review

http://www.kidney-international.org
& 2010 International Society of Nephrology

Anemia management in chronic kidney disease

Steven Fishbane1,2 and Allen R. Nissenson3,4
All authors provided equal contribution to this article
1

Department of Nephrology, Winthrop-University Hospital, Mineola, New York, USA; 2State University of New York School of Medicine
at Stony Brook, Stony Brook, New York, USA; 3Division of Nephrology, Department of Medicine, David Geffen School of Medicine
at UCLA, Los Angeles, California, USA and 4DaVita, Denver, Colorado, USA

Anemia is one of the most common and morbid

complications of chronic kidney disease, causing unpleasant
symptoms and reducing the quality of life. The availability of
recombinant human erythropoietin (rHuEPO) in 1989 has
been one of the most important developments in the care of
this population in the past several decades. Treatment with
erythropoiesis-stimulating agents (ESAs) has improved
patients lives, but recent studies have found that higher
hemoglobin (Hgb) targets cause harm, resulting in more
cautious treatment. Despite widespread recognition by
clinicians and patients of the value of this biological agent,
the high cost and new concerns over safety have led to a
reexamination of its use. Although rHuEPO is prescribed by
individual physicians and target Hgb is guided by current
evidence in the context of individual patients, critics within
and outside the medical community have charged that
rHuEPO is being overused, that financial motives are driving
its use, and that patients are suffering from adverse
consequences. Regulatory agencies, including the Centers for
Medicare and Medicaid Services and the US Food and Drug
Administration, have weighed in as well. In this review article,
issues related to the current and future status of ESA
treatment will be considered with a view to assessing factors
that result in a lack of clarity and need for further study. It is
essential that the renal community vigorously support
additional rigorous research to expand the evidence base for
optimal anemia management so that the debate over
appropriate ESA use remains where it belongs, in the
scientific domain.
Kidney International (2010) 78 (Suppl 117), S3S9; doi:10.1038/ki.2010.188
KEYWORDS: anemia; ESA; health policy
TO CITE THIS ARTICLE:
Fishbane S, Nissenson AR. Anemia management in chronic kidney disease.
Kidney Int 2010; 78 (Suppl 117): S3S9.

ANEMIA MANAGEMENT IN KIDNEY DISEASE: WHERE DO

WE GO FROM HERE?1,2

Anemia is an early and functionally important complication

of chronic kidney disease (CKD).1 It causes fatigue and
dyspnea and reduces patients quality of life.2 In 1989,
commercialization of the first erythropoiesis-stimulating
agent (ESA) was a major advance that led to widespread
improvement in anemia and to a reduction in the need for
blood transfusion. In addition, numerous studies have
indicated that ESA therapy results in an improvement in
the patients quality of life.3 As a result, ESA treatment is a
routine management component for hemodialysis patients,
and is frequently used in nondialysis CKD as well.
The first treatment with an ESA occurred on 2 December
1985, as Eschbach et al.2 administered recombinant epoetin-a
at a low dose of 2.5 m/kg to an 18-year-old hemodialysis patient
in Seattle, Washington. The patients hematocrit level did not
increase significantly. Shortly thereafter, in another hemodialysis patient, at a higher dose of 15 m/kg thrice weekly, the first
positive response was noted, with an increase in hematocrit
from 15 to 25% (J Eschbach, personal communication). This
led to clinical trials that resulted in the US Food and Drug
Administration (FDA) approval for ESAs in 1989. From the
beginning, an unwavering question has been how high to
target hemoglobin (Hgb) levels during ESA treatment.
Despite a lack of evidence indicating the value of any
specific target, or of higher Hgb targets, the mean Hgb that
hemodialysis patients in the United States has been treated
to has progressively increased over time (Figure 1).4 This
increase was probably due to overinterpretation of observational study results that associated higher Hgb levels in
hemodialysis patients with improved outcomes. Many such
studies have been published, usually finding that higher Hgb
levels, at least up to 12 g/dl, are associated with improved
outcomes such as reduced mortality risk.5,6 Whether these
findings reflect a true treatment benefit is questionable. As
hemodialysis patients who are sicker (and more likely to die)
tend to become anemic because of inflammation and other
processes, there is an intertwining of the exposure (anemia)
1,2

Correspondence: Steven Fishbane, Department of Nephrology,

Winthrop-University Hospital, 200 Old Country Road, Suite 135, Mineola,
New York 11501, USA. E-mail: sfishbane@metrorenal.com
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S Fishbane and AR Nissenson: Anemia management in CKD

12

20

11

EPO

15

10

10

Mean EPO dose

(in thousands of units)

Hemoglobin (g/dl)

Hemoglobin

0
91 92 93 94 95 96 97 98 99 00 01 02 03 04 05

Figure 1 | Mean monthly hemoglobin and epoetin dose for

prevalent hemodialysis patients (2007). (http://www.usrds.org/
adr_2007.htm)

and outcome (mortality) variables that hopelessly confounds

analyses.
Randomized controlled trials (RCTs) of lower and
higher Hgb targets during ESA treatment have for the
most part failed to confirm a mortality benefit for higher
Hgb targets. More pointedly, each of the three largest studies,
with over 3,000 subjects, found a strong trend toward
increased mortality and other risks with higher Hgb targets
(413 g/dl).79 The first to be published, in 1998 by Besarab
et al.,4 was conducted in hemodialysis patients and probably
did not receive sufficient attention given the related
safety findings. The second and third studies, both conducted
in nondialysis CKD, were published simultaneously in
November 2006, and the adverse safety findings resulted
in a new age of conservatism in ESA treatment. Changes to
the FDA prescribing instructions for ESA drugs occurred
twice in 2007, with the addition of a black box warning and
important new text on safety and risks of treatment.
Clinicians were, and continue to be, faced with important
questions on how to proceed with ESA treatment.
One immediate question is on target Hgb during ESA
treatment. The National Kidney Foundation (NKF)Kidney
Disease Outcomes Quality Initiative (KDOQI) panel recommends a target of 1112 g/dl,10 whereas the FDA label calls for
a range of 1012 g/dl.11 The current literature of RCTs is not
well suited for determining whether a 10 or 11 g/dl lower
limit is preferable. Because most studies used only two Hgb
treatment targets, and no intermediate targets, they do not
inform as to the relative efficacy and safety of lower Hgb
thresholds. Post hoc analyses of the relationship between Hgb
levels actually achieved in the studies and outcomes suffer
from the same issues of confounding discussed above for
observational studies. It is likely that the NKFs slightly higher
target offers a greater opportunity to optimize quality of life,
whereas the FDA target yields greater treatment flexibility
and less Hgb variability and cycling.12 Most helpful is the
NKFKDOQI guideline that calls for individualization of
target.10 This statement recommends that selection of the
Hb targetyin the individual patient should include
consideration of potential benefits (including improvement
in quality of life and avoidance of transfusion) and potential
harms (including the risk of life threatening adverse events).
S4

The chosen target should not be based on Hgb level alone,

but should carefully consider the individual patients clinical
status. For example, if a patient has an Hgb of 10.5 g/dl and
feels well, then there may be no clear reason to attempt to
increase Hgb further. In contrast, if the patient complains of
fatigue or dyspnea, then ESA dose should be increased to
raise Hgb toward the higher end of the therapeutic range.
One difficulty of Hgb targets for ESA treatment is the
failure to differentiate patients on hemodialysis from others
with kidney disease. The hemodialysis patient presents a
special case, as the Hgb level that treatment is based on is
measured before dialysis. In the vast majority of patients, this
means that the Hgb level is measured at a time of maximal
overhydration and is, therefore, diluted.13 This, of course, is
not the case in peritoneal dialysis or nondialysis CKD. As
a result, the same Hgb target leads to a greater relative red
cell mass in hemodialysis patients. More important, during
hemodialysis, the excess fluid is removed until the patient
is restored to their dry weight. As the fluid is removed,
the Hgb concentration rises and hemoconcentration occurs.
In some patients, this effect may be minor, as their need
for intradialytic fluid removal may be minimal. In others,
however, large volumes of fluid are removed and severe
hemoconcentration may occur. This could be potentially
harmful, as the increase in Hgb concentration results in
significant increases in whole blood viscosity. Surges in whole
blood viscosity increase endothelial sheer stress. This is
relevant as increased whole blood viscosity is associated with
a number of cardiovascular and atherothrombotic complications in the general population, as well as systemic lupus,
sickle cell disease, and polycythemia vera.1416 In hemodialysis patients, in whom atherosclerotic disease leads to areas
of vulnerable or ulcerated plaque, increased sheer stress
could result in increased atherothrombotic risk. This raises
questions as to (i) whether hemodialysis patients should
have the same Hgb targets as other kidney disease patients, (ii)
should Hgb in hemodialysis be measured before or after dialysis,
and (iii) whether more conservative Hgb targets should be used
for hemodialysis patients who have large interdialytic weight
gains. All are areas for debate and further study.
Another question that arises as we move forward with ESA
treatment is whether there is still need for additional study on
Hgb targets. Some inspiration comes from the experience of
Hampl and colleagues in Berlin, Germany.1721 A total of 330
in-center hemodialysis patients have been studied there with
ESA treatment to a target Hgb level of 14.5 g/dl in men and
13.5 g/dl in women. Despite this high Hgb target, their
reported outcomes have been outstanding. This stands in
contrast to the results of RCTs of anemia treatment to Hgb
normalization. In 10 years of follow-up, there were only
82 deaths out of 330 patients, with only 12.4% of patients
dying of cardiovascular causes. In addition, there was significant regression of left ventricular hypertrophy and
improved New York Heart Association cardiac status.
It is vitally important to note that the Berlin intervention was not just normalization of Hgb, but was also a
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S Fishbane and AR Nissenson: Anemia management in CKD

multifaceted approach that included intensive antihypertensive and cardioprotective therapy, aggressive iron treatment
to a target transferrin saturation of 50%, and supplementation with agents meant to optimize oxygen utilization, such
as L-carnitine, folic acid, and B vitamins. The antihypertensive therapy consisted of treatment with b-blockers, angiotensin-converting enzyme inhibitors, and angiotensin
receptor blockers (respective targets of 200 mg metoprolol,
10 mg ramipril, and 32 mg candesartan). These doses were
achieved in 7578% of patients, resulting in a mean
predialysis blood pressure level of 132/81 mm Hg and a mean
pulse rate of 61.8/min. This careful attention to blood
pressure stands in stark contrast to the major published RCTs
of Hgb normalization, in which antihypertensive treatment
was notably casual. A recent meta-analysis of Hgb normalization studies found that higher Hgb targets resulted in
significant increases in blood pressure.22 For example, in one
recent study, systolic blood pressure 4160 mm Hg occurred
in 50% of patients in the normal Hb group.7 Given the
importance of hypertension as an established risk factor for
death, cardiovascular events and left ventricular hypertrophy,23 it can be hypothesized that the safety risks found in
Hgb normalization RCTs could be explained by the lack of
attention to blood pressure management. Conversely, this
may be the main reason for the success of the Berlin group.
The evidentiary value of the anecdotal Berlin experience is
quite minimal compared with the published, well-powered
RCTs. It may be tempting to simply dismiss the findings as an
aberration. But science is often well served by careful
attention to outlier experience. One can reasonably question
whether experience such as this supports a need for new
studies of Hgb normalization, but coupled to very attentive
management of blood pressure and iron status.
A final issue to consider on the subject of moving forward
with anemia therapy is the anticipated change in ESA
reimbursement for hemodialysis patients. The current system
has been criticized as incentivizing potential overtreatment
with ESAs.24 As a result, legislation is anticipated that would
mandate the bundling of injectibles such as ESAs into the
hemodialysis composite rate.25 This would remove any
incentive for overtreatment, although absence of proper
safeguards could create incentives to undertreatment. Dialysis
providers would presumably seek to maintain Hgb targets
while reducing ESA dose to the greatest extent possible. This
could occur with a change to ESA administration by the
subcutaneous route,26 as well as by increased intravenous
iron supplementation,27 lowered Hgb targets, and increased
use of ancillary treatments including vitamin C, L-carnitine,
and androgens. It is unclear what combination of these
interventions will emerge as most important in a bundled
system. It is my opinion that there will not be a substantial
increase in subcutaneous dosing, as it may be unfair to
expose patients to discomfort for purely financial reasons.
It is, however, likely that intravenous iron use will increase.
The largest driver of ESA dose reduction, however, is likely
to be the lowering of Hgb targets.
Kidney International (2010) 78 (Suppl 117), S3S9

In conclusion, anemia treatment with ESAs, one of the

most important advances in the treatment of kidney disease
patients, has been reevaluated recently because of studies
demonstrating harm with higher Hgb targets. Although it is
clear that treatment is important for improving patients
quality of life, more cautious approaches to treatment
have been advocated. The special case of ESA treatment in
hemodialysis patients raises additional questions because of
potential hemoconcentration and increased whole blood
viscosity. The experience of Hampl and colleagues19 in Berlin
exposes the need to consider anemia treatment as not just
being focused on ESA treatment; rather, it raises interest in
the importance of carefully managing blood pressure and
iron status while treating anemia. With the bundling of ESA
treatment into the hemodialysis composite rate, additional
questions will arise. It is clear that additional research is
needed to fully understand how to best move forward with
anemia therapy.
Authors note

This article reflects content of a symposium presented at

Long Island College Hospital on May 3031, 2008.
ESA PAYMENT POLICY: WHERE KNOWLEDGE MEETS
POLITICS3

There has been no topic in recent memory that has stirred

scientific and lay communities as the treatment of anemia in
cancer and kidney patients. A recent Google search on
anemia and cancer yielded 402,000 results, and one on
anemia and kidney disease yielded 338,000! The cacophony
of voices have focused on a wide range of topics, such as the
prevalence and importance of anemia in these vulnerable
populations; the role of ESAs in benefiting or harming
patients; imputed motives of physicians prescribing ESAs or
dialysis facilities in which patients are treated; direct to
consumer marketing of ESAs; and the list goes on and on.
What is unfortunate is that the scientific community itself
has entered into the debate, but not always in a productive
way. Accusations of intentional misstatement of research
findings, inappropriate influence of industry on guideline
development, lack of focus on patient care by physicians
are just a few of the unsubstantiated statements made by
scientific colleagues and quickly picked up by the nonclinical
lay community, including public policy makers. In this
presentation, I present my view of the historical approach to
ESA use in patients with kidney disease, highlighting, in
particular, scientific and public policy issues that have, at
times inappropriately, driven clinical practice. As physicians,
we must always keep in mind that clinical decision making is
a one-on-one process between a physician and a patient that

Correspondence: Allen R. Nissenson, UCLA Medical Center, 200 Medical

Plaza, Suite 565, Los Angeles, California 90095, USA.
E-mail: anissenson@mednet.ucla.edu
Current address: 601 Hawaii Street, El Segundo, CA 90045, USA,
E-mail: allen.nissenson@davita.com
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should be predicated on doing the greatest good (benefit)

weighed against the potential harm of any intervention.
Since the descriptions by Bright,28 anemia has been a
known consequence of serious kidney disease. The evidence
for this and the pioneering work of countless scientists that
led to the recognition of kidneys as the controlling organs
for red blood cell production in humans is beyond the scope
of this paper. It should be pointed out, however, that before
the availability of recombinant human erythropoietin
(rHuEPO), anemia was a ubiquitous and severe complication
of advanced kidney disease. As illustrated in the initial
registration trial of rHuEPO, the typical hemodialysis patient
in the 1980s had a hematocrit level of 2225%, and onequarter of patients received up to 4 units of packed red blood
cells per month.29 The quality of life was poor, with few
patients having the energy needed to work or even carry out
minimal activities of daily living. The pivotal clinical trials
with rHuEPO, published by Eschbach et al.,29 demonstrated
that at a weekly dose of 150 U/kg, the average hematocrit level
increased to nearly 34%, and overall in this registration trial,
the mean achieved hematocrit was 36.5%. Within 2 months
of initiation of rHuEPO, virtually all patients were transfusion independent.
These impressive results, coupled with improvements in
quality of life using a variety of instruments, led FDA to
approve rHuEPO for use in dialysis patients in 1989. The
clinical benefits of this remarkable development, the first
recombinant protein developed and used in humans, led to
rapid adoption by nephrologists, patients, and payers. By the
end of 1992, only three and a half years after approval,
rHuEPO was being used in nearly 90% of hemodialysis and
over 50% of peritoneal dialysis patients. Even at this early
stage, as initial reimbursement policy was set, it was clear that
such policy was likely to be an important driver of ESA
use going forward. Initially, Medicare set reimbursement at
$40/dialysis treatment, irrespective of the dose. Fixed
reimbursement of course would promote underutilization
and would penalize patients who for legitimate clinical
reasons require high rHuEPO doses. For this time period, the
average rHuEPO dose in hemodialysis patients was around
2700 units, which was affordable, considering the fact that
the typical cost for rHuEPO at the time was $1011 per
thousand units. After considerable concern was expressed
by the renal community with regard to this approach,
Medicare modified its approach and began paying for
rHuEPO at $11/1000 units in 1991. Unlike the previous
payment policy, the new policy would reward increased doses
of rHuEPO, and by 1993, the average rHuEPO dose had risen
to 4200 units.
Starting in the late 1980s and through the early 1990s,
considerable clinical research took place in an attempt to
understand the benefits and risks of rHuEPO, and in
particular to better define the hematocrit level target for
patients undergoing therapy. It became clear that there were
benefits of achieving a hematocrit level in the low 30s
compared with the low 20s, and a Medicare expert panel at
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S Fishbane and AR Nissenson: Anemia management in CKD

this time recommended a target hematocrit level of 430%

on the basis of these studies, which unfortunately were not
particularly rigorous or observational in nature. There was a
steady increase in the fraction of patients achieving this target
hematocrit level through the early 1990s, and by 1995
about 60% of patients did indeed have a hematocrit level
exceeding 30%.
Because 40% of patients were still not achieving this goal,
and because of concern in the renal community about other
key areas of care for dialysis patients that needed improvement, Amgen conceived and funded the NKFDialysis
Outcomes Quality Initiative (NKFDOQI) in 1995 with
an initial $1 million grant. Guidelines on anemia, dialysis
adequacy, and vascular access were initially developed. The
initial version of the anemia guidelines was published in
1997, and among a number of recommendations included a
target hematocrit of 3336%; aggressive use of intravenous
iron to spare EPO; and preference of subcutaneous use of
EPO.30 At this time, only 43% of hemodialysis patients had
hematocrit 433% and the guideline was rapidly incorporated into clinical practice. This application was hindered,
however, by a new Medicare payment policy. The new policy
was to withhold payment for EPO in the 3-month rolling
average of hematocrit 436%. Clearly the fear of no payment
for EPO drove clinicians to target significantly lower
hematocrit levels, shifting the overall hematocrit distribution
curve to the left, and increasing the number of patients not
achieving the minimal goal. Significant efforts by the renal
community, led by the Renal Physicians Association, led
Medicare in 1998 to liberalize the policy. The change, to allow
for payment if the 3-month rolling average hematocrit was
436.5% or if the EPO dose was decreased by 20%, provided
the flexibility that was needed to permit clinicians once
again to prescribe EPO to achieve hematocrit 433% in more
number of patients.
By this time, the debate in the scientific and clinical
nephrology communities was not whether dialysis patients
benefitted from an improvement in anemia with rHuEPO,
but whether correction of anemia would provide even greater
benefits without harm. To address this question, a RCT of
Hgb normalization in hemodialysis patients with known
cardiac disease was funded by Amgen. The details of the trial
have been presented in detail elsewhere, and the results were
published in the New England Journal of Medicine in 1998.31
Known as the Normal Hematocrit Cardiac Trial (NHCT), or
the Besarab trial after its first author, this rigorous study
failed to show a benefit of targeting normal hematocrit in the
study population compared with targeting a lower hematocrit. The renal community was surprised and disappointed
and many explanations have been given for these findings
over the years since it was published. The conclusions,
however, have not changed. As stated by the authors, it is not
recommended to target normal Hgb when treating hemodialysis patients with known cardiac disease with rHuEPO.
A recent analysis of data from the group randomized to
the normal hematocrit group may provide some new insights
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S Fishbane and AR Nissenson: Anemia management in CKD

into the findings.32 Besarab and colleagues33 looked at

responsiveness to rHuEPO and found that patients who
were responsive to rHuEPO had a significantly better outcome than those who were refractory. This supports the
current hypothesis that a combination of underlying
inflammation, suboptimal achieved Hgb, and high rHuEPO
doses portend a poor outcome if normal Hgb is targeted in
such patients.33
Although the move to drive Hgb further toward normal
was essentially ended by the NHCT, even by 2001 only
75% of hemodialysis patients were achieving an Hgb
level 411 g/dl, the lower limit recommended at the time.
A revision of the NKFDOQI anemia guidelines was
published with few changes from the 1997 version, again
emphasizing a target Hgb level of 1112 g/dl, aggressive use
of intravenous iron, and use of subcutaneous EPO.34
Emphasis on the target Hgb level proposed was increased
by observational studies from the USRDS, showing that lower
achieved Hgb was associated with increased mortality,
hospitalizations, and cost.35
Although many additional observational studies were
published in 20002006, suggesting that NKFDOQI targets
afforded the best clinical outcomes,36 Medicare was getting
increasingly concerned about the use of rHuEPO, which had
become nearly a $2 billion cost, just for dialysis patients. Up
until 2005, Medicare reimbursed outpatient dialysis facilities
at a single composite rate that had not been updated for
nearly two decades. Injectable drugs (rHuEPO; iron; Vitamin
D) were reimbursed separately at 95% of the average
wholesale cost. As analyses by MedPac pointed out, most
dialysis facilities barely broke even or lost money on the
composite rate, but were able to make up for this in part on
the separately billable drugs in which the acquisition cost was
less, in some cases considerably, than the average wholesale
cost.37 However, in 2005, Medicare changed this payment
policy after a small increase in the composite rate was
authorized by the Congress, by separately reimbursing
billable drugs at the much lower Average Acquisition Price,
and in 2006, at the Average Sales Price plus 6% for
administrative costs. In addition, a monitoring policy was
put in place that included the following: reimbursement
based on a single monthly Hgb level; full payment if a 25%
reduction in EPO occurred for Hgb level 1213 g/dl;
documentation of a 25% EPO reduction from the previous
month, or a 25% lower payment for EPO, for Hgb 413 g/dl;
denial of all claims for EPO4500,000 units/month. Clearly,
reimbursement policy was used as a tool to micromanage
clinical practice.
Year 2006 was when the most intense intersection of
science and politics entered the area of anemia management.
In May, new anemia guidelines were published by the
NKFKDOQI work group.38 An evidence-based statement,
in patients with CKD, Hgb should be 11.0 g/dl or greater,
and an opinion-based statement, ythere is insufficient
evidence to recommend routinely maintaining Hgb levels at
13.0 g/dl or greater in ESA-treated patients, were both
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included, but widely misunderstood. The interpretation by

many was that the group was now recommending a target
range increase from 1112 to 1113 g/dl. Although this was
not the intention, this impression was so widespread that it
showed that the guideline group could have done a better job
of articulating what it really meant. Suggestions by some of
our own colleagues that undue influence of Amgen in the
process, because several of the work group members had been
or were Amgen consultants, fueled concern over what some
felt would lead to significant overuse of rHuEPO.39
This bandwagon soon got even more crowded when
Cotter et al.40 published a paper on rHuEPO use in the
prestigious health policy journal Health Affairs. The bias of
these investigators was clear without reading the paper or
others from this group by the subtitle of the current paper:
Untested research findings have been translated too quickly
into policy that encourages large epoetin doses. The perfect
storm continued when, in November 2006, during the
American Society of Nephrology meeting, two important
RCTs of rHuEPO use in CKD patients not on dialysis
were published in the New England Journal of Medicine.41,42
The details of these studies have been presented in numerous
publications, with the CHOIR study showing harm of
targeting Hgb 13.5 g/dl in CKD stage 34 patients, and
CREATE showing no harm. Quality of life improved for
all patients in CHOIR compared with baseline, but no
incremental benefit of targeting the higher Hgb, whereas the
higher Hgb group in CREATE (with a glomerular filtrarte
rate similar to that in CHOIR, but with a high target of
1315 g/dl) had a significantly better quality of life than the
lower target group. The fact that the findings of these two
trials in similar patient groups were different was appropriately noted in an accompanying editorial by Remuzzi and
Inglefinger43 who stated, in part, These two studies suggest
caution in the full correction of anemiaywe need more
information about the ideal target level.
The train was far out of the station when the throttle was
pushed to full by additional events as 2006 came to a close.
First, Pizzi et al.44 from Pennsylvania published a study on
the Economic implications of non-adherence to treatment
recommendations for hemodialysis patients with anemia.
Although this is an interesting analysis, it is based on the
assumption that the dose of EPO does not need to be
changed over time to achieve any given target Hgb. It is well
known that this is not the case. The conclusion of the study,
therefore, that there is considerable overuse of EPO is not an
accurate interpretation. Again, the question is not whether
clinicians are adhering to opinion-based guideline recommendations, but whether EPO is being used appropriately to
achieve whatever target Hgb is chosen. Around the same
time, the US Government Accountability Office issued a
report on the end-stage renal disease (ESRD) program and
bundling Medicares payment for drugs into the dialysis
composite rate.45 The US Government Accountability Office
stated, Medicare could realize greater system efficiency if all
ESRD services, including drugs, were bundled under a single
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paymentywould encourage facilities to use drugs more

prudently. The theme here is clear: there is EPO overuse, for
economic gain, to the possible harm of patients, and this
needs to be controlled.
This series of events, coupled with concerns over the safety
of ESAs in patients with cancer, and the rising overall costs of
ESAs to Medicare, precipitated a hearing in the House Ways
and Means Committee in December 2006. The witnesses
included Drs Cotter, Pizzi, and Singh, and representatives
from US Government Accountability Office and Medicare.
After criticizing guideline developers, nephrologists, and
dialysis facilities for overusing EPO and putting patients at
risk, the conclusion was that Medicare had to move much
more quickly toward a bundled payment system, as
recommended by the US Government Accountability Office,
to protect the public trust.
The Centers for Medicare and Medicaid Services is not the
only agency involved in ESA debates. The FDA is responsible
for overseeing the safety of pharmaceuticals and biologicals,
and in March 2007, following a cancer advisory panel
meeting, issued a black box warning for ESA labels, the
highest level of label alert advising prescribers and patients of
the possibility of death or serious adverse effects of a product.
Unfortunately, however, the black box warning was based on
oncology studies and was not consistent with use of ESAs in
kidney patients. Among the changes made to the previous
label was the removal of a target Hgb range, which was
replaced by use the lowest doseythat willyraise the
Hgbyto avoid blood transfusion, measure Hgb twice a
week, and withhold the doseyif the Hgb exceeds 12 g/dl.
The renal community pushed the FDA to clarify that these
recommendations should apply to oncology patients only,
and the FDA agreed to have a cardiorenal advisory panel
review the issue later in the year.
The NKFKDOQI panel reviewed the most recent guidelines in light of all of these events, including the apparent
misinterpretation of the 2006 iteration of the guidelines, and
decided that sufficient new information was available to
consider a revision. Relevant new studies were considered,
including CHOIR and CREATE, among others, and in
September 2007, a revised guideline was published: an
opinion-based statement clarified the target Hgb range,
which was stated to be 1112 g/dl.46 An evidence-based
statement was made that the Hgb target should not be greater
than 13 g/dl. These recommendations, as well as all of the
available evidence on ESA use in kidney patients, were
considered by the FDA cardiorenal panel on 11 September
2007. Key areas of consideration were target Hgb, Hgb
variability and cycling, and hyporesponsiveness to ESAs. The
panel recommended that the FDA modify the label to include
an appropriate target Hgb range (now 1012 g/dl), and
comment on cycling and hyporesponsiveness, recommendations that were implemented.
Just when it seemed that one could return to science in
this area, and better define and study the key answered
questions about anemia management, further political
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S Fishbane and AR Nissenson: Anemia management in CKD

distraction was added into the mix. An apparent discrepancy

in the data on the NHCT presented by the FDA at the
September panel and in the original publication was reported
by someone to the New England Journal of Medicine.
The journal contacted the authors requesting a clarification,
possibly even a retraction of the paper. The discrepancy was
clearly and easily explained by the authors in a letter to the
journal,47 but accusations of intentional misleading continue
to be made.48
In 2008, while scientists are still trying to resolve the
debate over target Hgb, and increase understanding of
hyporesponsiveness and cycling, Medicare is again changing
payment policy to further drive clinical practice through
reimbursement. This new policy will likely further move
the Hgb distribution curve to the left, increasing the
number of patients with Hgb below 10 g/dl, decreasing the
quality of life, and possibly increasing the risks of other
adverse outcomes. Meanwhile, the move to a bundled
payment system, in which ESAs become a cost rather than
a potential profit, continues. One might speculate how this
will change anemia management practices, but the focus will
be on achieving target Hgbs at the lowest cost with the
combination of ESA, iron, and other approaches necessary
to achieve this end. Once again, reimbursement drives
medical practice.
As regulators and legislators continue to develop policies
that directly affect medical practice and patient outcomes, we
need to collaborate as a renal and scientific community,
rather than look for villains within our midst. A collaboration between clinicians, payers, regulators, legislators,
and patients can focus on what anemia management should
be about: optimizing clinical outcomes, including quality
of life, and minimizing risks, while maintaining public
trust by achieving our clinical goals in the most cost-effective
way possible. As we go about this, it would be wise to
consider recent recommendations by Berwick about the
science of improvement:49 embrace a wider range of
methodologiesRCTs are not the only evidence that
matters; reconsider thresholds for action on evidence
our current obsession with Po0.05 needs reexamination;
rethink views about trust and biasstudying a particular
subgroup, for example, may not be biased but the right
thing to do depending on the question and circumstances;
and be careful about mood, affect, and civility in evaluationsimputing motives on others, as this saga has
unnecessarily distracted the real debate and has created an
atmosphere of blame rather than a focus on the real issues,
namely, the need for clearer scientific data and the need for
science and the needs of patients to drive public policy rather
than the other way around.
DISCLOSURE

SF has received consulting fees and lecture fees from Roche, AMAG,
and Watson. ARN has received consulting fees from Amgen, Affymax,
Advanced Magnetics, and Medgenics, equity/stock options with
Advanced Magnetics, and grant support from Roche, Affymax, and
Amgen, and is a full-time employee of DaVita.
Kidney International (2010) 78 (Suppl 117), S3S9

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S Fishbane and AR Nissenson: Anemia management in CKD

ACKNOWLEDGMENTS

25.

ARN is supported in part by the Richard Rosenthal Dialysis Fund.

26.

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