REVIEWS

Iron supplementation to treat anemia

in patients with chronic kidney disease
Anatole Besarab and Daniel W. Coyne
Abstract | Iron deficiency is prevalent in patients with chronic kidney disease (CKD), and use of oral and
intravenous iron in patients with CKD who do not require dialysis might obviate or delay the need for treatment
with eythropoiesis-stimulating agents (ESAs). Patients on hemodialysis have lower intestinal iron absorption,
greater iron losses, and require greater iron turnover to maintain the ESA-driven red cell mass than do healthy
individuals. In these patients, intravenous iron reduces ESA dose requirements and increases the likelihood
of maintaining levels of hemoglobin within the desired range. Oral iron is inferior to intravenous iron in
patients on hemodialysis, in part because elevated serum levels of hepcidin prevent intestinal absorption
of iron. Increased levels of hepcidin also impair the normal recycling of iron through the reticuloendothelial
system. Levels of serum ferritin and transferrin saturation below 450 pmol/l and 20%, respectively are
indicative of iron deficiency, but values above the normal range lack diagnostic value in patients with CKD on
dialysis. The availability of various iron preparations and new developments in delivering iron should enable
adequate provision of iron to patients with CKD. This Review examines the efficacy, safety and use of iron
supplementation therapy for the treatment of anemia in patients with CKD.
Besarab, A. & Coyne, D. W. Nat. Rev. Nephrol. 6, 699–710 (2010); published online 19 October 2010; corrected online 12 December 2011;
doi:10.1038/nrneph.2010.139

Introduction
Compared with healthy individuals, individuals with
end-stage renal disease (ESRD) demonstrate major
differ­ences in iron metabolism: decreased duodenal iron
absorption, decreased iron transport capacity because of
a reduced transferrin concentration, increased iron loss
owing to frequent blood sampling, occult gastrointestinal
bleeding and other means (such as losses of blood into
dialysis tubing and dialyzers), and an increased rate of
iron turnover to maintain the decreased red blood cell
mass (Figure 1).1 At hemoglobin levels of 100–120 g/l,
red blood cell losses associated with hemodialysis equate
to iron losses of 6–7 mg daily in addition to physio­
logical iron losses of 1–2 mg daily. With the additional
losses from periodic laboratory evaluations, annual
iron losses can exceed 1.5–3.0 g.2 Occult blood loss con-
tributes to anemia in patients with advanced CKD who
are not yet on hemodialysis, and as many as 25–45% of
such patients might be iron-deficient.3,4
During erythropoiesis, committed erythroid progeni-
tors (burst-forming unit-erythroid [BFU‑E] and colony-
forming unit-erythroid [CFU‑E]) appear sequentially and
mature morphologically into recognizable erythroblasts
(Figure 2). Erythropoietin is critical for multiplica­tion,
Competing interests
A. Besarab declares associations with the following companies:
Affymax, AMAG Pharmaceuticals, Amgen, Hoffman–La Roche,
Watson Pharmaceuticals. D. W. Coyne declares associations
with the following companies: AMAG Pharmaceuticals,
Pharmacosmos, Sanofi–Aventis, Watson Pharmaceuticals. See
the article online for full details of the relationships.
differentiation and survival of these cells.5,6 The duration
of this erythropoietin-dependent first stage varies from
8 days to 13 days and shortens as erythrocyte production
increases. Each erythroblast ultimately produces about
32 daughter cells that leave the bone marrow as reticulo­
cytes complete with their full content of hemoglobin. This
second stage of rapid cell division and hemoglobinization
takes about 4 days. Virtually all of the iron needed to gen-
erate a hemoglobin-laden reticulocyte is taken up within
2–3 days during this stage (Figure 2). Clearly, therefore,
the treatment of anemia in patients with CKD must both
promote the production of erythroblasts and ensure that
iron levels are adequate to enable optimal hemoglobin
formation in the daughter cells.
Anemia was thought to increase the incidence of
cardio­vascular events and the risk of death in patients
with CKD. Since the development of erythropoiesis-
stimulating agents (ESAs) in the late 1980s (discussed in Division of Nephrology
and Hypertension,
detail elsewhere7), anemia in patients with CKD has been Henry Ford Hospital,
treated with these agents to reduce the need for blood CFP 511, 2799 West
transfusions, improve health-related quality of life and Grand Boulevard,
Detroit, MI 48301, USA
to decrease the risk of cardiovascular events and death. (A. Besarab). Division
The dose of ESAs needed to achieve adequate levels of Nephrology,
Washington University
of hemo­globin varies widely from <1,000 U to 30,000 U School of Medicine,
per hemo­dialysis treatment. The dose and frequency of 660 South Euclid
ESA administration is, therefore, usually flexible. Findings Avenue, St Louis,
MO 63110, USA
from randomized trials indicate that ESAs improve (D. W. Coyne).
quality of life and cardiovascular outcomes when used
Correspondence to:
to treat patients with hemoglobin levels that correspond to A. Besarab
moderate anemia (90–120 g/l). However, ESA therapy in abesara1@hfhs.org

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REVIEWS
Key points
■■ Iron deficiency is prevalent in patients with chronic kidney disease (CKD) and
should be treated
■■ Inconsistent and inadequate absorption of oral iron frequently leads to the
need for administration of intravenous iron
■■ Hepcidin (levels of which are frequently increased in patients with CKD) impairs
iron absorption and the normal recycling of iron through the reticuloendothelial
system
■■ Low levels of serum ferritin and transferrin saturation indicate iron deficiency,
but values in or above the normal range lack diagnostic value
■■ Frequent, small repeat doses of intravenous iron are more effective than
infrequent, large doses for maintaining levels of hemoglobin and reducing the
requirement for erythropoiesis-stimulating agents (ESAs)
■■ Relative thrombocytosis (owing to iron deficiency) might contribute to the
increased cardiovascular risk seen with high ESA doses
Reticuloendothelial stores
ferritin level: 33–450 pmol/l
ferritin level: 110–1,800 pmol/l
32 mg per day
Transferrin
Transferrin saturation
Tissue 200 mg Gut
15–50% (men),
12–45% (women)
TSAT 20%
36 mg per day Loss: 1 mg per day
Red blood cells
2,050–2,500 mg Net loss through
(hematocrit 0.41–0.50) hemodialysis:
1,750 mg
(hematocrit 0.35)
4.5–6.0 mg per day
Figure 1 | Iron distribution in the average adult. Values for healthy individuals are
shown in black print whereas those for patients with end-stage renal disease
(ESRD) on hemodialysis are shown in red print. The overall balance of iron in
patients on chronic maintenance hemodialysis is impaired. Transport of iron is
decreased by a reduction in circulating transferrin levels. At the same time, dialysis-
associated blood losses lead to loss of iron from the body. Daily incorporation of
iron into red blood cell hemoglobin and its release from senescent cells is actually
increased in patients with ESRD on hemodialysis compared with healthy individuals.
Note that both occult blood loss in stool and loss of red blood cells in tubing
increase the daily loss of iron in patients with ESRD on hemodialysis.90
patients with hemoglobin levels >120 g/l reduces the need
for blood transfusions, but increases the risk of adverse
cardiovascular events.8,9 A full discussion of the ongoing
controversy with regard to the level of hemoglobin that
should prompt ESA therapy is beyond the scope of this
Review. However, we do believe that avoidance of blood
transfusion in renal transplant candi­dates is important
to prevent sensitization owing to the formation of pre-
formed reactive antibodies, and recommend the initiation
of ESA therapy in these patients when the level of hemo-
globin is <100 g/l rather than <90 g/l. Iron therapy can be
initiated in any patient with symptoms of iron deficiency
irrespective of their level of hemoglobin.
Moderate anemia is frequently observed in patients with
nondialysis-dependent CKD (NDD-CKD) who are not
receiving ESA therapy. Our clinical experience has shown
that use of oral and intravenous iron in such patients can
increase their hemoglobin levels—delaying or obviating
the need for ESAs. Results from studies also demonstrate
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that use of intravenous iron can lower ESA dose require-
ments in patients with CKD who are on dialysis.10,11 As the
increased cardio­vascular risk associated with ESA therapy
might be a result of the high doses of these agents rather
than of the elevation in hemo­globin levels, iron supplemen-
tation might reduce the risks associ­ated with ESA therapy.
Nevertheless, the long-term safety of iron administration
has not been thoroughly tested in patients with CKD. This
Review examines the efficacy, safety and rational use of
iron therapy for the treatment of anemia in patients with
CKD. Although ESA therapy is mentioned throughout this
Review, these agents are not the main focus of this article
and as such will not be discussed in detail as they have been
comprehensively reviewed elsewhere.7,12
Iron deficiency anemia and CKD
Iron dynamics
Iron absorption from food seems to be unimpaired in
patients with CKD in whom levels of ferritin (a protein
that stores iron) are not elevated.13,14 Eschbach and co-
workers13,14 observed that the proportion of iron absorbed
from food in the gastrointestinal tract of patients with
uremia varied inversely with the logarithm of serum
levels of ferritin. The researchers concluded that uremia
did not interfere with physiological iron absorption but
their findings clearly indicated that the amount of iron
absorbed from dietary sources might not be suffi­cient
to meet the requirements for erythropoiesis in these
patients. Findings from a 1984 study (before ESA therapy
became available) indicated normal iron uptake by red
blood cells as a result of oral administration of ferrous
sulfate with ascorbic acid in fasting patients.15 However,
the extent of absorption varied widely (4–30% of a 50 mg
oral dose of ferrous sulfate, mean 13%). Only one-third of
the patients had normal iron incorporation into red blood
cells after this treatment, and none showed an improve-
ment in their hematocrit. By contrast, intravenous iron
therapy increased both iron uptake by red blood cells
and hematocrit.14 Although these results indicate that
iron utilization is decreased in patients on dialysis who
are not receiving ESAs, even with ESA use iron utiliza-
tion remains suboptimal, particularly in the presence of
inflammation. In some patients, low levels of transferrin,
which result in a low capacity for binding iron, impair the
metabolic cycling of iron in patients without CKD.
Acquired gastrointestinal disease is increasingly
recog­nized as an additional malabsorptive mechanism
of iron deficiency anemia in patients on hemodialysis:
auto­immune atrophic gastritis and Helicobacter pylori
infection are frequently present in such patients. 16,17
Endoscopic abnormalities consisting of chronic and
acute gastritis, duodenitis or duodenal ulcer gastritis are
found in up to 90% of asymptomatic patients on hemo-
dialysis.18 Moreover, histological examination of multiple
antral gastric biopsy samples documented the presence
of chronic active gastritis in these patients.18
Inflammation
Patients with CKD often exhibit chronic inflammation.
Furthermore, uremia is considered an inflammatory
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CD34
Stem Progenitor cells Precursor cells
cells (BFU-E, CFU-E) (erythroblasts) Reticulocytes

GM-CSF
IGF-I Apoptosis
IL-3
SCF

Neocytolysis
(spleen)

Erythropoietin-dependent

~8–13 days 4 days

Figure 2 | Erythropoiesis. Erythropoietin is required in the first stage of erythropoiesis (in which multipotent stem cells form
progenitor BFU-E and CFU-E cells) but not in the second stage (in which precursor cells form erythroblasts and reticulocytes).
The interval from stem cell to erythroblast is ~17 days, with 8–13 days spent in the BFU and CFU stages. Erythropoietin acts
on BFU-E and CFU-E cells for approximately 7–10 days. Sites of action of erythropoietin and other growth factors during the
stages of erythropoiesis are shown. The stippling indicates potential apoptosis of progenitor cells. The erythropoietin-
independent phase of erythropoiesis begins with the erythroblast and ends with the released reticulocyte. Each erythroblast
produces a progeny of 32 cells, which must synthesize the appropriate amount of hemoglobin before they are released into
the circulation. Reticulocytes released into the circulation undergo volume surface area remodeling but are subject to
neocytolysis (premature death, which only occurs when erythropoietin levels decline abruptly below a critical level) for up
to 10 days as they traverse the spleen. Abbreviations: BFU-E, burst-forming unit-erythroid; CFU-E, colony-forming unit-
erythroid; GM-CSF, granulocyte–macrophage colony-stimulating factor; IGF-I, insulin-like growth factor I; IL-3, interleukin 3;
SCF, stem cell factor. Permission obtained from Wolters Kluwer © Besarab, A. & Yee, J. in Principles and Practice of Dialysis,
4th edn Ch. 30 (ed. Henrich, W. L.) 499–523 (Lippincott Williams & Wilkins, Baltimore, 2009).

state even in the absence of apparent infection or obvious
inflammatory conditions. Early observational clinical
studies associated high serum ferritin levels with infec-
tion19,20 or mortality.21 Hyperferritinemia-associated
morbidity could be related to inflammatory processes
that are not associated with iron, and high serum ferritin
levels might merely be a marker of acute-phase infection
or inflammation,22 which would make the association
between hyperferritinemia and increased risk of infec-
tion and death a mere epiphenomenon. Indeed, levels of
the inflammatory cytokine tumor necrosis factor were
decreased in patients on dialysis who received intra­
venous iron compared to those in patients who did not
receive this therapy. 23 In the same vein, Feldman and
co-workers (who initially noted a tendency towards an
increased risk of death in patients on dialysis who were
receiving high doses of intravenous iron)24 revised their
conclusions when they used models that adjusted for bias
by indication.25
The role of hepcidin
In many patients with CKD, poor absorption of dietary
iron and an inability to use the body’s iron stores con-
tribute to anemia. These abnormalities in iron balance
result from increased levels of the hormone hepcidin (a
25 amino acid peptide synthesized in hepatocytes that is
a key regulator of iron levels). Hepcidin is released into
the circulation and binds to solute family 40 member 1,
which is also termed ferroportin 1. After binding to
target cells (chiefly enterocytes and tissue macrophages),
the hepcidin–ferroportin 1 complex is internalized and
degraded, which leads to decreased iron efflux from
iron-exporting tissues into plasma. By this mechanism,
hepcidin inhibits dietary iron absorption, the efflux of
recycled iron from splenic and hepatic macrophages, and
the release of iron from storage in hepatocytes.26
Hepcidin synthesis is stimulated by excessive plasma
iron and iron stores and inhibited by increased erythro-
poietic activity. The results of a 2010 study indicated that

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a b Enucleating erythoblast c

Reticulocyte Macrophage Reticulocyte

Figure 3 | Photomicrographs of erythroblastic islands, where erythroid precursors proliferate, differentiate and enucleate.
The interaction of cells within the erythroblastic island is essential for both early and late stages of erythroid maturation.
a | Conventional photomicrograph of an erythroblastic island. b | Scanning electron microscopy image of an erythroblastic
island. Macrophages phagocytose extruded erythroblast nuclei at the end stage of erythroid maturation.
c | Photomicrograph showing immunofluorescence staining of an erythroblastic island. Central macrophages can be
identified by their unique immunophenotypic signature. The macrophages are adhesive and function as nurse cells. Both
macrophages and erythroblasts display adhesive interactions that maintain island integrity. Such interactions enable
regulatory feedback within islands and also trigger intracellular signaling pathways that regulate gene expression for
cellular growth within the erythroblastic islands. Permission obtained from the American Society of Hematology ©
Chasis, J. A. & Mohandas, M. Blood 112, 470–478 (2008).

erythroblasts produce a circulating factor that inhibits
production of hepcidin and maximizes the delivery of
iron to the erythron.27 As bone marrow erythropoiesis
occurs in erythroblastic islands that surround macro­
phages (Figure 3),28 hepcidin inhibition facilitates the
mobilization of iron stored in the reticuloendothelial
system in macrophages to the surrounding maturing
red blood cells.
The role of abnormalities in hepcidin synthesis in
anemia associated with renal disease and in resistance
to erythropoietic therapies remains unclear because
of the difficulty in measuring levels of the biologically
active form of this hormone and the direct influence of
inflamma­tion on hepcidin synthesis.29 Currently available
immunoassays mostly measure levels of pro­hepcidin.
Until 2 years ago, immunoassays to measure serum
levels of hepcidin did not measure the intact hormone.
However, even when hepcidin level is measured using a
reliable immunoassay of the intact hormone30 or by mass
spectroscopy, variation in hepcidin levels within the same
individual might reflect not only changes in iron state
and changes in renal elimination owing to kidney failure
but also changes that occur because of inflammation.
Inflammation increases hepcidin concentrations,
leading to iron sequestration in macrophages, which
results in low levels of circulating iron and eventually
anemia. The fact that serum hepcidin levels are closely
linked to systemic inflammation might limit the useful-
ness of this marker in assessing iron status in patients with
CKD. Whether diagnosis of different forms of anemia will
be facilitated by improved hepcidin assays or whether
anemia treatment will be enhanced by the develop­ment
of hepcidin agonists and antagonists remains unclear.31
For these reasons, hepcidin will not be further discussed
in this Review as an indicator of iron status.
Absolute and functional iron deficiency
Iron deficiency is a frequent finding in patients who
have anemia associated with renal disease, particularly
in those receiving ESAs. As these agents enable the pro-
duction of supraphysiologic levels of red blood cells, iron
deficiency in these patients can be either absolute or
functional. The rate of iron delivery to the bone marrow
is determined by the amount of iron in the circulation,
where it is bound to the iron-transporting protein trans-
ferrin. As transferrin concentration is reduced by 30%
in patients with ESRD, functional iron deficiency can
develop in such patients because the demands of the
ESA-stimulated bone marrow for iron outstrip the supply
capacity of transferrin.
Previous studies of iron status in patients with renal
diseases discriminated between absolute and functional
iron deficiency.32,33 Absolute iron deficiency reflects
minimal to no stores of iron, and is thought to be present
when transferrin saturation and ferritin levels are both
low (for example, <20% and <449 pmol/ml, respectively).
Functional iron deficiency describes the inadequate
release of iron to support the needs of erythropoiesis,
despite the presence of adequate stores of iron, and
typically occurs when erythropoiesis is driven by ESA
therapy in patients with inflammation. Functional iron
deficiency is thought to be present when serum levels of
ferritin are high but transferrin saturation is low. Studies
over the past 5 years, however, undermine this dichoto-
mous view. Although patients on dialysis without ade-
quate iron stores are likely to also have low serum levels of
ferritin, some of these individuals have elevated levels
of serum ferritin, and a few patients also have trans­ferrin
saturation values >20%. Additionally, many patients
with CKD who have adequate levels of stored iron have
iron-restricted erythropoiesis, which can be successfully
treated with intravenous iron therapy.34,35
Discriminating between absolute and functional iron
deficiency is difficult in clinical practice without histo­
logical examination of the bone marrow (Figure 4).
Although patients with absolute iron deficiency are more
likely than those with functional deficiency to respond
to intravenous iron, about 30% of patients with func-
tional iron deficiency will respond to such treatment.
Consequently, in patients on hemodialysis who have
iron-restricted erythropoiesis, a trial of intravenous iron
therapy is recommended when hemoglobin is below target
levels or high ESA doses are used, and serum ferri­tin
and transferrin saturation values are equivocal.

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In a trial of patients with NDD-CKD, Stancu and
colleagues35 found that the proportion of patients who
responded to intravenous iron was higher among patients
with iron-deficient bone marrow than among those with
iron-replete bone marrow (63% versus 30%). Peripheral iron
indices, such as a transferrin saturation of 15% and a serum
ferritin level of 169 pmol/l had a moderate accuracy (15%
transferrin saturation, positive predictive value 76% and
negative predictive value 72%; 169 pmol/l serum ferritin
level, positive predictive value 74% and negative predictive
value 70%) in predicting a 10 g/l increase in hemoglobin
in response to intra­venous iron therapy. The chances of a
positive response to intravenous iron therapy increased
by 7% for each 1% decrease in transferrin saturation.36 As
an erythropoietic response was observed in one-third of
patients with an iron-replete bone marrow, and periph-
eral iron indices had only a moderate utility in predict-
ing a response to iron supplementation, the researchers
concluded that a test to predict a patient’s response to
intravenous iron therapy would be a useful tool in the
management of anemia in patients with NDD-CKD.
Diagnosis
Iron deficiency should be diagnosed by a global examina­
tion of the patient’s symptoms and appropriate laboratory
investigations. Inflammation or infection can elevate
serum ferritin levels and reduce trans­ferrin levels, and
malnutrition can also reduce transferrin levels. Trans­
ferrin is also a nutritional marker and levels of this
protein are as powerful a predictor of death as serum
albumin levels.37 Consequently, a transferrin saturation
value within the normal range could mask functional
iron deficiency and the need for iron therapy. A low ferri-
tin level (for example, <450 pmol/l in patients with CKD
on hemodialysis or <225 pmol/l in patients with NDD-
CKD) is a reliable indicator of absolute iron deficiency,
and such patients generally require treatment. A moder-
ately high serum ferritin level (>1,123 pmol/l), however,
does not exclude iron deficiency or assure replete iron
stores.38 Decisions on the use of iron supplementation
in patients with high serum levels of ferritin should be
driven by the severity of anemia, the use and dose of ESA,
and the history of iron administration.
Treatment options for anemia
Many patients with CKD and anemia (irrespective of
whether they are on dialysis) do not respond adequately
to anemia treatment (that is, reach target levels of hemo-
globin) or require high doses of ESA and iron. As men-
tioned earlier, use of high ESA doses in patients with
hemoglobin levels >120 g/l is associated with increased
cardiovascular morbidity and mortality, particularly
when high-dose ESAs are used in individuals who
respond poorly to treatment. Iron deficiency is the major
impediment to the cost-effective use of ESAs. Conversely,
iron supplementation without ESA treatment is usually
unsuccessful, particularly in patients on hemodialysis.
For these reasons, most patients with advanced CKD
require concurrent ESA and iron administration to treat
CKD-associated anemia efficiently.
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Figure 4 | Microphotograph of bone marrow staining for
iron. Iron (blue) is located mainly in the macrophages
(arrow, lower left). Image courtesy of P. Beris, Athens
University, Greece.
The choice of iron therapy depends both on the stage
of renal disease and, if the patient is on dialysis, the
dialysis modality chosen. The use of intravenous iron
was avoided for nearly half a century as it was consid-
ered potentially dangerous, and its use was restricted to
patients who could not tolerate oral iron supplementa-
tion. This attitude changed with the advent of ESAs to
treat CKD-associated anemia, especially in patients on
hemodialysis. The introduction of various iron formula-
tions, such as the low-molecular-weight iron dextrans
ferrous gluconate and iron sucrose (also known as iron
saccharate), which are safer than the previously available
agent, high-molecular-weight iron dextran, has reduced
the clinician’s concerns for the risk of anaphylaxis. Except
among patients treated with high-molecular-weight
iron dextrans, which are still available, serious or life-
threatening adverse events of intravenous iron seem to
be rare.
The management of iron deficiency anemia in patients
with NDD-CKD is controversial, particularly with regard
to the use of oral versus intravenous iron supplementa-
tion. In practice, oral administration of iron (for example,
as iron sulfate, iron fumarate or heme) is preferred in
patients with NDD-CKD because of its convenience and
to avoid systemic adverse events such as hypotension or
anaphylactoid reactions.
Oral iron therapy
The primary source of iron in the diet is heme and its
absorption is efficiently regulated such that its accumula­
tion by the gut is prevented when iron is supplied in
excess.39 In patients with CKD, iron absorption seems
to be normal in the absence of any underlying gastric
or duodenal pathology,13 but ingestion of certain foods
and drugs can interfere with oral iron absorption.
Furthermore, absorption of iron salts, such as ferrous
sulfate, can be influenced both positively and negatively
by various amino acids.40 Iron salts should, therefore, be
taken on an empty stomach, although this practice might
increase gastric symptoms and hinder patients’ compli-
ance with therapy. Proton pump inhibitors that alter
REVIEWS
duodenal pH and the conversion of iron from Fe2+ to
Fe3+ also interfere with iron absorption. Other commonly
prescribed medications, such as calcium acetate, lantha-
num carbonate, and aluminum-containing ant­a cids
also impair iron absorption.
In the ESA era, oral iron supplementation should be
used whenever possible in patients with NDD-CKD
although on occasion intravenous iron will be needed
in those with ongoing slow blood losses caused by
disease or treatment with anticoagulant or antiplatelet
drugs. By contrast, an early study indicated that oral
iron supplementation was rarely successful in patients
on hemo­dialysis.41 In this study, the participants received
~200 mg of elemental iron daily for 6 months using one
of four iron preparations in conjunction with 100 mg
ascorbic acid. The group that achieved the highest trans­
ferrin saturation values (that is, >20%) during the study
period were those treated with ferrous fumarate. Another
double-­blind, placebo-controlled study evaluated the
efficacy of oral iron administration in 49 patients on
hemodialysis.42 Iron-replete patients randomly assigned
to oral iron supplementation showed signs of depleted
iron stores similar to that observed in patients assigned
to placebo. Oral (nonheme) iron is usually inadequate for
maintenance of iron stores in patients on hemodialysis,
but heme-containing polypeptides are of interest as they
could overcome some of the limitations of traditional
oral iron preparations.43 Ofalabi et al.44 compared the
efficacy of 200 mg per day iron fumarate versus 24 mg per
day heme-containing polypeptide and found no differ­
ences in either the efficacy or the profile of adverse effects
between the two treatments.44 In summary, no specific
oral iron preparation can be definitively recommended
over another.
The ineffectiveness of oral iron preparations in patients
on hemodialysis might result from problems with iron
incorporation into red blood cells. A small study (before
the advent of ESA therapy) in 14 patients on hemo­
dialysis compared the kinetics of an 59Fe isotope as well
as whole-body 59Fe counts following administration of
radiolabeled iron, either intravenously as iron dextran or
orally as iron sulfate.15 Following oral iron supplementa-
tion, iron absorption was normal (13% of dose) but the
time required to reach maximal red cell incorporation
was prolonged to 33 days.15
Intravenous iron therapy
Each intravenous iron product available obtained
approval for clinical use because it increased hemoglobin
levels better than oral iron supplements or controls. The
response of hemoglobin to intravenous iron is related to
the amount of iron administered, with 1 g of iron gener-
ally considered an adequate test of iron responsiveness.
Patients with adequate levels of iron who received peri-
odic intravenous iron supplementation maintained better
serum ferritin levels and had lower requirements for
ESAs than did patients who received no intra­venous iron
or just oral iron.45 In traditional inter­mittent (loading)
dose regimens, intravenous iron is given only when
transferrin saturation is <20% and/or serum ferri­t in
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levels fall to <450 pmol/l, with a subsequent pulse dose of
1 g iron, which is administered over the course of several
hemodialysis treatments.
In a summary of seven studies of presumably iron-
replete patients on hemodialysis, administration of a
weekly dose of intravenous iron increased hematocrit by
14% and reduced epoetin alfa dose by 38%.46 In another
study, administration of 6.25–21.3 mg of ferrous glucon-
ate at every hemodialysis session was more effective in
increasing hemoglobin and maintaining stable serum
ferritin levels than 62.5 mg of ferrous gluconate every
1–4 weeks.47 Different intravenous iron regimens have
been investigated in patients on hemodialysis—a ‘main-
tenance’ regimen of 25–100 mg of iron every 1–2 weeks
(to maintain transferrin saturation >20% and serum
levels of ferritin >450 pmol/l) versus a traditional ‘load
and hold’ regimen of intermittent repletion of 1 g of iron
(administered only when transferrin saturation was
<20% or serum ferritin levels were <450 pmol/l). Patients
who received the maintenance regimen required 50%
less ESAs overall than did those in the other group to
maintain the same levels of hemoglobin.10 Surprisingly,
the cumulative amount of iron needed over a 72-week
period was identical for the two regimens. When two
different threshold values for transferrin were used
(20–30% versus 30–50%), a further 40% reduction in the
ESA dose was achieved, although 2–3 times more iron
was transiently needed to achieve the higher of the two
transferrin values.11
In contrast with the 33 days needed for orally admin-
istered iron to reach maximal red blood cell incorpora-
tion alluded to above, the time to maximal red blood cell
incorporation for intravenous iron dextran was 8.6 days
(within the normal time frame of 4–10 days). 15 After
3 months of either oral or intravenous iron therapy in
patients on hemodialysis, hemoglobin levels remained
unchanged in the oral-therapy group whereas those in the
intravenous-therapy group increased.15 Intravenous iron
therefore seems to be better utilized than orally admin-
istered iron in patients on maintenance hemo­dialysis
who are not treated with ESAs. The use of ESAs should
magnify this difference. Whether regular supple­mentation
with oral iron could reduce the amount of intravenous
iron needed in ESA-treated patients is unknown.
Safety
Intravenous iron administration was viewed with appre-
hension in the pre-ESA era and as a consequence was
little used in the management of anemia in patients with
CKD. Before ESAs became available, the risk and conse-
quences of hemochromatosis as a result of blood trans­
fusion or iron administration to patients with anemia on
dialysis were frequently reported. To observe the effects
of hemochromatosis on parenchymal organs, serum
ferri­tin levels had to exceed 4,500–6,700 pmol/l, and were
commonly >11,300 pmol/l.48
The iron storage capacity of the reticulo­endothelial
system is ~5 g. The risk of iron overload increases
when transferrin saturation is persistently >50%, and
iron overload with parenchymal iron deposition is
 REVIEWS

a 25 – b 10,000 –

9,000 –

20 – 8.000 –

Serum ferritin level (pmol/l)

7,000–
Number of patients

15 – 6,000 –

5,000 –

10 – 4,000 –

3,000 –

5– 2.000 –

1,000–

0– 0–
0 200 2,000 20,000 200,000 Negative 1+ 2+ 3+ 4+
Ferritin (pmol/l) Hepatosplenic iron scores
Figure 5 | Serum ferritin level and reticuloendothelial iron accumulation in patients on hemodialysis treated for anemia with
blood transfusions in the pre-ESA era. a | Serum ferritin levels in 120 patients on maintenance hemodialysis.50 Only 15 of
patients had serum ferritin <100 pmol/l, the remaining patients had levels 2,250–45,000 pmol/l. Average iron overload was
8.8 g accrued over 3.6 years (the storage capacity of the reticuloendothelial system is ~5 g). Postmortem analysis showed
that 16 of 22 patients with serum ferritin levels >2,250 pmol/l had tissue that stained positive for iron; all had iron in the
reticuloendothelial system, one had iron in hepatocytes, and four patients had iron in cardiac myocytes. None had fibrosis.
b | Correlation of serum ferritin concentration with semiquantitative scores for hepatosplenic iron deposits in 36 patients on
hemodialysis.49 Reticuloendothelial staining for iron increases in proportion with serum ferritin concentrations. Hepatic iron
level had been maintained <22 mg/kg of body weight (the threshold that induces hepatic damage) even after 7–8 years of
repeated blood transfusions (data not shown). Risk of damage (fibrosis) from intravenous iron administration was low
(<20%), damage was mild, and only occurred in patients with a 4+ score of bone marrow iron. Median serum ferritin levels in
these patients was 5,620 pmol/l, markedly higher than the current recommended values of 1,120–1,800 pmol/l.
Abbreviation: ESA, erythropoiesis-stimulating agent. Permission for panel a obtained from Oxford University Press ©
Gokal, R. et al. Q. J. Med. 48, 369–391 (1979) and for panel b from Elsevier Ltd © Ali, M. Lancet 1, 652–655 (1982).

character­ized by very high serum ferritin levels (typi-
cally >4,494 pmol/l) and transferrin saturation >70%.49
Before the availability of ESAs, iron accumulation
occurred in patients with CKD on dialysis owing to
repeated blood transfusions. These patients typically
had serum ferritin levels >4,494 pmol/l (Figure 5), high
levels of iron in macrophages in the liver and spleen, but
very little parenchymal iron accumulation (in hepato-
cytes or cardiac myocytes).49,50 Only three of 16 patients
on dialysis with ferritin levels >2,247 pmol/l had iron in
parenchymal cells. By contrast, none had fibrosis and all
16 had abundant levels of iron in the reticuloendothelial
system.50 Moderately high levels of serum ferritin (that
is, ≤4,500 pmol/l) were not associated with excessive
iron storage in tissues in a postmortem examination of
indivi­duals who were on hemodialysis.51,52
However, all intravenous iron products can lead
to acute adverse reactions, which can be minor to life
threatening. The low-molecular-weight iron dextrans
seem to have a markedly lower incidence of associated
severe anaphylactoid reactions than high-molecular-
weight iron dextrans.53,54 Nevertheless, all such agents are
associated with life-threatening anaphylaxis. Ferric glu-
conate55 and iron sucrose56 have a reduced incidence of
anaphylactoid reactions, but can cause hypotension with
increasing doses. Consequently, these two iron prod-
ucts must be given as several divided doses to provide
1 g of iron, the standard dose needed to treat anemia.57
Ferumoxytol can be administered as a 510 mg injection,
with a second dose 3–7 days later.58,59 Ferumoxytol can
also occasionally cause anaphylactoid reactions. Phase
III trials of this drug in patients with CKD excluded
patients with iron allergies or more than two drug aller-
gies, as such patients seem to be at an increased risk of
severe drug reactions.58,59 Ferric carboxy­maltose can be
administered as a series of 200 mg injections, or as a 1 g
infusion.60 This last iron product is approved in Europe,
but not in the USA owing to safety concerns (because of
a high incidence of anaphylactoid reactions and deaths).
The FDA has requested additional safety data to be
obtained from clinical studies, which are presently being
conducted in the USA. Caution and careful monitoring
should, however, be used when administering any intra-
venous iron product and the risks of potential adverse
reactions should be balanced against the benefits.
Mechanisms of harm
The high level of oxidative stress present in most patients
with CKD on hemodialysis61 has been hypothesized to be
exacerbated by the administration of iron, and in particu-
lar intravenous iron. This hypothesis proposes that iron
administration at doses well below those associated with
parenchymal iron overload increases the risk of infec-
tions, cardiovascular events and death. Findings from
in vitro studies indicate that iron supplementation could
increase markers of oxidative stress.62 Early observa-
tional clinical studies associated iron administra­tion with
indices of cardiovascular disease63 or risk of death24 in

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© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
patients on hemodialysis. The redox balance could have
a substantial pathogenetic role in these processes through
the regulation of signaling pathways, gene expression, cell
proliferation and fibrosis. Oxidative stress is involved in
uremia-related inflammation64 and experimental evi-
dence indicates that labile iron might change the redox
state to produce increased oxidative stress.65 However,
interpretation of the contribution of intravenous iron
therapy to these processes is confounded by the observa­
tion that hemodialysis itself, even with so-called bio­
compatible membranes, produces an imbalance between
the production of reactive oxygen species and anti­oxidant
mechanisms.66 The observation by Drüeke et al.63 that
intima–media thickness of the common carotid artery
and wall-to-lumen thickness ratio were associated with
plasma levels of advanced oxida­tion protein products,
serum levels of ferritin and the annual intravenous iron
dose administered are hypothesis-generating only, and
provide no proof of causality.63 Although of interest, dis-
cussion of whether iron chelators could provide protection
against the effects of labile iron67 is premature.
Subsequent observational studies found that the
increased mortality in patients on hemodialysis was
largely linked to high serum ferritin levels,21 owing to the
confounding effects of malnutrition and inflammation.68
A low, rather than a high, serum iron level was strongly
associated with high mortality and hospitalization in
patients on hemodialysis. Similarly, high trans­ferrin
saturation values were associated with low mortality in
patients with NDD-CKD who were under the care of
the US administration’s Veterans Affairs department.69
Lastly, the relationship of iron use to death in patients
on hemodialysis occurs only at extremely high annual
doses of iron (that is, >4,800 mg per year), and can be a
manifestation of confounding by indication.68 Finally,
a 2009 observational study of 1,774 patients on main­
tenance hemodialysis who were followed up for 9.5 years
concluded that long-term survival was favorably affected
by indicators of iron sufficiency (serum ferritin level
>1,350 pmol/l and transferrin saturation >25%) and by
moderate iron administration.70
A number of randomized trials have assessed the safety
of iron administration in patients with CKD, but all are
of relatively short duration and small size compared to
the trials of ESA in this setting.71–75 In short-term studies,
single doses of iron sucrose (but not of ferric gluconate)
induced transient proteinuria in patients with NDD-
CKD, although the clinical relevance of this finding is
unknown.71 The DRIVE (Dialysis Patients’ Response
to Intravenous Iron with Elevated Ferritin) study,72 a
random­ized trial in which patients on hemodialysis (with
serum ferritin levels of 1,124–2,696 pmol/ml and trans-
ferrin saturation values ≤25%) were treated with high
doses of epoetin alfa (>30,000 U per week), found that
1 g of intravenous iron did not increase the risk of infec-
tion and resulted in reduced numbers of serious adverse
events compared with those who had no iron over the
3 months of observation. A 6-month, double-blind
trial of intravenous iron versus placebo in patients with
class II and III heart failure (according to the New York
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© 2011 Macmillan Publishers Limited. All rights reserved
Heart Association) included 41% of patients with an esti-
mated glomerular filtration rate <60 ml/min/1.73 m2.73
In these patients, intravenous iron improved symptoms,
functional capacity (as measured by a 6 min walking test)
and quality of life. Among the patients randomly allo-
cated to receive intravenous iron therapy, no increase in
the incidence of infections, hospitalizations, or deaths
was observed versus placebo. Trials have yet to find
definitive evidence to support the hypothesis that use
of intravenous iron is harmful in patients with CKD on
hemo­dialysis. Two large, randomized, ongoing trials will
address the important question of whether intravenous
or oral iron supplementation affects the progression of
renal dys­function in patients with CKD.74,75
Administration of ESAs can result in increased platelet
counts, because these agents can induce iron deficiency,
which has long been known to increase the platelet
count. The increased number of thrombovascular and
cardiovascular events associated with ESA therapy
might, in part, result from increased platelet counts.
Co-administration of iron would prevent this increase
and thus reduce the risk of thrombovascular and cardio­
vascular events. A randomized trial of iron in oncology
patients receiving ESAs found lower platelet counts and
a lower rate of thrombovascular events in patients treated
with iron supplementation than in patients who did not
receive this therapy.76 Streja et al.77 found that a high
platelet count was associated with low iron stores and
with prescription of high doses of recombinant human
erythropoietin in a large population of patients on
hemodialysis. Data from the DRIVE trial in patients
on hemodialysis indicated that platelet counts decreased
significantly in patients who received intravenous iron
(by a mean of 29,000 per μl, P = 0.017), but remained
unchanged in patients who were not given iron. Our
research group reported a mean decrease in the platelet
count of 50,000 per μl in patients with iron deficiency
who were not receiving dialysis and were being treated
with intravenous iron.78 Alternatively, thrombocytosis in
ESA-treated patients on hemodialysis might be mediated
by ESA rather than by iron deficiency.79 In patients with
normal kidney function who have iron deficiency, correc­
tion of the deficiency reduces the platelet count. This
reduction is associated with changes in levels of endo­
genous erythropoietin but not in levels of other platelet
cytokines, such as thrombopoietin, leukemia inhibitory
factor, interleukin 6 and interleukin 11. Obtaining data
on platelet counts from participants in large trials of
iron therapy for anemia would be of great interest and
would enable the relationships between platelet counts,
iron deficiency, intravenous iron administration and
cardiovascular events to be examined in detail.
Factors in the choice of iron therapy
Intravenous iron can produce a marked increase in the
hemoglobin level (to 120 g/l) of some patients with CKD
and iron-deficiency anemia, without ESA therapy.80 Some
patients with NDD-CKD who remain anemic despite
treatment with oral iron supplementation for 5–6 weeks
subsequently respond to intravenous iron therapy.58
 REVIEWS

Patients with NDD-CKD and anemia Patients with CKD and anemia on dialysis

Patients on hemodialysis Patients on CAPD

Do patients have an iron-replete state?
■ Transferrin saturation >25%
■ Serum ferritin level >225 pmol/l

Yes No

Treatment No treatment Maintenance iron therapy:

with ESAs with ESAs
Maintenance iron therapy:
■ To achieve transferrin saturation >30%
and serum ferritin level >450 pmol/l
■ Oral iron supplementation preferable
to intravenous iron
■ ‘Disguising’ oral iron therapy by
prescribing it in multivitamin formulation
increases patients’ adherence
■ Addition of decussate to oral iron
formulation decreases constipation
■ Intravenous iron supplementation is
more costly than oral iron therapy, but
the cost differential might decrease
over time because of the ESA-sparing
effect of intravenous iron therapy
■ Low-dose intravenous iron
(25–62 mg weekly)
■ Transferrin saturation maintained at
>25%
■ Stable serum ferritin levels at
450–1,800 pmol/l
■ Additional intravenous iron administered
to patients who require high ESA dose
or have a hemoglobin level that is
persistently below target
Maintenance iron therapy:
■ Relatively low ongoing blood losses
compared with patients on hemodialysis
■ Intravenous iron administration of
500 mg or 1 g of iron as a slow infusion
over 4–6 h maintains adequate levels
of hemoglobin for 6 months to 1 year
■ Alternatively, monthly doses of
100–250 mg iron can be administered
intravenously at each visit to the clinic

Patients on proton pump inhibitors, antiplatelet agents or anticoagulants usually

develop hyporesponsiveness to ESAs owing to iron deficiency
■ Administer cumulative dose of 1 g iron intravenously
■ Low-molecular-weight dextran as a single 500 mg or 1 g dose infused over 1.5–4 h
■ Patients monitored in clinic
■ Patients with ongoing gastrointestinal bleeding might require up to three 1 g infusions
of iron per year

Figure 6 | A treatment algorithm for the management of anemia in patients with CKD. Clinical decision support systems are
used within the Henry Ford Health Care System and patients with NDD-CKD and anemia are treated according to a
computerized anemia-management program. Abbreviations: CAPD, continuous ambulatory peritoneal dialysis; CKD, chronic
kidney disease; ESA, erythropoiesis-stimulating agent; NDD-CKD, nondialysis-dependent CKD.

A meta-analysis of studies published between 1970 and
200981 concluded that iron supplementation was advis-
able for all iron-deficient patients with CKD who were
receiving ESA therapy—consistent with FDA recom-
mendations. Another meta-analysis identified 13 trials
(6 of which included patients with CKD and 7 of which
included patients on hemodialysis) in which compari-
sons of efficacy and safety assessments were made over a
period of up to 2 months.60 In patients on hemodialysis,
those treated with intravenous iron therapy had consider­
ably greater hemoglobin levels than those treated with
oral iron (weighted mean difference, 8.3 g/l). Increases in
the hemoglobin level were positively associated with the
dose of intravenous iron. For patients with CKD, a sub-
stantial difference (but smaller than that observed with
patients on hemodialysis) in hemoglobin level favored
the intravenous iron group (weighted mean difference
3.1 g/l). Although data for all-cause mortality were
sparse, no differences in adverse events were observed
in the groups of patients who received intravenous iron
versus oral iron. In each of four randomized trials that
included patients with NDD-CKD who were not treated
with ESAs, the hemoglobin response was greater with
intravenous than with oral iron.60 Iron supplementation
can avoid or delay the need for ESA therapy in some
patients with NDD-CKD.82
The amount of iron required to maximize the hemo-
globin response and repletion of iron stores can only be
estimated by the severity of anemia, taking into account
indications of whether iron stores are low. Patients
should receive the amount of iron needed to correct the
red blood cell mass, usually as 75–125 mg intravenous
weekly doses, until the desired total amount is given. We
calculate the amount of iron required on the basis that
1 mg of iron is needed to achieve each 1 ml increase in the
amount of packed red blood cells. The increase in packed
red blood cells is estimated from the starting and target
hematocrit and the estimated blood volume of the patient
(70–80 ml/kg body weight). Thus, the required amount
in mg of iron is calculated as (desired hematocrit–­initial
hematocrit) × 75. Using this calcula­t ion, therefore,
750 mg of iron would be needed to obtain an increase
in the patient’s hematocrit from 24% to 34%. In patients
who are iron depleted, additional iron is need to account
for ongoing blood losses occurring during the period of
correction (about 3 months), estimated as 600–700 mg.
When the total amount of iron required exceeds 1 g,
iron replenishment is best achieved by administration
of 100–125 mg of iron three times a week. Patients’ iron
status and levels of serum ferritin and transferritin
must be monitored at monthly intervals to enable the
cost-effective management of anemia with epoetin alfa.

NATURE REVIEWS | NEPHROLOGY VOLUME 6  |  DECEMBER 2010  |  707

© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS

In the Henry Ford Health Care System, clinical deci-
sion support systems are used to provide treatment
recom­mendations for an individual patient. In particular,
patients with NDD-CKD and anemia are treated accord-
ing to a computerized anemia-management program.83
Longitudinal data on patients’ transferrin saturation and
serum ferritin levels are entered into this program,
and used to direct their treatment (Figure 6).
Novel methods of iron delivery
New preparations that permit rapid, high-dose
administra­t ion of iron could change the outpatient
management of iron deficiency anemia. In a random-
ized study, a single 15 min injection of ferric carboxy­
maltose, repeated up to twice if required, resulted in
53.2% of patients with NDD-CKD achieving a ≥10 g/l
increase in hemoglobin level by day 56 without ESAs,
compared with only 29.9% of patients who were given
oral iron supple­ments.84 Administration of two 510 mg
ferumoxytol injections about 1 week apart increased the
mean hemoglobin level by 10 g/l compared with a <2.0 g/l
increase in hemoglobin levels in patients randomly
assigned to receive oral iron supplementation.85
Administration of iron via the dialyzate during each
hemodialysis session is also undergoing testing. In a
preliminary 6‑month study of stable patients on hemo­
dialysis, soluble ferric pyrophosphate (a chelated iron)
added to the dialyzate readily diffused into the blood
compartment and was safe and effective.86
Occasionally, patients clearly have adequate iron
stores but respond poorly even to large ESA doses. In
such circumstances, several options exist. Ascorbic
acid (500 mg) administered intravenously after dialysis
1–3 times weekly can mobilize tissue iron stores.87 The
patients’ serum ferritin levels remained unchanged with
this treatment, but their transferrin saturation increased
from 27% to 54% and their hematocrit increased from
27% to 32%. As ascorbic acid is metabolized to oxalate,
which is removed poorly by dialysis, we recommend
that no more than 300 mg be administered three times
a week. Findings from another study in patients with
high ESA requirements showed that administration of
300 mg of ascorbic acid with each dialysis treatment
over 6 months increased hemoglobin levels and reduced
C‑reactive protein levels from 190 nmol/l to 95 nmol/l.
A trend towards decreased levels of serum ferritin was
also evident in the treated group, whereas hemoglobin
and iron parameters remained unchanged in the control
group.88 In another study, patients with iron overload
but not aluminum overload were treated with desferri­
oxamine mesilate.89 The dose of epoetin alfa required
decreased dramatically from 400 U/kg to 25 U/kg and
hemoglobin levels increased to 110 g/l.89
Conclusions
Neither any specific value for transferrin saturation nor
the upper limit for serum ferritin levels (<2,700 pmol/l)
can assure adequate delivery of iron to the erythron
during ESA therapy. Suboptimal responses to ESA
therapy are commonly caused by the failure to supply
adequate amounts of iron. This functional iron defi-
ciency can only be discerned by a response to challenge
with intravenous iron therapy. The decision to use intra-
venous iron therapy versus oral iron supplementation
should be made on the basis of the individual patient’s
overall condition. If the benefits outweigh the risks, a
trial of intravenous iron therapy might be warranted.
The typical patient who merits a trial of intravenous iron
supplementation is without evidence of active infection
and has a history of failure to achieve target hemoglobin
levels despite administration of large doses of ESA.
Review criteria
We searched PubMed for papers in the English language
published between 1970 and June 2009. Search terms
included “iron metabolism” and “chronic kidney disease”.
Only full-text papers were chosen for discussion in this
Review. Our extensive collection of papers was also
searched for further suitable articles.

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Author contributions
A. Besarab and D. W. Coyne contributed equally to all
aspects of this manuscript.
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CORRECTION
Iron supplementation to treat anemia in patients with chronic
kidney disease
Anatole Besarab & Daniel W. Coyne
Nat. Rev. Nephrol. 6, 699–710; doi:10.1038/nrneph.2010.139
In the version of this article initially published online and in print, incorrect volume and
page numbers were given for reference 90. The correct reference is Sargent, J. A. &
Acchiardo, S. R. Iron requirements in hemodialysis. Blood Purif. 22, 112–123 (2004).
The error has been corrected for the HTML and PDF versions of the article.

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