Hemodialysis International 2017; 21:S125–S131

Scholarly Review

Clinical practice guidelines on iron

therapy: A critical evaluation

Lucia DEL VECCHIO, Francesco LOCATELLI

Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco, Italy

Abstract
Anemia is common among patients with chronic kidney disease (CKD) and it is managed primarily
with erythropoiesis-stimulating agents (ESA) and iron therapy. Following concerns around ESA ther-
apy and economic constraints, IV iron is more and more administered worldwide.
Several guidelines or position papers, which give indications on iron therapy in CKD patients, have
been issued in Nephrology. Unfortunately, the field is characterized by a lack of evidence. As a
result, the recommendations/suggestions are not uniform.
There is general consensus to prescribe iron therapy to patients who are clearly iron deficient. In
addition, iron therapy may increase Hb values, delay the start of ESA therapy in ESA-na€ıve patients
and reduce ESA dose in ESA-treated patients. However, there is debate on the safety and efficacy of
IV iron therapy when given in the presence of already high serum ferritin levels. In addition, not all
the guidelines/position papers differentiate between non-dialysis/dialysis patients and between the
presence/absence of ESA therapy. Many international Bodies or Societies suggest caution when
administering IV iron during infections. A trial of oral iron should be considered as a first step,
especially in the ND-CKD population. Finally, recommendations on the prevention of anaphylactic
reactions following IV iron therapy are given by several bodies. There is consensus that IV iron is
to be administered in the presence of resuscitative facilities (including medications) and personnel
trained for emergencies.

Key words: Iron, chronic kidney disease, erythropoiesis stimulating agents, guidelines, anaphy-
laxis

Correspondence to: F. Locatelli, Department of Nephrology
and Dialysis, Ospedale Alessandro Manzoni, ASST Lecco,
Via dell’Eremo 9/11, 23900 Lecco, Italy. E-mail: f.locatelli@
asst-lecco.it
Conflict of Interest: Prof. Francesco Locatelli is a member of
Advisory Board of Akebia, Amgen and Astellas and was
speaker at meeting supported by Asta-Zeneca, Roche and
Vifor-Fresenius Medical Care. Dr Lucia was member of Advi-
sory Boards for Roche and Astellas and received honoraria
from Takeda and was speaker at a meeting supported by
Vifor-Fresenius Medical Care.
Disclosure of grants or other funding: None.
INTRODUCTION
Anemia is common in patients with chronic kidney dis-
ease (CKD); functional or absolute iron deficiency often
play a significant role. The treatment with erythropoiesis
stimulating agents (ESA) also increases the need of iron
for hemoglobin (Hb) synthesis.
On the wave of the findings of the Trial to Reduce Car-
R
diovascular Events with AranespV Therapy (TREAT)
study1 and of economic constraints,2 iron therapy has
been used more and more in both the non-dialysis (ND)
and dialysis CKD population.
In this paper, we will compare and discuss the
suggestions/recommendations of several international

C 2017 International Society for Hemodialysis

V
DOI:10.1111/hdi.12562
S125
Del Vecchio and Locatelli

Table 1 Indications to iron therapy in CKD patients

Organization Indication to iron therapy Upper limits
7
KDIGO, 2012 ESA-na€ıve and ESA therapy Serum ferritin 500 ng/mL
TSAT 30%
 Serum ferritin <500 ng/mL
 TSAT <30%
ERBP,8 2013 ESA-na€ıve Serum ferritin 500 ng/mL
TSAT 30%
 CKD-ND
Serum ferritin 500 ng/mL
 Serum ferritin <200 ng/mL TSAT 30%
 TSAT <25%
 CKD-5D
 Serum ferritin <300 ng/mL
 TSAT <25%
ESA therapy
 CKD all stages
 Serum ferritin <300 ng/mL
 TSAT < 30%
KDOQI,13 2013  CKD all stages None (if high ferritin, weigh potential
risks and benefits of persistent
 Serum ferritin <500 ng/mL
anaemia, ESA dosage, comorbid
 TSAT <30%
conditions, and health-related
quality of life)
Canadian Guidelines,14  CKD all stages None
2013
 Serum ferritin <500 ng/mL
 TSAT <30%
NICE,11 2015  CKD all stages Serum ferritin 500–800 ng/mL
 Serum Ferritin <200 ng/mL
 TSAT <20% (unless ferritin >800 ng/mL)
 %HRC less than 6% (unless ferritin
CARI,9 2013  Serum Ferritin <200 ng/mL Serum Ferritin 1200 ng/mL
 TSAT <20% TSAT 30%

organizations or bodies on iron therapy in CKD patients
(Table 1).
THE PLANET OF INTERNATIONAL
GUIDELINES ON ANEMIA TREATMENT
As for other specialties, several guidelines have been
issued in nephrology. Unfortunately, the grade of the
available evidence is often suboptimal.3 Even when the
evidence is of high grade, its interpretation may differ.
Even though all the guidelines start from the same
evidence, they can give conflicting recommendations or
suggestions. Thus, there is room for expert opinions. This
is particularly true for iron therapy, since it is cheap and
has been used for decades in CKD patients, well before
the introduction of evidence-based medicine.
The first nephrological guidelines on anemia were
issued in 1997 from the “Dialysis Outcomes Quality Ini-
tiative” (DOQI).4 The initiative was then extended to all
CKD patients (the Kidney Disease Outcomes Quality Ini-
tiative [KDOQI]). On the wave of the US experience, the
European Renal Association-European Dialysis and Trans-
plant Association (ERA-EDTA) started its own program:
the European Best Practice Guidelines (EBPG). The first
EBPG guideline on anemia treatment were published in
1999.5
Considering the huge organizational and economic
effort that is necessary to produce and update guidelines,

S126 Hemodialysis International 2017; 21:S125–S131


the nephrological community planned a single set of
international guidelines under the aegis of Kidney Disease
Improving Global Outcomes (KDIGO).6 In 2012, KDIGO
published a set of guidelines on anemia treatment in CKD
patients.7 In 2015, KDIGO organized a conference that
discussed controversies on iron therapy in CKD patients.8
Moving forward, the ERA-EDTA agreed to issue only
suggestions for clinical practice in areas in which evidence
is lacking or weak, together with position statements
about existing guidelines. The European Renal Best Prac-
tice (ERBP) was then created.3 In 2013, the ERBP Work-
ing Group on Anaemia produced a position statement on
KDIGO guidelines9; among the covered points, iron treat-
ment, and markers of iron stores were largely discussed.
The Caring for Australasians with Renal Impairment
(CARI) was started in 1999. It is distinguished by a strong
methodological support, thanks to more than 100 experts
who have been directly formed by CARI over the years.
Caring for Australasians with Renal Impairment collabo-
rates with the KDIGO initiative, but it is still producing
and updating its own set of guidelines. Its last recommen-
dations on iron therapy goes back to July, 2013.10
The National Institute for Health and Clinical Excel-
lence (NICE) is an independent organization, which is
located in the United Kingdom. The topic of interest of
guidelines are proposed by the Ministry of Health; several
national bodies representing patients or caregivers can
also be involved and asked for advice. National Institute
for Health and Clinical Excellence published and updated
several guidelines on anemia treatment.11,12 A review is
planned in June, 2017.
Also the Canadian Society of Nephrology has its own
set of guidelines. They were first published in 1999.13
The majority of their recommendations are based on the
analysis of the evidence made by other bodies (mainly in
the United States). However, they hold an independent
interpretation of the evidence.
Both KDOQI14 and the Canadian Society of Nephrolo-
15
gy wrote a commentary on KDIGO recommendations.
HOW TO DEFINE IRON DEFICIENCY
OR EXCESS: SERUM MARKERS
Currently, the markers of iron metabolism most used
worldwide are serum iron, transferrin saturation (TSAT)
(or total iron binding capacity), and serum ferritin.
Their sensibility and sensitivity are far from being opti-
mal,16 since they are influenced by many confounders. In
particular, they are affected by malnutrition and inflam-
mation, which are both frequently observed in CKD
Hemodialysis International 2017; 21:S125–S131
Clinical practice guidelines on iron therapy
patients. Moreover, they have diurnal variations17; in dial-
ysis patients, the timing of blood collection may then
influence obtained data. However, they are cheap and
easy to measure.
Other, more sophisticated markers have been proposed
over the years. However, they are either more expensive
or more complex to interpret. As a consequence, they
have not entered in depth clinical practice. Hepcidin,
which is the main mediator of iron homeostasis, is still
employed only for research purposes.
At present, all the nephrological guidelines use serum
iron, TSAT (or total iron binding capacity) and serum fer-
ritin to guide indications to iron therapy. In this respect,
NICE guidelines stand out from the other bodies. In their
last update, they recommend to use as the first choice the
percentage of hypochromic red blood cells (% HRC) (iron
deficiency if more than 6%), but only if processing of
blood sample is possible within 6 hours.13 If the testing
of HRC is not available, the use of the reticulocyte hemo-
globin content (CHr) (less than 29 pg for iron deficiency)
or the reticulocyte Hb equivalent are suggested. The use
of the combination of serum ferritin and transferrin satu-
ration is left only if the patient has thalassemia or thalasse-
mia trait, or the other two tests are not available.
In the absence of clinical trials that specifically tested
the optimal frequency for testing iron status, KDIGO
guidelines suggest to evaluate iron status at least every 3
months during ESA therapy.7 The recommendation is not
graded. Considering that iron deficiency is an important
cause of ESA hyporesponsiveness,18,19 NICE guidelines
suggest to test iron deficiency more often than every 3
months in people receiving hemodialysis (HD) (even once
a month).13 The same suggestion is given by CARI
guidelines.11
INDICATIONS TO IRON THERAPY
In the last decade, indications to iron therapy have broad-
ened. The findings of the TREAT study not only under-
lined possible risk of ESA therapy when aiming at
complete anemia correction, but also showed that iron
therapy can increase Hb levels and stabilize anemia delay-
ing the start of ESA therapy (at least in the ND-CKD pop-
ulation).20 Similarly, Stancu et al.17,21 showed that some
patients with adequate intra-marrow iron stores can
obtain an increase of Hb levels following IV iron
administration.
More recently (i.e., after the publication of KDIGO
guidelines7 and the related ERBP position statement9), the
R
FerinjectV assessment in patients with Iron deficiency
anaemia and non-dialysis-dependent chronic kidney
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Del Vecchio and Locatelli
disease (FIND-CKD) trial22 showed that targeting high
ferritin levels (400–600 ng/mL) with intravenous (IV)
iron therapy can reduce the need for other anemia man-
agement including ESAs (see below the chapter IV vs.
oral iron therapy).
Consequently, iron therapy is now prescribed not only
to those patients who are clearly iron deficient, but also as
a tool to increase Hb values. In ESA-na€ıve patients this
may avoid or delay the start of ESA therapy. In ESA-
treated patients it can either increase Hb levels or reduce
ESA dosage.
There is general consensus on these theoretical princi-
ples, as there is uniform consensus to prescribe iron ther-
apy in patients with absolute iron deficiency (i.e., serum
ferritin < 100 ng/mL and TAST < 20%) and anemia,
whether or not on ESA therapy. Conversely, no clear indi-
cations are available for the minority of the patients who
are iron deficient but have normal Hb levels without ESA
therapy. In addition, there is a lively debate on the upper
levels of ferritin and TSAT at which start or stop iron
therapy.
KDIGO guidelines recommend iron therapy for a broad
range of values of serum ferritin and TSAT (500 ng/mL
and 30%, respectively).7 The recommendation is the
same for patients who are on ESA therapy or are ESA
na€ıve and independently from the CKD status (ND vs.
dialysis patients). Due to the lack of evidence for the top-
ic, the strength of the recommendation is low (the guid-
ance is suggested, but not strongly recommended, and
the evidence to support is weak or contradictory). They
also suggested the possibility of a single course of IV iron
therapy for dialysis patients receiving ESA with serum fer-
ritin >500 ng/mL after due consideration of potential
acute toxicities and long-term risks. Canadian Guidelines
generally endorse this recommendation.16 KDOQI gener-
ally accepted the KDIGO recommendation.15
ERBP did not go along with the KDIGO recommenda-
tion for a number of reasons.10 First, the proposed limits
of serum ferritin and TSAT were considered too wide.
Indeed, the upper limit of serum ferritin and TSAT for
iron prescription is the same as the limit that should not
be exceeded. Another criticism is that the strength of the
recommendation does not take into account the degree of
iron deficiency. Indeed, the likelihood to obtain an
increase in Hb level following iron therapy is higher in
those with absolute iron deficiency. Conversely, in the
patients with adequate bone marrow iron stores, the
chance to obtain an increase in Hb level is lower. More-
over, in those who are ESA na€ıve, without iron deficiency
and contraindications to ESA, the start of ESA therapy
may be more effective than iron. A distinction should also
S128
be made on CKD status, since ND-CKD patients are more
likely to obtain an increase of Hb following iron therapy
in the absence of ESA.
Altogether, in ESA na€ıve patients ERBP suggested a trial
of iron therapy in the presence of absolute iron deficiency
or to obtain an increase in Hb concentration without
starting ESA only when TSAT is <25% and ferritin is
<200 ng/mL (< 300 in dialysis patients).10 For those
who are already on ESA, iron therapy is suggested if
TSAT is <30% and ferritin is <300 ng/mL.10 In HD
patients, a course of IV iron therapy can be considered in
those having higher serum ferritin levels in the presence
of hyporesponsiveness to ESA or a risk/benefit ratio going
against ESA use.10
CARI guidelines mostly give indications on iron thera-
py for ESA-treated patients. Before starting ESA, serum
ferritin and TSAT should be higher than 100 ng/mL and
20%, respectively.11
THE UPPER LIMIT OF IRON SERUM
MARKERS TO NOT BE EXCEED
FOLLOWING IRON THERAPY
At present no clear evidence has demonstrated an upper
limit for ferritin level that can be considered either safe or
dangerous. However, several observational data indicate
that very high ferritin levels and excessive iron therapy
can be associated with poor outcome.23,24 Unfortunately,
association studies are biased by the fact that serum ferri-
tin is also a marker of inflammation and by treatment
indications. Other data showed signs of iron overload in
those with high ferritin levels.25,26 Many HD patients now
exceed the upper limits of serum ferritin suggested by
several guidelines, especially in the United States.27 It is
unknown whether this is due to excessive iron use,
decrease ESA dosage and thus less erythropoiesis, or
both.28
KDIGO recommends to not exceed a TSAT of 30% and
serum ferritin of 500 ng/mL during iron therapy, inde-
pendently of CKD status and ESA use (but the descriptive
chapter says that, one the basis of the findings of the Dial-
ysis Patients’ Response to IV Iron with Elevated Ferritin
(DRIVE) trial,29,30 a single course of IV iron therapy could
be considered for dialysis patients on ESA with serum fer-
ritin >500 ng/mL).7 KDOQI is in agreement with the
KDIGO recommendation.15
ERBP does not fully agree with the interpretation of the
evidence made by KDIGO and thus with its recommenda-
tions.10 The safety and efficacy of administering IV iron to
ESA-na€ıve HD patients with high serum ferritin levels has
Hemodialysis International 2017; 21:S125–S131

not been established. The fact that KDIGO guideline indi-
cates the possibility of administering iron therapy even in
patients who already have high serum ferritin levels
(around 500 ng/mL) certainly has contributed to a signifi-
cant rise in ferritin levels in the CKD population, especial-
ly in the HD setting, shifting to the right the distribution
curve. Altogether, ERBP confirmed the same upper limits
as KDIGO, suggesting caution in exceeding a ferritin value
of 500 ng/mL when TSAT is adequate (>30%).10
According to NICE guidelines serum ferritin levels
should not rise above 800 ng/mL in people treated with
iron.13 To prevent this, the dose of iron should be
reviewed when serum ferritin levels reach 500 ng/mL. No
differentiation is made on CKD status and ESA use. Of
note, the recommendation dates 2006.
Finally, CARI and Canadian guidelines gave even a
higher limit for serum ferritin. Indeed, CARI indicates a
ferritin range of 200 to 500 ng/mL and a TSAT 20% to
30% as optimal targets for iron therapy during ESA use
and to reduce iron dose when serum ferritin exceed 500
ng/mL.11 However, it remarks that ferritin levels 1200
ng/mL have shown no sign of toxicity in short-term stud-
ies. Again, no differentiation is made on CKD status and
no recommendation is given for ESA-na€ıve patients.
According to Canadian guidelines, the current evidence
does not permit a clear delineation for an upper limit of
TSAT or ferritin levels (even if a significant rise in Hb lev-
els is less likely when serum ferritin exceeds 500 ng/mL
and TSAT  30%).16
There is a common believe that research to evaluate the
long-term safety of iron administration is needed, espe-
cially in patients with high serum ferritin levels.
ORAL VS. INTRAVENOUS IRON
ADMINISTRATION
There is wide consensus that IV iron is more effective
than oral iron in HD patients. This is probably true also
in ND-CKD patients.18,31,32 Due to a lack of evidence, no
guidelines has systematically considered the utility of new
oral iron molecules, which are possibly better absorbed
by the gastro-intestinal tract with fewer side effects. Simi-
larly, none of the guidelines have considered specifically
the efficacy and utility of new IV iron molecules, which
allow the administration of a high iron dose in a single
administration in ND-CKD patients.
International guidelines differ on the strength given to
the choice of the administration route. Compared to the
others, ERBP puts more emphasis on the use of oral iron
as a first step in ND-CKD patients to preserve the veins of
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Clinical practice guidelines on iron therapy
the arm for a future dialysis access.10 On the contrary,
CARI guidelines indicate parenteral iron as a preference
in all CKD patients.11
IRON THERAPY AND INFECTIONS
Iron is essential for bacterial growth in the host, especially
for intracellular microorganisms. Accordingly, the human
body has developed mechanisms of defense for withhold-
ing iron from microorganisms. For this reason, there is
the fear that free iron in the circulation may enhance bac-
terial growth.33 Some studies have suggested that iron
excess could also impair neutrophil and T-cell function,
reducing body’s defenses.34,35 The issue is of importance,
considering that many patients with acute infections are
prescribed IV iron because they have developed function-
al iron deficiency secondary to infection.
Unfortunately, few data exist relating IV iron adminis-
tration and infection risk in CKD patients, with conflict-
ing results.36–40 Given that the evidence relating IV iron
with increased infection risk is scanty, available guidelines
gave little or no room to the topic.
KDIGO guidelines suggest to avoid administering IV
iron to patients with active systemic infections (not grad-
ed).7 In the single patient the severity of an infection
should be considered together with an immediate need
for IV iron (as opposed to delaying treatment until resolu-
tion of an infection). European Renal Best Practice had no
major comments on this KDIGO suggestion, implying its
agreement.10 Similarly, the Canadian Society of Nephrolo-
gy gave its approval to the KDIGO suggestion. In the lack
of clear evidence on the risk of IV iron administration
during active infections, KDOQI does not make any rec-
ommendation about the use or avoidance of IV iron in
the setting of infection, leaving to the clinician the final
judgment of pro and contra.15
RECOMMENDATIONS ON THE
MANAGEMENT OF ANAPHYLACTIC
REACTIONS
Following IV iron administration, rare but severe anaphy-
lactic reactions have been described for decades. The risk
was higher for certain types high-molecular weight iron
dextran. However, no iron molecules are without risk, as
stated in 2013 by the European Medicines Agency
(EMA).41 This rare adverse event should always been bal-
anced with the awaited benefits of IV iron therapy.
Patients with known allergies, immune, or inflammatory
conditions and with a history of severe asthma, eczema, or
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Del Vecchio and Locatelli
other atopic allergy are at increased risk of hypersensitivi-
ty. Furthermore, IV iron medicinal products should be
contraindicated in patients with history of hypersensitivity
reactions to the active substance or any of the excipients of
these products. According to this official position, iron
preparations should be given only in an environment
where resuscitation facilities are available, so that patients
who develop an allergic reaction can be treated immediate-
ly. Patients should be close monitored for signs of hyper-
sensitivity during and for at least 30 minutes after each
administration of IV iron. The same recommendation is
given by the Food and Drug Administration (FDA).
Conversely, KDIGO, KDOQI, and Canadian Guidelines
suggest to monitor the patient for 60 minutes after the
infusion of the initial dose of IV iron only and that resus-
citative facilities (including medications) and personnel
trained to evaluate and treat serious adverse reactions
should be available. European Renal Best Practice position
paper did not give any suggestion on this topic (it was
published before the EMA official position).
Manuscript received March 2017; revised March 2017.
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