HF trial concerning anaemia in heart failure pa-
tients accepted hemoglobin levels between 9.0 g/dL and
12.0 g/dL, the darbepoetin alfa administered subcutane-
ously every two weeks until hemoglobin levels reached
at 13 g/dL and monthly there after, if hemoglobin levels
reached 14.5 g/dL darbepoetin stopped and placebo was
administered [24]. The eligibility criteria in EPOCARES
study accepted hemoglobin levels compatible with mild
anemia between 10.3 - 12.6 gr/dL for men and 10.3 -
11.9 gr/dL for women. The study designs encompass
three groups of patients with different treatment sched-
ules in order to investigate the hematopoietic and non-
hematopoietic effects of erythropoietin [25]. It is obvious
that the two studies exhibit considerable discrepancy in
anemia definition among CRS patients as well as in tar-
get hemoglobin levels.
Meanwhile the Food and Drug Administration (FDA)
on June 24, 2011 announced its alert concerning the
“Modified dosing recommendations to improve the safe
use of Erythropoiesis-Stimulating Agents (ESAs) in
chronic kidney disease” according to which stated that: 1)
“Using of ESAs to target a hemoglobin level greater than
11 g/dL increases the risk of serious adverse cardiovas-
cular events and has not been shown to provide addi-
tional patient benefit”; 2) “No clinical trial to date has
identified a hemoglobin target level, ESA dose, or dosing
strategy that does not increase these risks”. Especially for
patients with CKD not on dialysis recommends initiating
treatment with ESAs when hemoglobin level is less than
10 g/dL and if the rate of hemoglobin decline indicates
the likelihood of red blood cell transfusion in order to
avoid alloimmunization and/or other transfusion-related
risks. Finally recommends that: “If the hemoglobin level
exceeds 10 g/dL, reduce or interrupt the dose of ESA and
use the lowest dose of ESA sufficient to reduce the need
for red blood cell transfusions”.
FDA recommendations refers not only to ESRD pa-
tients but also to patients with cardio-renal syndrome
anaemia especially type 2 and 4 so it is wise to accept
these recommendations in clinical practice when we treat
with ESAs patients with cardio-renal syndrome anaemia.
In conclusion we have to pay much more attention in
treating cardio-renal anaemia either by erythropoiesis
stimulating agents or intravenous iron. It seems likely
that, according to FDA, the target hemoglobin must not
exceed 11 g/dL. ESAs administration has to begin with
the lower recommended doses until target hemoglobin is
achieved and then dose titration must be prompted. If
patient does not exhibit successful response it is not wise
to increase ESAs dose until definite convincing results
prove the safety of this strategy.
REFERENCES
[1] C. Longhini, C. Molino and F. Fabbian Cardiorenal,
“Syndrome: Still Not a Defined Entity,” Clinical and Ex-
perimental Nephrology, Vol. 14, No. 1, 2010, pp. 12-21.
doi:10.1007/s10157-009-0257-4
[2] C. Ronco, P. McCollough, S. D. Anker, I. Anand, N.
Aspromonte, S. M.Bagshaw, et al., “For the Acute Dialy-
sis Quality Initiative (ADQI) Consensus Group. Cardio-
Renal Syndromes: Report from the Consensus Confer-
ence of the Acute Dialysis Quality Initiative,” European
Heart Journal, Vol. 31, No. 6, 2010, pp. 703-711.
doi:10.1093/eurheartj/ehp507
[3] H. M. Krumholtz, Y. T. Chen, V. Vaccarino, Y. Wang, M.
J. Radford, W. D. Bradford, et al., “Correlates and Impact
on Outcomes of Worsening Renal Function in Patients ≥
65 Years of Age with Heart Failure,” American Journal
of Cardiology, Vol. 85, No. 9, 2000, pp. 1110-1113.
doi:10.1016/S0002-9149(00)00705-0
[4] D. E. Forman, J. Butler, Y. Wang, W. T. Abraham, C. M.
O’Conor, S. S. Gottlieb, et al., “Incidence, Predictors at
Admission, and Impact of Worsening Renal Function
among Patients Hospitalized with Heart Failure,” Journal
of the American College of Cardiology, Vol. 43, No. 1,
2004, pp. 61-67. doi:10.1016/j.jacc.2003.07.031
[5] R. N. Foley, A. M. Murray, S. Li, C. A. Herzog, A. M.
McBean, P. W. Eggers and A. J. Collins, “Chronic Kid-
ney Disease and the Risk for Cardiovascular Disease,
Renal Replacement, and Death in the United States
Medicare Population, 1998 to 1999,” Journal of Ameri-
can Society of Nephrology, Vol. 16, No. 2, 2005, pp.
498-495. doi:10.1681/ASN.2004030203
[6] G. C. Fonarow, K. F. Adams, W. T. Abraham, C. W.
Yancy and W. J. Boscardin, “For the ADHERE Scientific
Advisory Committee, Study Group, and Investigators.
Risk Stratification for In-Hospital Mortality in Acutely
Decompensated Heart Failure: Classification and Regres-
sion Tree Analysis,” The Journal of the American Medi-
cal Association, Vol. 293, No. 5, 2005, pp. 572-580.
[7] G. L. Smith, J. H. Lichtman, M. B. Bracken, M. G. Shli-
pak, C. O. Phillips, P. DiCapua, et al., “Renal Impairment
and Outcome in Heart Failure. Systematic Review and
Meta-Analysis,” Journal of the American College of Car-
diology, Vol. 47, No. 10, 2006, pp. 1987-1996.
doi:10.1016/j.jacc.2005.11.084
[8] A. Kazory and E. A. Ross, “Anemia: The Point of Con-
vergence or Divergence for Kidney Disease and Heart
Failure,” Journal of the American College of Cardiology,
Vol. 53, No. 8, 2009, pp. 639-647.
doi:10.1016/j.jacc.2008.10.046
[9] W. McClellan, S. L. Aronoff, W. K. Bolton, S. Hood, D.
L. Lorber, K. L. Tang, et al., “The Prevalence of Anemia
in Patients with Chronic Kidney Disease,” Current
Medical Research and Opinion, Vol. 20, No. 9, 2004, pp.
1501-1510. doi:10.1185/030079904X2763
[10] A. Sandhu, S. Soman, M. Hudson and A. Besarab,
“Managing Anemia in Patients with Chronic Heart Fail-

I. KOULOURIDIS, E. KOULOURIDIS
28
ure; What Do We Know?” Vascular Health and Risk
Management, Vol. 15, No. 6, 2010, pp. 237-252.
[11] D. V. Vlahakos, K. P. Marathias and N. E. Madias, “The
Role of the Renin-Angiotensin System in the Regulation
of Erythropoiesis,” American Journal of Kidney Diseases,
Vol. 56, No. 3, 2010, pp. 558-565.
doi:10.1053/j.ajkd.2009.12.042
[12] P. van der Meer, D. J. Lok, J. L. Januzzi, P. W. de la
Porte, E. Lipsic, J. Van Wijngaarden, et al., “Adequacy of
Endogenous Erythropoietin Levels and Mortality in
Anaemic Heart Failure Patients,” European Heart Jour-
nal, Vol. 29, No. 12, 2008, pp. 1510-1515.
doi:10.1093/eurheartj/ehn205
[13] J. W. Eschbach and J. W. Adamson, “Anemia of End-
Stage Renal Disease (ESRD),” Kidney International, Vol.
28, No. 1, 1985, pp. 1-5. doi:10.1038/ki.1985.109
[14] A. K. Abu-Alfa, “CKD Series: Evaluation and Treatment
of Anemia in Chronic Kidney Disease,” Hospital Physi-
cian, Vol. 39, No. 7, 2003, pp. 31-38, 46.
[15] G. Remuzzi and J. R. Ingelfinger, “Correction of Anemia-
Payoffs and Problems,” The New England Journal of
Medicine, Vol. 355, No. 20, 2006, pp. 2144-2146.
doi:10.1056/NEJMe068233
[16] T. B. Drueke, F. Locatelli, N. Clyne, K. U. Eckardt, I. C.
MacDougall, D. Tsakiris, et al., (for the CREATE Inves-
tigators), “Normalization of Hemoglobin Level in Pa-
tients with Chronic Kidney Disease and Anemia,” The
New England Journal of Medicine, Vol. 355, No. 20,
2006, pp. 2071-2084. doi:10.1056/NEJMoa062276
[17] A. K. Singh, L. Szczech, K. L. Tang, H. Barnhart, S.
Sapp, M. Wolfson, et al., (for the CHOIR Investigators),
“Correction of Anemia with Epoetin Alfa in Chronic
Kidney Disease,” The New England Journal of Medicine,
Vol. 355, No. 20, 2006, pp. 2085-2098.
doi:10.1056/NEJMoa065485
[18] J. K. Ghali, I. S. Anand, W. T. Abraham, G. C. Fonarow,
B. Greenberg, H. Krum, et al., (for the STAMINA-HeFT
Group), “Randomized Double-Blind Trial of Darbepoetin
Alfa in Patients with Symptomatic Heart Failure and
Anemia,” Circulation, Vol. 117, No. 4, 2008, pp. 526-535.
doi:10.1161/CIRCULATIONAHA.107.698514
[19] M. A. Pfeffer, E. A. Burdmann, C. Y. Chen, M. E. Coo-
per, D. de Zeeuw, K. U. Eckardt, et al., (for the TREAT
Investigators), “A Trial of Darbepoetin Alfa in Type 2
Diabetes and Chronic Kidney Disease,” The New Eng-
land Journal of Medicine, Vol. 361, No. 21, 2009, pp.
2019-2032. doi:10.1056/NEJMoa0907845
[20] S. D. Solomon, H. Uno, E. F. Lewis, K. U. Eckardt, J. Lin,
E. A. Burdmann, et al., (for the TREAT Investigators),
“Erythropoietic Response and Outcomes in Kidney Dis-
ease and Type 2 Diabetes,” The New England Journal of
Medicine, Vol. 363, No. 12, 2010, pp. 1146-1155.
doi:10.1056/NEJMoa1005109
[21] Y. Zhang, M. Thamer, J. S. Kaufman, D. J. Cotter and M.
A. Herman, “High Doses of Epoetin Do Not Lower Mor-
tality and Cardiovascular Risk among Elderly Hemodi-
alysis Patients with Diabetes,” Kidney International, Vol.
80, No. 6, 2011, pp. 663-669. doi:10.1038/ki.2011.188
[22] I. Koulouridis, M. Alfayez, T. Trikalinos, E. M. Balk and
B. L. Jaber, “Dose of Erythropoiesis-Stimulating Agents
(ESAs) and Adverse Outcomes in Chronic Kidney Dis-
ease (CKD): A Meta-Regression,” Poster Presentation,
American Society of Nephrology Kidney Week 2011, 8-13
November 2011, Philadelphia.
[23] National Kidney Foundation KDOQI, “Clinical Practice
Guidelines and Clinical Practice Recommendations for
Anemia in Chronic Kidney Disease,” American Journal
of Kidney Diseases, Vol. 47, Suppl. 3, 2006, pp. S11-S15.
doi:10.1053/j.ajkd.2006.03.010
[24] J. J. V. McMurray, I. S. Anand, R. Diaz, A. P. Maggioni,
C. O’Connor, M. A. Pfeffer, et al., (on Behalf of the
RED-HF Committees and Investigators), “Design of the
Reduction of Events with Darbepoetin Alfa in Heart Fail-
ure (RED-HF): A Phase III, Anaemia Correction, Mor-
bidity-Mortality Trial,” European Journal of Heart Fail-
ure, Vol. 11, No. 8, 2009, pp. 795-801.
doi:10.1093/eurjhf/hfp098
[25] K. Van der Putten, K. E. Jie, M. E. Emans, J. A. Joles, M.
J.Cramer , B. K. Velthuis, et al., “Erythropoietin Treat-
ment in Patients with Combined Heart and Renal Failure:
Objectives and Design of the EPOCARES Study,” Jour-
nal of Nephrology, Vol. 23, No. 4, 2010, pp. 363-368.