JRSSEM 2022, Vol. 02, No. 3, 328 – 336
E-ISSN: 2807 - 6311, P-ISSN: 2807 - 6494
DOI : 10.36418/jrssem.v2i03.276 https://jrssem.publikasiindonesia.id/index.php/jrssem
IRON THERAPIES FOR IRON DEFICIENCY IN CHRONIC
KIDNEY DISEASE: A LITERATURE REVIEW
Zhela Fatin Fatiha, Nining Lestari, Aulia Nissa Rizky Hariyono, Tia Mella Citra, Ayu
Mayangsari, Tri Agustina
Department of Medicine, Faculty of Medicine, University of Muhammadiyah Surakarta, Indonesia
*
e-mail: j500190007@student.ums.ac.id, [email protected].id, j500190026@student.ums.ac.id,
*Correspondence: j500190007@student.ums.ac.id,
Submitted
: 07 October 2022
Revised
: 18 October 2022
Accepted
: 25 October 2022
Abstract : Chronic kidney disease is a condition when kidney function fails gradually due to
kidney damage. One of the causes of anemia in CKD is iron deficiency. Conventional oral iron
treatment is not effective to treat iron deficiency anemia due to poor absorption and various
side effects. Newer oral iron therapies with better tolerability and offer the potential to
normalize iron without the need for intravenous iron. To review the currently available status
oral iron therapies and summarizes the latest clinical trial evidence for their use. We researched
Google Scholar and PubMed using keyword "iron" OR "ferri" OR "Ferro" OR "iron therapy" AND
"Iron deficiency" AND "renal insufficiency, chronic" OR "chronic kidney disease" OR "kidney
failure, chronic" OR "chronic renal disease" of last ten years. Total 8 articles recorded the
identification stage by the criteria for inclusion. The articles are randomized controlled trials.
Total 2.674 patients CKD of various types with or without anemia, age range 18-72 years were
treated with oral iron therapies (ferric citrate, ferrous sulfate, sucroferric oxyhydroxide, ferric
carboxymaltose) with varying doses. The most side effects of the therapies are gastrointestinal
intolerance. Oral iron therapies are considered safe but drug development is still needed to
minimize side effects.
Keywords: iron deficiency;iron treatment;chronic kidney disease.
Zhela Fatin Fatiha, Nining Lestari, Aulia Nissa Rizky Hariyono, Tia Mella Citra, Ayu Mayangsari,
Tri Agustina |329
INTRODUCTION
Chronic Kidney Disease is a chronic
condition decline in kidney function that
takes for months to years. Chronic disease
affects up to 13% of adults and the most
common complication is anemia and
markedly increases the risk of early
cardiovascular events and death. A
common complication of CKD is iron
deficiency. Iron deficiency is an important
factor in the pathogenesis of anemia in
patients with chronic disease not
dependent on dialysis (ND-CKD). Iron
deficiency affects 60% of men and 70% of
women with ND-CKD. Anemia is a
condition in which the level of hemoglobin
in the blood is reduced. Anemia can be
caused by a variety of pathological and
physiological reactions. Iron deficiency
anemia is anemia caused by reduced levels
of iron needed for Hb synthesis (Block et al.,
2015); Kapoh et al., 2021).
Identification of iron deficiency
requires prompt assessment of diet,
obvious or hidden causes of blood loss, and
drugs that may interfere with iron
absorption, and iron supplementation in
most cases. Clinical practice guidelines
recommend that levels of people with CKD
and anemia with hemoglobin, 13.0 g/dL for
men, and 12.0 g/dL for women are treated
with iron rather than erythropoiesis-
stimulating agents (ESAs) to increase
hemoglobin if saturation is present
transferrin (TSAT) 30% and serum ferritin
level 500 mcg/L. However, ESAs themselves
have a considerable side (Macdougall et al.,
2017).
Iron therapy is the first choice of
therapy for anemia in CKD patients
diagnosed with iron deficiency, and in some
patients with normal Hb levels without
epoetin therapy. Combination of iron and
epoetin therapy is required to stimulate
iron deficiency. The principle of iron
deficiency treatment is to find out the
causative factors, overcome and provide
therapy with iron preparations that are
given orally and parenterally. Oral therapy
is safer, cheaper, and has the same efficacy
as parenteral therapy (KDIGO, 2013; NKF
KDOQi, 2006; (Kapoh et al., 2021).
The most commonly used
supplements but offer oral therapy is not
very effective. However, ferrous sulfate has
been shown to be relatively effective in
increasing iron and hemoglobin
concentrations in individuals with CKD and
does not require dialysis, but the effect of
oral iron supplementation on FGF23 is less
clear, especially in patients with Chronic
Kidney Disease. In addition to sulfate,
citrate can also be used. However, it is not
clear whether iron citrate is more effective
in reducing FGF23 in CKD patients by
increasing circulation to restrict absorption
of phosphate when compared to ferrous
sulfate (Womack et al., 2020).
MATERIALS AND METHODS
This study is a literature review study
using the PRISMA (Preferred Reporting
Items for Systematic Reviews and Meta-
Analysis) method in CKD (chronic kidney
disease) patients who were given oral iron
therapy to determine iron status based on
330 | Iron Therapies For Iron Deficiency In Chronic Kidney Disease: A Literature Review
parameters of changes in iron status values.
This research article was searched on
PubMed and Google Scholar with a
limitation of the last 10 years and then
collected in Microsoft Excel. We conducted
an electronic literature search on Google
scholar and PubMed. The keywords used
are "iron" OR "ferri" OR "Ferro" OR "iron
therapy" AND "Iron deficiency" AND "renal
insufficiency, chronic" OR "chronic kidney
disease" OR "kidney failure, chronic" OR
"chronic renal disease".
The inclusion criteria in this study were
oral iron therapy in CKD patients who had
anemia due to iron deficiency. There are no
restrictions on age, gender, ethics, race and
country. All articles are RCTs (randomized
controlled trial) in English and Indonesian.
RESULTS AND DISCUSSION
This review uses the PRISMA (Preferred
Reporting Items for Systematic Reviews and
Meta-Analysis) method. The inclusion
criteria for this type of article are RCT
(randomized controlled trial), oral iron
administration in CKD patients with iron
deficiency and the search limitation of the
last ten years. A search for "iron deficiency,
iron treatment, chronic kidney disease"
total 3358 returns 997 articles on Google
Scholar, 2361 on PubMed. The study results
that have been obtained and screened
based on inclusion and exclusion criteria.
Then remove duplication (n: 3304), title
screening (n:280), abstract screening (n:
81), then the full text screening used as the
final result is 8 articles.
Figure 1. Prisma Diagram
Table 1. Study Characteristics
Records identified total 3368
from:
Google Scholar (n = 997)
PubMed (n = 2361)
Records removed before
screening:
Duplicate records removed
(n = 64)
Records screened through the
title (n = 280)
Records excluded (n = 3024)
Reports assessed for eligibility
(n = 8)
Reports excluded: (n = 73)
1. Articles not a RCT
2. Inclusion criteria doesn’t
match
Studies included in review
(n = 8)
Identification
Screening
Included
Zhela Fatin Fatiha, Nining Lestari, Aulia Nissa Rizky Hariyono, Tia Mella Citra, Ayu Mayangsari,
Tri Agustina |331
No
Author
Tittle
Location
Year
1
Rabeca
Womack
et al.
Effect of Ferric Citrate
versus Ferrous Sulfate
on Iron and Phosphate
Parameters in Patients
with Iron Deficiency
and CKD
United States
2020
2
Iain C.
Macdou
gall
et al.
Erythropoietic
response to oral iron in
patients with
nondialysis-dependent
chronic kidney disease
in the FIND-CKD trial
Denmark
2017
3
(Fishban
e et al.,
2017)
Effects of Ferric Citrate
in Patients with
NondialysisDependent
CKD and Iron
Deficiency Anemia
United States
2017
4
Geoffrey
A. Block
et al.
A 12-Week, Double-
Blind, Placebo-
Controlled Trial of
FerricCitrate for the
Treatment of Iron
Deficiency Anemia
andReduction of
Serum Phosphate in
Patients With CKD
Stages 3-5
United States
2015
5
(Iguchi
et al.,
2018)
Effect of ferric citrate
hydrate on FGF23 and
PTH levels in patients
with non-dialysis
dependent chronic
kidney disease with
normophosphatemia
and iron deficiency
Japan
2017
6
(Ketteler
et al.,
2019)
Effects of sucroferric
oxyhydroxide and
sevelamer carbonate
on chronic kidney
disease mineral bone
United
Kingdom
2018
332 | Iron Therapies For Iron Deficiency In Chronic Kidney Disease: A Literature Review
disorder parameters in
dialysis patients
7
(Wüthric
h et al.,
2013)
Randomized Clinical
Trial of the Iron-Based
Phosphate Binder PA21
in Hemodialysis
Patients
United States
2013
8
(Onken
et al.,
2014)
Ferric carboxymaltose
in patients with iron
deficiency anemia and
impaired renal
function: the REPAIR-
IDA trial
United
Kingdom
2013
Table 1. shows the results of this research literature review which includes a journal
biography (title, author, study location, and year of publication). From the results of the
literature search, it was found that 8 articles were used in this study.
Table 2. Subject Characteristics
No
Study
Population
Female/Male
(treatment)
Traetment
Side Effect
Outcome
1.
Rabeca
Womack
et al.
2020
60 adults with
moderate to
severe CKD
and iron
deficiency
20/10 (ferric
citrate)
29/11 (ferrous
sulfate)
Ferric citrate 2
g trhee times
a day with
meals, n=30
Ferrous sulfate
325 mg three
times a day, n
=30
For 12 weeks
The most
commonly
reported side
effects are
change in
stool color
(n=24),
constipation
(n=20),
diarrhea
(n=14)
Treatment
with ferric
citrate for 12
weeks
resulted in a
greater mean
incrase in
TSAT and also
increased
hepcidin
cencentration
s more than
ferrous sulfate
2.
Iain C.
Macdouga
ll
et al.
2017
308 patients
Not reported
Oral iron 200
mg elemental
iron/day
Frequent
gastrointestin
al side-effects
Oral iron
theraphy for
four weeks
reported
21.6% patients
showed
Zhela Fatin Fatiha, Nining Lestari, Aulia Nissa Rizky Hariyono, Tia Mella Citra, Ayu Mayangsari,
Tri Agustina |333
hemoglobin
(Hb) increase
1g/dL.
3.
(Fishbane
et al.,
2017)
234 adults with
nondialysis-
dependent
CKD and iron
deficiency
anemia
76/41 (ferric
citrate)
71/45
(placebo)
Oral ferric
citrate
(n=117)
Placebo
(n=117)
Gastrointestin
al effects were
most
common, with
diarrhea and
constipation
in patients
treated with
both ferric
citrate and
placebo. None
of the deaths
or serious
adverse
effects were
thought to be
drug-related.
Increase Hb
concentration
1.0 g/dl or
more in 16
weeks.
Treatment
with ferric
citrate safe
and
efficacious for
iron deficiency
anemia
patients with
NDD-CKD.
4.
Geoffrey
A. Block
et
al.
2015
149 patients
with GFR < 60
mL/min/1.73
m
2,
iron
deficiency
anemia, and
serum
phosphate
levels ≥ 4.0 to
6.0 mg/dl. IV
iron or
erythropoiesis-
stimulating
agents were
prohibited.
50/22 (ferric
citrate)
43/26
(placebo)
Ferric citrate
210 mg or
placebo for 12
weeks
Most side
effects were
gastrointestin
al, with
discolored
feces (n=24),
diarrhea
(n=15),
constipation
(n=14)
Ferric citrate
treatment
increased Hb
levels, repletes
iron stores,
and reduces
serum
phosphate
levels, urinary
phosphates
excretion, and
FGF-23 in
patients with
CKD stages 3
to 5 and iron
deficiency
anemia.
5.
(Iguchi et
al., 2018)
40 patients
were included
with 17
patients in the
Not reported
FCH-group
250 mg with
each meal,
SFC-group 50
Not reported
In FCH-group
serum intact-
PTH levels
decreased,
334 | Iron Therapies For Iron Deficiency In Chronic Kidney Disease: A Literature Review
FCH-group, 14
patients in the
SFC-group,
and 9 patinets
in thecontrol-
group.
mg once a day
for 12 weeks
FGF23 levels
not decrease.
Except in
patients
whose eGFR
declined, FCH-
group
decreased
CFGF23 levels.
6.
(Ketteler
et al.,
2019)
1059 patients
737/322
Sucroferric
oxyhydroxide
1-3 g/day
(n=710)
Sevelamer
2.4-14.4 g/day
(n=349)
For 24 weeks
Not reported
Treatment
with
sucroferric
oxyhydroxide
or sevelamer
significantly
reduced
serum FGF23.
7.
Rudolf P.
(Wüthrich
et al.,
2013)
154 patients
46/80 (PA21)
10/14
(sevelamer-
HCl)
PA21 with
dosage 1.25,
5.0, 7.5, 10.0,
or 12.5 g/d
Sebelamer-
HCl 4.8 g/d
For 6 weeks
Most side
effects
reported were
hypophospha
temia (n=23),
discolored
feces (n=15),
and
hyperphospha
temia (n=10).
Treatment
with PA21
significanly
reduces serum
phosphorus in
hemodialysis
patinets with 5
to 12.5 g/d
dosage
8
(Onken et
al., 2014)
2584 patients
were
randomized
treated with
FCM group
and iron
sucrose-group
810 females
(FCM)
818 females
(iron sucrose)
FCM 750 mg
in one week
Iron sucrose
200 mg
administered
in up to five
infusions in 14
days
The most
common
adverse
effects were
nausea,
hypertension,
flushing,
dizziness and
dysgeusia.
Treatment
with FCM
group
increased Hb
1.13 g/dl and
0.92 g/dl with
iron sucrose.
FCM group
are safe and
effective
alternative to
multiple lower
dose iron
sucrose
infusions in
iron deficiency
Zhela Fatin Fatiha, Nining Lestari, Aulia Nissa Rizky Hariyono, Tia Mella Citra, Ayu Mayangsari,
Tri Agustina |335
anemia
patients with
NDD-CKD
Table 2. shows the results of the
literature review of this study covering the
authors, population, gender of participants,
treatment, side effects, and the conclusion.
CKD patients with or without anemia,
aged 18-72 years were given oral iron
therapy (ferric citrate, ferrous sulfate,
sucroferric oxyhydroxide, ferric
carboxymaltose) with varying doses. The
dose of administration varies according to
the research that has been done.
According to
Rabeca et al
who used Ferric
citrate at a dose of 2 g three times a day
with meals and ferrous sulfate 325 mg three
times a day for 12 weeks, with the results of
therapy using ferric citrate reported to
increase TSAT and hepcidin more than
ferrous sulfate. According to
Markus et al
who used sucroferric oxyhydroxide 1-3
g/day reported that this therapy can
significantly reduce serum FGF23 levels,
and there was a history of
hyperphosphatemia and prescription of
stable doses of phosphate binders for 1
month before screening. Study by
Jane et al
using ferric carboxymaltose at a dose of
750 mg for one week can increase Hb levels
to 1.13 g/dl. In this study, there were side
effects caused by the use of oral iron
therapy, the most patients experienced
gastrointestinal intolerance
. Iain et al
in
their study gave oral iron therapy 200 mg
elemental iron/day proven to increase
hemoglobin levels for four weeks in 21.6%
of the participants.
Steven et al
explained
that in the oral therapy group, ferric citrate
can increase hemoglobin concentrations of
1.0 g/dl or more in 16 weeks and this
therapy is safe and effective in NDD-CKD
patients with iron deficiency anemia.
Geoffrey et al's
study used ferric citrate to
increase hemoglobin levels, replete iron
stores, and suppress serum phosphate
levels, urinary phosphate excretion, and
suppress FGF23 serum levels in grade 3 to
5 CKD patients with iron deficiency anemia.
Akira et al's
study found that FCH-group
can reduce intact PTH serum levels. A
different study was conducted by
Rudolf et
al
performed PA21 administration with
varying dosage of 1.25, 5.0, 7.5, 10.0, or 12.5
g/d in patients whose receiving vitamin D
or calcimimetics had to be on a constant
dose for a least 1 month before screening
and during the study, therapy with PA21 5
to 12.5 g/dl dose can significantly
suppressing serum phosphorus in
hemodialysis patients.
Oral iron therapy can increase
hemoglobin levels in the body and
suppress FGF23 serum levels. The most side
effects of therapies were gastrointestinal
problems. Oral iron therapies are
considered safe but drug development is
still needed to minimize side effects.
336 | Iron Therapies For Iron Deficiency In Chronic Kidney Disease: A Literature Review
DISCUSSION
This study was conducted to determine
the efficacy of iron therapy in CKD patients
with iron deficiency anemia. Iron deficiency
anemia is a condition where the total
amount of iron in the body is less than
normal due to reduced iron supply for
erythropoiesis and results in low Hb
formation. If the iron content in the body is
low, it will inhibit the formation of red blood
cells in the bone marrow so that the Hb
level decreases below normal limits.
Various studies have proven that iron
supplements can increase Hb. Iron
supplementation is beneficial because it
can improve Hb status in a short time.
several factors that can affect iron
administration therapy, namely, patient
compliance, diseases that can interfere with
iron absorption, supplementation doses,
and empty body iron reserves (Wahtini,
2019).
The principle of giving iron therapy in
iron deficiency anemia is knowing the
causative factors and overcoming and
providing replacement therapy with iron
preparations. In the case of iron deficiency
anemia, after identifying the cause of the
disease and treating it, iron replacement
therapy is needed to improve Hb levels and
rebuild iron stores in the body.
Administration of iron can be prepared in
two ways: oral and parenteral (Gunadi D,
2020).
Oral treatment of iron deficiency
anemia is clearly cheaper than parenteral
treatment. From a practical point of view,
oral therapy is the first line to replace iron
stores because it allows a normal
absorption mechanism, and thus can
prevent complications and risks of iron
overload. Iron given by oral therapy must
meet the requirements that each tablet or
capsule contains 50-100 mg of elemental
iron which is easily released in an acidic
environment, is easily absorbed, and has
less side effects. There are four irons that
can be given orally, namely Ferric Citrate,
ferrous sulfate, sucroferric oxyhydroxide,
ferric carboxymaltose.
One way to overcome the weakness of
oral iron therapy can be overcome by using
parenteral iron therapy. In a meta-analysis
study when compared oral iron therapy
with intravenous therapy, intravenous
therapy was more effective than iron
therapy. Parenteral iron therapy is given if
there are indications such as
malabsorption, lack of tolerance for oral
administration, and the patient is
uncooperative and requires a rapid
increase in Hb (Kapoh et al., 2021).
CONCLUSIONS
Oral administration of iron therapy can
increase hemoglobin levels, and suppress
serum FGF23 levels in CKD patients with
iron deficiency anemia. The most side
effects are gastrointestinal problems. Oral
iron therapies are considered safe but drug
Zhela Fatin Fatiha, Nining Lestari, Aulia Nissa Rizky Hariyono, Tia Mella Citra, Ayu Mayangsari,
Tri Agustina |337
development is still needed to minimize side effects.
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for possible open access publication
under the terms and conditions of the Creative Commons Attribution (CC BY SA) license
(https://creativecommons.org/licenses/by-sa/4.0/).
