Blood Reviews 24 (2010) 39–47

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Blood Reviews
journal homepage: www.elsevier.com/locate/blre

REVIEW

Anemia in renal disease: Diagnosis and management

Christina E. Lankhorst a, , Jay B. Wish b,*
a
Division of Nephrology, University Hospitals Case Medical Center, 11100 Euclid Ave, Cleveland, OH 44106, United States
b
Case Western Reserve University, Division of Nephrology, University Hospitals Case Medical Center, 11100 Euclid Ave, Cleveland, OH 44106, United States

a r t i c l e i n f o s u m m a r y

Keywords: Chronic kidney disease (CKD) is a widespread health problem in the world and anemia is a common com-
Anemia plication. Anemia conveys significant risk for cardiovascular disease, faster progression of renal failure
Chronic kidney disease and decreased quality of life. Patients with CKD can have anemia for many reasons, including but not
Erythropoietin invariably their renal insufficiency. These patients require a thorough evaluation to identify and correct
Erythropoiesis-stimulating agents
causes of anemia other than erythropoietin deficiency. The mainstay of treatment of anemia secondary to
Ferritin
Transferrin saturation
CKD has become erythropoiesis-stimulating agents (ESAs). The use of ESAs does carry risks and these
Iron deficiency agents need to be used judiciously. Iron deficiency often co-exists in this population and must be evalu-
Erythropoietin resistance ated and treated. Correction of iron deficiency can improve anemia and reduce ESA requirements. Partial,
but not complete, correction of anemia is associated with improved outcomes in patients with CKD.
Ó 2009 Elsevier Ltd. All rights reserved.

Introduction Pathophysiology of anemia in patients with CKD

Chronic kidney disease (CKD) affects approximately 26 million
adults in the United Sates and millions of others are at risk.1 CKD
is associated with significant morbidity and mortality, and these
patients face many other medical problems related to CKD. One of
the major medical issues facing this population is anemia, which
often develops early in the course of CKD and contributes to poor
quality of life. It has been shown to be strongly predictive of adverse
effects, including complications and death from cardiovascular
causes.2 Prior to the availability of human recombinant erythro-
poietin, patients receiving chronic dialysis treatment frequently
required blood transfusions, exposing them to iron overload, viral
hepatitis and HIV, and increasing production of antibodies to
human antigens which can severely limit transplantation options.
The introduction of recombinant human erythropoietin in the
late 1980s drastically changed the treatment of anemia in patients
with CKD. The benefits of anemia treatment in this population
reach far beyond the improvement of fatigue and decreased phys-
ical activity to a broad spectrum of physiologic functions. Thus the
presence of anemia should be sought, diagnosed, and treated early
in patients with CKD. The optimal hemoglobin (Hb) targets are still
controversial and studies defining these goals are ongoing. The
costs of anemia management in the chronic kidney disease popu-
lation are considerable and need to be considered along with the
risks and benefits.
* Corresponding author. Tel.: +1 216 844 3163, mobile: +1 216 849 3950; fax: +1
216 844 3328.
E-mail addresses: christina.lankhorst@uhhospitals.org (C.E. Lankhorst), jaywish@
earthlink.net (J.B. Wish).
Tel.: +1 216 844 5525, mobile: +1 216 965 9058; fax: +1 216 844 5204.
Anemia is defined by the World Health Organization as a Hb
concentration less than 13.0 g/dL in adult males and non-
menstruating females and less than 12.0 g/dL in menstruating
females.3 Anemia is a common problem in patients with CKD,
and its incidence increases as glomerular filtration rate declines.
Population studies such as the National Health and Nutrition
Examination Survey (NHANES) by the National Institutes of Health
and the Prevalence of Anemia in Early Renal Insufficiency (PAERI)
study suggest that the incidence of anemia is less than 10% in
CKD stages 1 and 2, 20–40% in CKD stage 3, 50–60% in CKD stage
4 and more than 70% in CKD stage 5.4,5
The cause of anemia in patients with CKD is multifactorial. The
most well-known cause is inadequate erythropoietin (EPO) pro-
duction, which is often compounded by iron deficiency. As renal
failure progresses, the contribution of EPO deficiency to anemia
increases. The role of decreased renal EPO synthesis in CKD-
associated anemia is supported by the severe anemia seen in
anephric patients.6 However, the mechanisms impairing renal
EPO production are not well understood. The production capacity
of EPO remains significant even in end stage renal disease (ESRD)
as these patients have been shown to respond with increased
EPO synthesis in the setting of an additional hypoxic stimulus.7
This suggests that the decrease in EPO production in CKD is, in part,
a physiologic response to achieve a chronically reduced Hb
concentration.
Typically, EPO is produced in the peritubular capillary endothe-
lial cells in the kidney relying on a feed-back mechanism measuring
total oxygen carrying capacity. Hypoxia inducible factor (HIF),
which is produced in the kidney and other tissues, is a substance

0268-960X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.blre.2009.09.001
40 C.E. Lankhorst, J.B. Wish / Blood Reviews 24 (2010) 39–47
whose spontaneous degradation is inhibited in the presence of
decreased oxygen delivery due to anemia or hypoxemia. The
continued presence of HIF leads to signal transduction and the
synthesis of EPO. Therefore the usual response is increased EPO pro-
duction in the setting of anemia. The EPO then binds to receptors on
erythroid progenitor cells in the bone marrow, specifically the
burst-forming units (BFU-E) and colony-forming units (CFU-E).
With EPO present, these erythroid progenitors differentiate into
reticulocytes and red blood cells (RBCs). The absence of EPO leads
to pre-programmed apoptosis. This is mediated by the Fas antigen.
The decreased red blood cell production and continued loss of blood
(by programmed red blood cell death) leads to worsening anemia.
There are other factors in chronic kidney disease which contrib-
ute to anemia. Acute and chronic inflammatory conditions have a
significant impact on anemia in the CKD population by pro-
inflammatory cytokines decreasing EPO production and inducing
apoptosis in colony-forming unit-erythroid cells (CFU-E). The early
induction of apoptosis in CFU-E cells stops the process of develop-
ment into RBC. Inflammatory cytokines have also been found to
induce the production of hepcidin, a recently discovered peptide
generated in the liver, which interferes with RBC production by
decreasing iron availability for incorporation into erythroblasts.
This also impairs the production of RBC. Fig. 1 illustrates the
above-mentioned interactions.
Red blood cells also have a decreased life span in patients with
CKD. While the normal life span of an RBC is about 120 days, it
has been demonstrated that this is shortened to only 60–90 days
in CKD patients. In patients without CKD, the bone marrow has
significant capacity to increase red blood cell production and to cor-
rect for the shortened life span, but this response is blunted in pa-
tients with CKD by the relative EPO deficiency. Uremic toxins have
been implicated as contributing to apoptosis as the anemia will of-
ten improve after initiation of dialysis. There have been a number of
prospective and observational studies that have demonstrated
improved Hb levels and decreased dose of erythropoiesis-stimulat-
ing agents (ESAs) with increased adequacy of dialysis.8–11 It has
Fig. 1. Erythropoiesis in chronic kidney disease. Ag, antigen; EPO, erythropoietin; Fe, iron; IFN, interferon; IL, interleukin; RBCs, red blood cells; TNF, tumor necrosis factor.
Courtesy of Iain Macdougall, MD. Reprinted with permission from National Kidney Foundation: Primer on Kidney Diseases, 5th Edition. Philadelphia: Saunders Elsevier 2009;
507.
been hypothesized that it is the middle molecules (molecular
weight range of 500–2000 daltons) of uremia that contribute to
bone marrow suppression.12
Evaluation of anemia in patients with CKD
As noted above, the prevalence of anemia in chronic kidney dis-
ease is as high as 10% in patients with CKD as early as stages 1 and
2. Since the consequences of untreated anemia can be severe, reg-
ular monitoring of the Hb level is needed for optimal care of this
population. The 2006 National Kidney Foundation (NKF) Kidney
Disease Outcomes Quality Initiative (KDOQI) clinical practice
guidelines and clinical practice recommendations for anemia in
CKD advocate annual screening for anemia of all patients with
CKD. Further evaluation should be undertaken if anemia is present
(Hb less than 13.5 g/dL in men and 12.0 g/dL in women per KDOQI
guidelines13). Note that the Hb thresholds for evaluation in the
KDOQI guidelines do not separate menstruating versus non-
menstruating women as the WHO guidelines do. This needs to be
taken into consideration when evaluating women with early stages
of CKD. These recommendations are also based on the assumption
that these patients had normal blood counts in the past. A
previous diagnosis of anemia secondary to other causes, such as
thalassemias and sickle cell disease, may alter the decision tree
for when and how to evaluate a patient’s anemia. For example, a
patient with sickle cell disease whose baseline Hb is about 8 g/dL
when not in crisis, prior to any known renal disease, would be
assessed differently from another patient without previous anemia
who presents with CKD stage 3 and Hb of 10 g/dL.
The initial evaluation, when considering anemia related to CKD,
is geared toward eliminating causes other than EPO deficiency.
This is because EPO deficiency is a diagnosis of exclusion. As with
any clinical evaluation, a thorough patient history is paramount.
The history should include any prior diagnosis of anemia and the
presence of symptoms related to anemia, such as fatigue, exercise
 C.E. Lankhorst, J.B. Wish / Blood Reviews 24 (2010) 39–47
Fig. 2. Flowchart for the evaluation of the chronic kidney disease patient with anemia. CBC, complete blood count; TIBC, total iron-binding capacity; Fe, iron; TSAT, transferrin
saturation. Adapted from Kidney Disease Outcomes Quality Initiative: Am J Kidney Dis 2006;47(Suppl. 3):S1–145.
intolerance, dyspnea, and changes in mentation. The laboratory
evaluation should include a complete blood count with red blood
cell indices, reticulocyte count, transferrin saturation (TSAT), and
serum ferritin. A reticulocyte hemoglobin content (CHr), if
available, may also be helpful in the diagnosis of iron deficiency.
Typically the anemia of EPO deficiency is normocytic (normal
mean corpuscular volume, or MCV) and normochromic (normal
mean corpuscular hemoglobin concentration or MCHC). These
can also be assessed when evaluating a peripheral smear. Microcy-
tosis (or low MCV) is suggestive of iron deficiency, but may also be
seen in hemoglobinopathies such as thalassemia. Macrocytosis (or
high MCV) could be suggestive of vitamin B12 or folate deficiency.
If the MCV is high, or it is normal with a pleomorphic RBC smear or
high red blood cell distribution width (RDW), folate and vitamin
B12 levels should be checked.
In a steady state, serum ferritin levels correlate with the iron
bound to tissue ferritin in the reticuloendothelial system. Serum
ferritin does not carry or bind to iron. Its function is unknown,
but is presumed to limit free iron, which is toxic to cells.14 Serum
ferritin is also an acute phase reactant; therefore it increases in the
setting of acute and chronic inflammation, independent of tissue
iron stores. It is proposed that the elevated serum ferritin of
inflammation decreases available iron and this limits the growth
of pathogens that are iron dependent, such as bacteria and fungi.15
The TSAT is a measure of circulating iron which is available for
delivery to the bone marrow. It is calculated by dividing the serum
iron concentration by the total iron-binding capacity (TIBC) and
then multiplying by 100. TIBC measures the maximum amount
of iron the blood can carry, which indirectly measures transferrin
since it is the most dynamic iron carrier. TIBC is used because it
is less expensive than a direct measurement of transferrin. A TSAT
of less than 16% in an anemic patient with CKD is consistent with a
functional or an absolute iron deficiency. The normal levels for
ferritin are 30–300 ng/mL in men and 15–250 ng/mL in women.
Ferritin levels below these ranges are consistent with low total
body iron stores and, along with a low TSAT, are diagnostic of abso-
lute iron deficiency. Functional iron deficiency is seen when the
ferritin levels are within or higher than the above-mentioned
ranges and coincide with a low TSAT. This scenario is often observed
with the administration of ESAs, which cause iron demand by the
41
erythroid marrow to outstrip the ability of the reticuloendothelial
system to release iron to circulating transferrin. Supply and demand
are the problems in this state, not a total body iron deficiency.16
The hallmark of functional iron deficiency is that it responds to
iron supplements with an increase in hemoglobin and/or decrease
in ESA requirements. This is despite the normal or elevated ferritin
levels. Patients with normal to elevated serum ferritin levels and
low TSAT may not respond to intravenous iron therapy,
presumably due to reticuloendothelial blockade. This suggests that
hepcidin has completely prevented the release of iron from macro-
phages to circulating transferrin. Hepcidin is an acute phase
reactant protein produced in the liver. It inhibits intestinal iron
absorption along with iron release from stores. In an inflammatory
state the lower availability of iron has an antimicrobial effect.17
Since many microorganisms require iron to reproduce, the
increased level of hepcidin, and the resulting decreased available
iron, limits reproduction. Zaritsky et al. monitored hepcidin levels
in patients with chronic kidney disease and performed a multivar-
iate analysis comparing these levels with other indicators of
anemia. Their findings suggest that increased hepcidin levels may
contribute to abnormal iron regulation and erythropoiesis.18 There
is no uniform testing or recommendations for testing,19 but this
may be important for future evaluation of anemia.20
The reticulocyte count is an inexpensive and useful test in the
evaluation of anemia. Reticulocytes are released into the circula-
tion about two days prior to maturation into red blood cells. The
reticulocyte count assesses the number and percentage of reticulo-
cytes in circulating in the blood. Normally, about 1–2% of red blood
cells in the circulation are reticulocytes. When the bone marrow is
stimulated due to anemia, more reticulocytes are released into the
blood, increasing their number and percentage. The reticulocyte
count helps distinguish red blood cell underproduction from ane-
mia caused by red blood cell loss or destruction. Since the typical
reticulocyte count is represented as a percentage of total circulat-
ing red blood cells, a corrected reticulocyte count (or reticulocyte
index) needs to be calculated to address the effect of anemia on
the count. In anemia the reticulocyte percentage may be elevated,
but the absolute number of reticulocytes is low. With inadequate
or deficient EPO production in patients with CKD, the reticulocyte
count would be expected to be low (absolute reticulocyte count
42 C.E. Lankhorst, J.B. Wish / Blood Reviews 24 (2010) 39–47
less than 40,000–50,000 cells per microliter of whole blood). If a
patient is found to have an elevated reticulocyte count, it would
be inconsistent with anemia related to CKD as the bone marrow
responds appropriately to sufficient amounts of EPO. In a patient
with an elevated reticulocyte count, the physician should pursue
an evaluation for hemolysis or extravascular blood loss.
The reticulocyte Hb content (CHr) is a measure of the amount of
Hb in the reticulocytes. The CHr is a reasonably good reflection of
how much iron was available to the bone marrow for incorporation
into new red blood cells a few days before, which is a more clinically
relevant time frame than the 60–120 days life span of the entire RBC
population. It has been shown that CHr compares favorably with
serum ferritin and TSAT in predicting a response to intravenous
iron.21 One study demonstrated that a CHr cutoff of 629 pg tended
to miss a number of patients who ultimately responded to intrave-
nous iron. It was concluded that a cutoff of 632 pg showed a much
greater utility, and a majority of the patients who received intrave-
nous iron therapy on the basis of a CHr 632 pg had an average of
23% reduction in their erythropoietin requirements.22
In the assessment of anemia related to CHr, it would seem that
the measurement of erythropoietin would confirm the diagnosis of
EPO deficiency, but routine testing for EPO is not recommended in
CKD patients. This is partly because patients who respond to the
administration of exogenous ESAs often have normal or even ele-
vated EPO levels, although this may be an inappropriately low level
for the degree of anemia present. Furthermore, an EPO level is an
expensive test and its result will not necessarily drive therapy.
Therefore, EPO deficiency is a diagnosis of exclusion in CKD pa-
tients with anemia. If the evaluation outlined above is unrevealing
but the level of anemia is out of proportion to the stage of renal
failure, then other causes must be considered in addition to EPO
deficiency. Fig. 2 is an overview of anemia assessment in patients
with CKD.
Clinical manifestations of anemia
Anemia has a profound impact on patients with CKD. The most
common symptoms are fatigue (both with activity and at rest), loss
of libido, dizziness, shortness of breath, and decreased sense of
well being. These symptoms generally occur when the Hb is less
than 10 g/dL and become more severe as Hb levels decrease
further. Other more dangerous adverse outcomes include cardio-
vascular disease with left ventricular hypertrophy (LVH) and con-
gestive heart failure. These may occur when the patient is
otherwise asymptomatic and contribute to the excess cardiovascu-
lar morbidity and mortality rate observed among patients with
CKD. In patients who already have coronary artery disease,
decreased myocardial oxygen delivery may lead to worsening
anginal symptoms. Decreased peripheral oxygen delivery due to
anemia also leads to peripheral vasodilation, increased sympa-
thetic nervous system activity, increased heart rate and stroke
volume and, ultimately, LVH. It has been demonstrated that LVH
strongly correlates with adverse outcomes (hospitalization and
mortality) in patients with CKD. A 0.5 g/dL decrease in hemoglobin
below normal correlates with a 32% increase in LVH risk, whereas a
5 mmHg increase in systolic blood pressure correlates with only an
11% increase in LVH risk.23
Anemia has also been associated with a decline in renal
function in some patient groups. Decreased tissue oxygen delivery
caused by anemia stimulates the renin-angiotensin-aldosterone
system and contributes to renal vasoconstriction. These factors
can further exacerbate proteinuria, which may lead to worsening
renal failure. In patients with type 2 diabetes, anemia has been
shown to be an independent risk factor to the progression of renal
disease. Other complications associated with anemia consist of
reduced cognitive function and mental acuity, impaired quality
of life and the need for blood transfusion.24–27 Treatment of anemia
associated with CKD has been shown to result in improved exercise
capacity, energy, and physical mobility.25 Subjective symptoms
also improve; such as quality of life, depression and cognition.26
Evidence supporting regression of LVH, fewer cardiac events or
decreased mortality from ESA treatment is not compelling and will
be discussed in greater detail below.
Erythropoiesis-stimulating agents
Since the introduction of recombinant human erythropoietin in
the late 1980s, ESAs have become the mainstay of treatment of
anemia in patients with CKD. Treatment with ESAs corrects the
underlying pathophysiology of anemia in CKD while reducing the
need for transfusions and their associated complications.28 The
first ESA available was epoetin alfa and it was the only therapeutic
option for over 10 years. Darbepoetin alfa became available in
2001. While both are approved by the US Food and Drug
Administration (FDA) for the treatment of anemia in CKD and in
cancer patients,29–32 only epoetin alfa is also FDA approved for
the treatment of anemia associated with HIV and prior to major
surgeries with the risk for increased blood loss.30,31 Epoetin alfa
has a shorter half-life than darbepoetin alfa, although the half-life
of both drugs is extended when they are administered subcutane-
ously. Although the bioavailability of subcutaneous epoetin alfa is
between 20% and 30%, the prolonged half-life following subcutane-
ous injection, compared with IV infusion, potentially allows less
frequent injections. The dose of epoetin alfa required to achieve
the same hemoglobin response is about 30% lower with subcutane-
ous compared with intravenous administration.33 Darbepoetin alfa
does not show any significant difference in Hb dose response be-
tween the subcutaneous and intravenous routes of administration.
The package inserts suggest using epoetin alfa three times a week
and darbepoetin alfa once a week, although darbepoetin has also
been approved by the FDA for use every two weeks.29–31 Both ESAs
have been shown to have success with extended dosing intervals. A
retrospective review of the extended dosing of epoetin alfa with
intervals ranging form weekly to biweekly to once every three
weeks was reported by Germain et al., with the most common dos-
ing interval every two weeks.34 In this study, hemoglobins were
maintained at greater than 11 g/dL in 82% of patients. The PROMPT
study was a randomized prospective trial in which patients were
administered epoetin alfa at intervals of every one, two, three or
four weeks.35 Hemoglobin levels were maintained above 11 g/dL
in 90% of patients on every two-week dosing intervals and 75%
in groups with every three-week and every four-week dosing
intervals. Similar studies have been performed with darbepoetin
alfa. Jadoul et al. examined hemodialysis patients on every two-
week dosing and when extended to every four-week dosing, 83%
of the patients maintained hemoglobin levels above target.36 This
was a small study, but a later, larger study confirmed the efficacy
of the extended dosing in CKD patients.37
There are ESAs that are currently in use in countries other than
the United States. Epoetin beta is similar to epoetin alfa in its
efficacy, safety, pharmacokinetics and pharmacodynamics.
Continuous erythropoietin receptor activator (CERA) was created
by integrating a large polymer chain into the erythropoietin mole-
cule. It has been shown to have an extended half-life of about 130 h
which is independent of intravenous or subcutaneous administra-
tion. There are other treatments for the anemia of CKD currently in
clinical development. Hematide is an erythropoietin-mimetic
peptide, the amino acid sequence of which is completely unrelated
to native or recombinant erythropoietin but shares the same
functional and biologic properties.38 Hypoxia inducible factor
 C.E. Lankhorst, J.B. Wish / Blood Reviews 24 (2010) 39–47
(HIF) stabilizers are competitive inhibitors of HIF prolylhydroxy-
lases39,40 and asparagyl-hydroxylase, enzymes involved in the
metabolism of HIF and its transcriptional activity. Therefore, HIF
stabilizers cause an increase in endogenous erythropoietin produc-
tion and are orally active.
Clinical trials of ESAs in patients with CKD have documented
improved quality of life and functional status as well as relief of
symptoms associated with anemia.41 ESAs also reduce the need
for transfusions, thereby decreasing the risks of immunologic sen-
sitization, infections and iron overload. Although a survival advan-
tage among CKD patients treated with ESAs has not been
demonstrated in randomized clinical trials, a two-year historical
cohort study showed that those hemodialysis patients treated with
ESAs lived longer than those not treated.42 Observational studies
have suggested increased survival among hemodialysis patients
with Hb levels greater than 12 g/dL. But randomized control trials
with higher target hemoglobins have not shown a reduction of
death or cardiovascular events. The largest of these trials in
hemodialysis patients demonstrated higher mortality rates in
patients with targeted hemoglobin greater than 14 than those
patients with targeted hemoglobins of 10.43
There is debate about the effect of ESAs on the progression of
renal failure. Roth et al. conducted a 48-week randomized open-
label trial comparing patients with chronic kidney disease who re-
ceived epoetin alfa versus those who did not receive any ESA. CKD
was defined by serum creatinine of 3–8 mg/dL and serial GFRs
were measured using 125I-iothalamate clearance. The target
hematocrit was 35% (equal to hemoglobin of 11.7 g/dL) for those
patients receiving epoetin alfa. The study demonstrated no differ-
ence in the mean change of glomerular filtration rate from initial
to the last available calculation.44 The study was not powered to
assess if different starting GFRs made a difference in the outcome.
A randomized controlled trial by Gouva et al. showed treatment
with epoetin alfa to a target hemoglobin of greater than 13 g/dL
in patients with chronic kidney disease slowed the progression of
renal disease. The need for renal replacement therapy was actually
reduced by 60%.45 More recent data suggest that any benefit on the
progression of renal disease from ESA therapy depends on the
hemoglobin target. Higher hemoglobin targets have been shown
to increase the rate of initiation of dialysis.46
Renal anemia causes increased sympathetic nerve activity and
is linked to cardiovascular complications, such as increased blood
pressure and left ventricular hypertrophy. Treatment with ESAs
improves heart failure symptoms and leads to regression of left
ventricular hypertrophy.24,47,48 This is seen with lower hemoglobin
targets (10–11 g/dL). Risks associated with higher hemoglobin tar-
gets (greater than 13 g/dL) will be discussed later in this article.
Several studies have suggested that the administration of ESAs
to anemic CKD patients decreases hospitalizations and thereby re-
duces the overall cost of care.49–51 Furthermore, there are data to
suggest that ESA-treated anemic CKD patients are more productive
workers and consume fewer resources.52,53
Despite the numerous physiologic benefits of ESA therapy
among patients with CKD, there are risks. Randomized controlled
trials have shown increased rates of cardiovascular complications
in hemodialysis patients with high (13–15 g/dL) versus low (10–
11.5 g/dL) hemoglobin targets.43,54,55 The Cardiovascular Risk
Reduction of Early Anemia Treatment with Epoetin Beta (CREATE)
trial is a prominent randomized clinical trial addressing Hb targets.
In this study 603 patients were enrolled from 94 centers in 22 coun-
tries and were randomly assigned to two treatment groups to test
the hypothesis that complete correction of anemia in patients with
stages three to four CKD improves cardiovascular outcomes as
compared with partial correction of anemia.46 The eligible patients
were over 18 years of age with mild to moderate chronic anemia re-
lated to their chronic kidney disease, a glomerular filtration rate of
43
15.0–35.0 mL/min (by the Cockcroft–Gault formula) and a blood
pressure less than 170/95. Patients with advanced cardiovascular
disease, non-renal cause of anemia, previous ESA treatment, and
anticipated need for renal replacement therapy within six months
were excluded. This was an open-label, randomized two-group
study with parallel group design. Patients with moderate anemia
(Hb, 11.0–12.5 g/dL) were randomized to receive either early or late
treatment with epoetin beta, an ESA primarily used overseas, espe-
cially in Europe. The immediate treatment group had a hemoglobin
goal of 13–15 g/dL and the delayed treatment group had a lower
target of 10.5–11.5 g/dL. For the second group, treatment was de-
layed until the hemoglobin dropped below 10.5 g/dL. This trial’s
primary endpoint was a composite of eight cardiovascular events.
Secondary endpoints included left ventricular mass index, quality
of life scores, and the progression of chronic kidney disease. There
was no statistically significant difference in the risk of cardiovascu-
lar events between the two groups (58 versus 47 in high and low
groups retrospectively, hazard ratio of 0.78, 95% confidence interval
0.53–1.14, with P value of 0.20), although the trend was toward in-
creased events in high-target hemoglobin group. Left ventricular
hypertrophy remained stable in both groups. Quality of life was
the only endpoint that was significantly better in the high-target
treatment arm. All other events were not statistically significant
in their differences.
The Correction of Hemoglobin and Outcomes in Renal Insuffi-
ciency (CHOIR) trial was an open-label, prospective, randomized
trail comparing the effect of correcting hemoglobin to a target of
13.5 g/dL versus a target of 11.3 g/dL.56 This trial enrolled 1432
patients at 130 sites within the US, over 18 years of age, who
had hemoglobin less than 11.0 g/dL and CKD defined by an esti-
mated glomerular filtration rate of 15–50 ml/min by Modification
of Diet in Renal Disease (MDRD) formula. Patients were excluded
if they had uncontrolled hypertension, active gastrointestinal
bleeding, iron overload, frequent transfusions in the previous six
months, active cancer, angina, or previous treatment with epoetin
alfa. Two randomly assigned groups of patients received epoetin
alfa. Group 1 had a target hemoglobin of 13–13.5 g/dL, which
was later amended to 13.5 g/dL. Group 2 had a target hemoglobin
of 10.5–11.0 g/dL, which was later changed to 11.3 g/dL. Epoetin
alfa was initially administered weekly, but was allowed to be de-
creased to every other week if the hemoglobin level was stable.
The patients in the higher hemoglobin group had a significantly
higher incidence of the composite end-point (death, myocardial
infarction, hospitalization for congestive heart failure and stroke),
congestive heart failure, death, and hospitalization (cardiovascular
and all-cause). There was no difference between the groups in the
rate of stroke, myocardial infarction, or renal replacement therapy
or in quality of life.
Treatment with ESAs has been reported to increase the risk of
adverse events in other studies. Patients with congestive heart
failure or ischemic heart disease treated with ESAs had an in-
creased risk of mortality and of non-fatal MI, vascular access
thrombosis, and other thrombotic events when epoetin alfa was
dosed to target hematocrit of 42%.43 Following the publication of
such studies, including CHOIR and CREATE, along with the studies
on cancer patients with higher targeted hemoglobin and worse
outcomes, the FDA issued a ‘‘black box” warning. The warning
advises physicians that patients experienced greater risks for death
and serious cardiovascular events when administered ESAs to tar-
get higher versus lower Hb levels (12.5 versus 11.3 g/dL; 14 versus
10 g/dL). The FDA recommends individualized dosing to achieve
and maintain Hb levels within the range of 10–12 g/dL. This
FDA recommendation is at odds with the US National Kidney
Foundation’s Kidney Disease Outcomes Quality Initiative
(NKF/KDOQI) anemia guidelines which recommend a target Hb of
11–12 g/dL, not to exceed 13 g/dL in anemic CKD patients treated
44 C.E. Lankhorst, J.B. Wish / Blood Reviews 24 (2010) 39–47
with ESAs. The bottom line is that the target Hb level should be
individualized to the patient’s symptoms, co-morbidities, and
ESA responsiveness within the range specified by the FDA, NKF/
KDOQI or other national evidenced based guideline.
In its own retrospective analysis of the normal hematocrit trial
in hemodialysis patients43 and the CHOIR study of CKD patients56
the FDA noted that the rate of rise of Hb in ESA-treated patients
was an independent risk factor for adverse outcomes irrespective
of the ESA dose and target Hb level. As a result, the FDA cautions
against a Hb rise of >2 g/dL in a four-week period and recommends
a 25% ESA dose reduction in such patients. The FDA also recom-
mends a 25% ESA dose reduction in patients trending toward
exceeding the Hb target range ceiling of 12 g/dL.
Although the intention to treat analysis of the CHOIR study indi-
cates a higher risk for the composite outcomes of death and cardio-
vascular events among patients randomized to the higher Hb target,
a secondary analysis of the CHOIR study by Sczcech et al. reveals
that when the analysis is adjusted for ESA dose and patients not
achieving their Hb target, the difference in outcomes between the
high and low Hb targets becomes non-significant and the use of a
high dose of ESA becomes the major predictor of adverse outcomes
in both target groups.57 The analysis cannot distinguish whether
this effect is due to toxicity of high doses of ESA per se and/or
whether patient factors resulting in ESA resistance (e.g. inflamma-
tion) account for the higher incidence of adverse events. Nonethe-
less, it seems prudent to avoid high doses of ESAs (defined as
>20,000 units/week epoetin alfa in the CHOIR study) in ESA-resis-
tant patients. Occasional excursions of Hb to the 12–13 g/dL range
in patients receiving modest doses of ESAs are likely not to be harm-
ful if the ESA dose is down-titrated accordingly.58
Another reported adverse effect of ESA therapy is hypertension.
It is caused by multiple mechanisms including: expansion of blood
volume, reversal of hypoxic vasodilation and increased blood vis-
cosity. A direct vasoconstrictive effect has also been proposed.59
The hypertension related to treatment is more common in patients
receiving hemodialysis, associated with a rapid rise in Hb level and
usually is seen within the first 90 days of treatment.29,30 Rarely,
seizures and hypertensive encephalopathy have occurred. Antihy-
pertensive treatment may need to be adjusted, so close monitoring
of the patient’s blood pressure is recommended.
A rare and serious complication associated with ESAs is pure red
blood cell aplasia (PRCA). PRCA is a result of the production of anti-
erythropoietin antibodies induced by the administration of exoge-
nous ESAs. This was primarily associated with the subcutaneous
use of epoetin beta sold outside of the United States. It was thought
to be secondary to the additive Tween 80 used to stabilize the sub-
stance. Tween 80 was never used in the United States and PRCA
remains rare in the US. PRCA should be suspected if a patient has
a sudden weekly drop in hemoglobin of about 1 g/dL or a weekly
transfusion requirement and a low reticulocyte count, despite a
high dose of an ESA for several months. White blood cell and plate-
let counts remain unaffected, differentiating this condition from
aplastic anemia. Iron deficiency also should be considered; this will
be discussed later in the article. PRCA is definitively diagnosed
when anti-erythropoietin antibodies are demonstrated in the
blood, or an examination of the bone marrow reveals normal cellu-
larity and less than 4% erythroblasts. PRCA is treated by discon-
tinuing the ESA and administering immunosuppressive therapy.
Patients generally respond after several months of treatment and
usually do not relapse after immunosuppressants are discontinued.
Iron therapy
Many anemic patients with CKD and inadequate EPO production
have coexisting iron deficiency. Iron deficiency almost always is
present in hemodialysis patients due to: bleeding when needles
are removed from the vascular access, blood infiltration of the vas-
cular access, vascular access procedures, frequent blood testing,
and clotting or general blood loss in the extracorporeal circuit.
The iron deficiency observed in patients with CKD not yet on
hemodialysis, and those on peritoneal dialysis, is often due to de-
creased oral iron intake from the prescribed dietary protein restric-
tion or decreased appetite for red meat. Iron deficiency often
develops, if it is not present initially, while a patient is receiving
ESA therapy. This is due to depletion of the existing iron stores with
the stimulation of new RBC production. Regular monitoring of iron
status is essential during the initiation of ESA therapy with monthly
assessment of serum ferritin and TSAT while the Hb level is rising
and then every three months after the Hb level has stabilized. The
target levels for serum ferritin and TSAT are higher in ESA-treated
patients than in the general population because of the development
of functional iron deficiency, in which the demand for iron by the
ESA-stimulated bone marrow exceeds the rate at which normal
reticuloendothelial iron stores can release it. The NKF/KDOQI ane-
mia guidelines recommend a target serum ferritin of greater than
200 ng/mL in hemodialysis patients and greater than 100 ng/mL
in patients with CKD not receiving hemodialysis and those receiv-
ing peritoneal dialysis patients when taking ESAs. The target TSAT
level is greater than 20%.13 While this is the recommended target,
the lowest all-cause and cardiovascular death risks where observed
in patients with TSATs in the 30–50% range.60
Iron can be administered orally or intravenously. Oral iron is
usually sufficient in patients with CKD not yet on dialysis or peri-
toneal patients who do not have the continual blood loss that is
typical in hemodialysis patients. Yet even in non-hemodialysis
patients, oral iron may not be effective due to gastrointestinal side
effects, poor compliance or the severity of iron deficiency. Oral iron
salts such as ferrous sulfate, gluconate and fumarate should be
administered one hour before or 2 h after meals to result in the
greatest absorption. Oral ferrous iron salts must be oxidized to
the ferric form by stomach acid to allow absorption by the small
intestine. This step can be impaired by food, antacids, histamine-
2 blockers or proton pump inhibitors. It has been shown that the
minimal effective dose is 200 mg of elemental iron daily. Each
325 mg tablet of ferrous sulfate contains 65 mg of elemental iron;
therefore three tablets must be administered over the course of
each day. As a result of inflammation or impaired iron mobilization
from stores, serum ferritin is often elevated in patients with
chronic kidney disease. This further reduces bioavailability of oral
iron to only 1–2%, so even the most compliant patients may not be
able to replete their iron stores with oral iron.
In CKD patients with mild to moderate iron deficiency, a three-
month trial of oral iron is recommended to assess the effectiveness
of that route of administration. For patients with severe iron
deficiency and all iron deficient hemodialysis patients, intravenous
iron supplements are recommended. There are four preparations of
intravenous iron currently available in the US: iron dextran, iron
sucrose, iron gluconate and ferumoxytol. The least expensive,
and the one approved by the FDA to be given in doses as large as
1000 mg, is iron dextran, but it has been associated with fatal ana-
phylactic reactions.61 As a result, FDA has issued a ‘‘black box”
warning recommending that patients undergo a 25 mg test dose
the first time the drug is given. If a patient does not have an
adverse reaction to this dose, he/she is less likely to have an ana-
phylactic reaction to the therapeutic dose of iron dextran, but fatal
anaphylactic reactions still occur with an uneventful test dose. This
risk notwithstanding, the use of a single iron dextran dose of 500–
1000 mg is appealing in non-hemodialysis patients who need to
travel long distances in order to receive their treatment. Further-
more, fewer IV iron doses also means fewer intravenous line place-
ments and therefore the preservation of the veins needed for the
 C.E. Lankhorst, J.B. Wish / Blood Reviews 24 (2010) 39–47
creation of permanent dialysis access for future hemodialysis. Iron
sucrose and iron gluconate do not require a test dose because they
have not been associated with fatal anaphylactic reactions. These
two preparations are FDA approved to be given in doses up to
250–300 mg, meaning non-hemodialysis patients will need more
trips to the clinic or hospital for infusions and more placements
of intravenous catheters to receive a total repletion dose of
1000 mg. These preparations have some non-fatal adverse reac-
tions such as nausea, vomiting, and hypotension. Generally, with
slower infusions of these medications, there is a decreased risk of
adverse side effects. Ferumoxytol, which was approved by the
FDA in June 2009, is an iron dextran nanoparticle which can be
administered in rapid injection of up to 510 mg over 17 s. In phase
3 studies in non-dialysis patients with CKD and iron deficiency
anemia, it was shown to have no more side effects than oral iron
and to be more effective in raising the Hb level than an ESA with
oral iron.62
Despite the benefits of iron supplementation, concerns have
been raised about potential toxicity of intravenous iron including
cellular and vascular damage resulting from oxidative stress and
impaired white blood cell function based on in vitro studies. In pa-
tients with CKD receiving intravenous iron sucrose, there has been
evidence of increased urinary excretion of markers of tubular
injury, but no increase in albuminuria. This has not proved to be
clinically significant in other studies. There was no increase in
hospitalizations or mortality seen in observational studies in
hemodialysis patients receiving less than 400 mg on average of
intravenous iron per month.60,63,64 Intravenous iron was not shown
to be a risk factor for bacteremia in hemodialysis patients in a
multivariate analysis.65 Serial liver biopsies were done in patients
with hemochromatosis and showed no significant organ injury
when serum ferritin level was less than 2000 ng/mL.66 The NKF/
KDOQI anemia guidelines recommend weighing ESA responsive-
ness, hemoglobin concentration, TSAT level, and the patient’s
clinical status when considering giving iron to a patient with a
ferritin greater than 500 ng/mL.
ESA resistance
ESA resistance is defined as a failure to achieve a target hemo-
globin greater than 11.0 g/dL in the setting of an epoetin alfa dose
of more than 500 units/kg per week or the equivalent of another
ESA. The causes can include iron deficiency, acute and chronic
inflammatory conditions, severe hyperparathyroidism, aluminum
toxicity, folate deficiency and PRCA. Iron deficiency is the most
common cause of ESA resistance, but it is followed closely by
inflammation and infection. The source of inflammation or infec-
tion may be difficult to elucidate, but it is often associated with
high levels of acute phase reactants, such as ferritin, erythrocyte
sedimentation rate (ESR), and C-reactive protein (CRP). The use
of dialysis catheters for vascular access has been shown to lower
Hb levels and increase ESA requirements. This may reflect an
inflammatory state induced by the presence of a catheter and its
biofilm without evidence of an active infection demonstrated by
positive cultures.67
The resistance to ESA therapy in the inflammatory state has led
to exploration of adjuvant treatment with vitamin C. Studies have
not shown significant benefit in patients with CKD not yet on dial-
ysis treated with vitamin C, although there have been many smaller
studies showing decreased ESA requirements with concomitant use
of vitamin C in patients undergoing hemodialysis.68–73 Vitamin C
therapy may produce some benefit in patients with CKD or under-
going peritoneal dialysis receiving oral iron, as it may promote
intestinal iron absorption. There have been several studies examin-
ing the use of L-carnitine as an adjuvant therapy for anemia, but the
45
evidence has been lacking its efficacy in patients with non-dialysis
CKD. There has been some benefit in reducing ESA doses in a sub-
group of hemodialysis patients, but it is not recommended for all
patients.74,75 Prior to the advent of ESA therapy, androgens were
used with some success in treating anemia in hemodialysis
patients, but with significant side effects. However evidence is lack-
ing for any benefit of androgen use in patients receiving adequate
ESA therapy and long-term androgen use has the potential for sig-
nificant toxicity.
Even with sufficient dosing of ESAs and iron therapy, patients
may still require red blood cell transfusions due to ESA resistance
or acute blood loss. In patients who are candidates for organ trans-
plantation, this is the option of last resort because sensitization
from transfusion can decrease the chance of a successful trans-
plant. There also still exists the small risk of bloodborne infections
such as hepatitis and human immunodeficiency virus. Unlike the
guidelines for ESA therapy, there is no recommended Hb threshold
at which a patient should be transfused. This is a clinical decision
based primarily on a patient’s symptoms, but must also take into
consideration acuity of Hb decline, concomitant diseases such as
coronary artery disease, and the patient’s candidacy for future
organ transplantation.
Conclusions
Anemia is a common and important complication among
patients with CKD and health care professionals should be familiar
with the best practices for its screening, evaluation and treatment.
Untreated anemia places patients at risk for cardiovascular events,
more rapid progression of chronic kidney disease and significantly
decreased quality of life. The cause of anemia is multifactorial in
patients with CKD, but inadequate production of EPO by the dis-
eased kidneys is the common denominator. The anemia generally
becomes more severe as a patient’s renal function declines. Once
other treatable causes of anemia are evaluated and addressed, pa-
tients who remain anemic will likely need to be treated with an
ESA. According to the NKF/KDOQI guidelines, ESA therapy should
be initiated when the patient’s Hb drops below 10 g/dL, with target
Hb level for treatment being 11–12 g/dL. It is also recommended
not to treat patients with ESAs to Hb above 13 g/dL as studies have
shown evidence of adverse events in patients with CKD maintained
at normal Hb levels without significant benefit. Both prior to and
during ESA treatment, patients with CKD often require iron supple-
mentation. This is frequently given orally in patients with CKD not
on hemodialysis and in patients on peritoneal dialysis. Hemodialy-
sis patients and those unable to respond oral iron require intra-
venous iron therapy. Intravenous iron therapy is associated with
adverse effects, including potentially fatal anaphylactic reactions
to iron dextran, but it also has significant benefits by increasing
Hb levels and decreasing ESA requirements. Despite adequate
treatment with iron and ESAs, patients may fail to increase Hb
and require transfusion. As more is learned about anemia in
patients with CKD, treatment methods and goals may continue to
evolve, but there is no question that current treatments have
significantly improved the quality of life and decreased transfu-
sions and their complications in this vulnerable population.
Practice points
 Anemia is a common complication in patients with chronic
kidney disease (CKD) and is associated with adverse out-
comes including poor quality of life, cardiovascular disease
and progression of renal failure.
 Evaluation of CKD patients with anemia is straightforward
and is directed at ruling out iron deficiency and, if clinically
46 C.E. Lankhorst, J.B. Wish / Blood Reviews 24 (2010) 39–47
indicated, other etiologies such as hemoglobinopathies,
blood loss and vitamin deficiencies.
 Most anemic patients with CKD will have erythropoietin defi-
ciency, which is a diagnosis of exclusion.
 Treatment of anemia in patients with CKD includes erythro-
poiesis-stimulating agents (ESAs), but attention must be paid
to repletion and maintenance of iron stores.
 The target hemoglobin level for anemic CKD patients receiv-
ing ESA therapy is 10–12 g/dL per the US Food and Drug
Administration.
 Maintenance of hemoglobin levels above 13 g/dL with ESA
therapy has been associated with and increased frequency
of adverse cardiovascular events in randomized clinical trials.
 When used according to practice guidelines, ESA therapy has
been associated with improved quality of life, reduction in
transfusion requirements and few significant adverse effects.
Conflicts of interest
CL reports no conflicts of interest. JW has served on advisory
boards for Amgen, Centocor Ortho Biotech, Watson, Affymax
and AMAG, in addition to serving on speakers bureaus for Amgen,
Watson, and AMAG.
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