Intravenous Versus Oral Iron Supplementation for the Treatment of

Anemia in CKD: Systematic Review and Meta-analysis

Benaya Rozen-Zvi, MD,1 Anat Gafter-Gvili, MD,2 Mical Paul, MD,3 Leonard Leibovici, MD,4
Ofer Shpilberg, MD,2 and Uzi Gafter, MD, PhD1
Background: Iron supplementation is essential for the treatment of patients with anemia of chronic
kidney disease (CKD). It is not clear which is the best method of iron administration.
Study Design: Systematic review and meta-analysis. A search was performed until January 2008 of
MEDLINE, Cochrane Central Register of Controlled Trials, conference proceedings in nephrology, and
reference lists of included trials.
Setting & Population: Patients with CKD (stages III to V). We included dialysis patients and patients
with CKD not on dialysis therapy (hereafter referred to as patients with CKD).
Selection Criteria for Studies: We included all randomized controlled trials regardless of publication
status or language.
Intervention: Intravenous (IV) versus oral iron supplementation.
Outcomes Measures: Primary outcomes assessed: absolute hemoglobin (Hb) level or change in Hb
level from baseline. We also assessed all-cause mortality, erythropoiesis-stimulating agent requirement, adverse events, ferritin level, and need for renal replacement therapy in patients with CKD.
Results: 13 trials were identified, 6 including patients with CKD and 7 including dialysis patients.
Compared with oral iron, there was a significantly greater Hb level in dialysis patients treated with IV iron
(weighted mean difference, 0.83 g/dL; 95% confidence interval, 0.09 to 1.57). Meta-regression showed
a positive association between Hb level increase and IV iron dose administered and a negative
association with baseline Hb level. For patients with CKD, there was a small but significant difference in
Hb level favoring the IV iron group (weighted mean difference, 0. 31 g/dL; 95% confidence interval, 0.09
to 0. 53). Data for all-cause mortality were sparse, and there was no difference in adverse events
between the IV- and oral-treated patients.
Limitations: There was significant heterogeneity between trials. Follow-up was limited to 2 to 3
months.
Conclusions: Our review shows that patients on hemodialysis therapy have better Hb level response
when treated with IV iron. For patients with CKD, this effect is small.
Am J Kidney Dis 52:897-906. 2008 by the National Kidney Foundation, Inc.
INDEX WORDS: Anemia; iron; chronic kidney disease; hemodialysis; hemoglobin; meta-analysis.

nemia is a common complication of chronic

kidney disease (CKD), associated with
morbidity and mortality.1-3 Treatment with erythropoiesis-stimulating agents (ESAs) is effective,4,5 but often limited by iron deficiency,6-8
which is very common in patients with CKD.9,10
Iron supplementation can be administered either
orally or intravenously (IV). Although oral iron
is less expensive, easier to administer, and may
be safer, IV iron enables the administration of
larger doses of iron and is better tolerated by
some patients.11 The main adverse reactions to
oral iron are gastrointestinal and may limit adherence and dose.12 The most feared adverse reaction to IV iron is anaphylaxis, which is more
common with iron dextran than with other preparations.13,14 In addition, there are concerns that
IV iron may promote infections by supplying
iron to pathogenic bacteria,15,16 cause endothelial damage, enhance atherosclerosis by generating oxidative stress,17 and accelerate kidney dam-

age in patients with CKD not on dialysis therapy

(hereafter referred to as patients with CKD).18
According to the National Kidney FoundationKidney Disease Outcomes Quality Initiative
(KDOQI) guidelines,19 to achieve and maintain
the target hemoglobin (Hb) level of 11g/dL, IV
From the Departments of 1Nephrology and Hypertension,
Hematology, 3Infectious Disease Unit, and 4Department of
Medicine E, Rabin Medical Center, Beilinson Hospital,
Petah-Tikva, and the Sackler School of Medicine, Tel Aviv
University, Tel-Aviv, Israel.
Received January 31, 2008. Accepted in revised form May
21, 2008. Originally published online as doi:
10.1053/j.ajkd.2008.05.033 on October 9, 2008.
B.R.Z and A.G.-G. contributed equally to this work.
Address correspondence to Benaya Rozen-Zvi, MD,
Department of Nephrology, and Hypertension, Rabin
Medical Center, Beilinson Hospital, 49100, Petah-Tikva,
Israel. E-mail: benayarz@gmail.com
2008 by the National Kidney Foundation, Inc.
0272-6386/08/5205-0011$34.00/0
doi:10.1053/j.ajkd.2008.05.033
2

American Journal of Kidney Diseases, Vol 52, No 5 (November), 2008: pp 897-906

897

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Rozen-Zvi et al

iron should be administered on a regular basis to

most hemodialysis patients, and according to the
European Best Practice Guidelines (EBPGs),20
IV iron should be administered at least once
every 2 weeks to reach and maintain the same
target Hb level. For patients with CKD and
peritoneal dialysis populations, both the KDOQI
guidelines and EBPGs do not specify the recommended method of iron supplementation, but
recommend at least 100 to 200 mg/d of elemental
iron if oral iron is selected. If adequate iron status
cannot be maintained by the oral method, IV iron
administration is recommended.19,20
Several randomized controlled trials have addressed the comparison of IV versus oral iron in
patients with CKD. To date, 2 systematic reviews
of iron supplementation included patients with
CKD. However, one included only pediatric patients,21 and the other included a mostly nonCKD population and did not reflect the unique
needs of patients with CKD.22
Because there is no consistent approach in
clinical practice, we undertook this systematic
review and meta-analysis to summarize all available evidence.

METHODS
Data Sources
We searched PubMed (January 1966 to January 2008),
CENTRAL (The Cochrane Library up to 2008, issue 1), and
conference proceedings of the American Society of Nephrology and European Renal Association-European Dialysis and
Transplant Association in nephrology between the years
2001 to 2007. The terms chronic kidney disease, chronic
renal failure, dialysis, hemodialysis, and peritoneal
dialysis were searched as both medical subject heading
terms and as text words and crossed with iron (medical
subject heading term and a text word) and specific IV and
oral iron preparations. The result was limited to randomized
controlled trials using a highly sensitive filter.23 References
of all included trials and reviews identified were scanned for
additional studies.

Study Selection
We included all randomized controlled trials comparing oral iron preparations versus different IV iron preparations in hemodialysis and peritoneal dialysis patients and
patients with CKD. CKD was defined as glomerular
filtration rate less than 60 mL/min (CKD stage 3) according to the KDOQI guidelines.24 We included trials regardless of publication status (published, conference proceedings, or unpublished), trial years, and language. Two

reviewers independently inspected each reference identified by the search and applied inclusion criteria. For
possibly relevant articles or in cases of disagreement
between the 2 reviewers, we obtained and independently
inspected the full article.

Data Extraction and Quality Assessment

Two reviewers independently extracted data from included trials. In case of disagreement between the 2
reviewers, a third reviewer extracted the data and results
were attained by consensus. We contacted all investigators of included trials for missing data. Two reviewers
independently assessed trials for method quality. We
individually assessed the following components: allocation concealment, generation of the allocation sequence,
and blinding. We graded allocation concealment and
generation as adequate, unclear, or inadequate.23

Denition of Outcomes
The primary outcome was absolute Hb level or change in
Hb level from baseline after 2 to 3 months of treatment.
When data for 2 to 3 months were unavailable, Hb level at
the end of the study was used. When both absolute Hb level
and change in Hb level from baseline were available, we
used the absolute end values as recommended in the Cochrane Handbook.23
Secondary outcomes included all-cause mortality at the
end of the trial, cardiovascular morbidity and mortality,
bacterial infections, adverse events, adverse events that
required discontinuation of iron therapy, number of patients with CKD who required renal replacement therapy
for the duration of follow-up, iron saturation and ferritin
level, ESA dose, number of patients who required ESA
dose increase, number of patients needed to be hospitalized, quality of life, and number of patients who needed
blood transfusions.
For efficacy outcomes, comparisons were conducted separately for dialysis and other patients with CKD. For safety
outcomes (mortality, adverse events, and need for renal
replacement therapy), comparisons were pooled for patients
with CKD and dialysis patients.

Data Synthesis and Analysis

We obtained mean and SD values for continuous variables. When mean or SD values were not available, we
calculated them by using data obtained from the investigators or figures or by recalculating them from other effect
estimates and dispersion measures.23
We analyzed data by calculating the weighted mean
differences (WMDs) for continuous variables and relative
risk (RR) for dichotomous data with 95% confidence intervals (CIs) (Review Manager [RevMan], version 4.2 for
Windows; The Cochrane Collaboration, Oxford, UK). We
used the DerSimonian and Laird random-effects model
because of heterogeneity of the data. We assessed heterogeneity of trial results by calculating a 2 test of heterogeneity
and the I2 measure of inconsistency. We predefined significant heterogeneity as 2 test P less than 0.1 or I2 measure
greater than 50%.25 We explored potential sources of hetero-

Iron Supplementation in Chronic Kidney Disease

geneity through meta-regression, assessing the effect of
the following variables in each study on the effect estimates for the primary outcome: baseline Hb level, percentage of patients receiving ESA and mean ESA dose, IV
iron dose, dialysis duration (for hemodialysis patients),
and mean glomerular filtration rate (for predialysis patients). Meta-regression was performed on the standardized mean difference (Comprehensive Meta Analysis,
version 2.2; BioStat, Englewood, NJ). The regression
slope with its SE and significance of the model are
reported. For the primary outcome, we conducted sensitivity analysis assessing the effect of allocation concealment
and generation.25

Units
Values for the following parameters are given throughout
in the first unit listed, and may be converted to the second
unit shown by multiplying by the conversion factor provided: hemoglobin (g/dL to g/L; 10); glomerular filtration
rate (mL/min/1.73 m2 to mL/s/1.73 m2; 0.01667).

RESULTS
The literature search identified 246 publications; of them, 46 were potentially eligible
publications on iron therapy in patients with
CKD. Reasons for exclusion are shown in Fig
1 and a list of excluded trials is provided as
supplementary material (Item S1) available
with this article at www.ajkd.org. Thirteen
trials performed between 1990 and 2008 fulfilled inclusion criteria. Seven trials included
435 dialysis (mainly hemodialysis) patients26-32

Figure 1. Trial flow shows

trial identification process. Abbreviations: RCT, randomized
controlled trial; IV, intravenous.

899

and 6 trials included 762 patients with CKD33-38

(Table 1).
Dialysis Patients
Primary Outcome: Hb Level
Seven trials reported end Hb levels or change
in Hb levels from baseline. Hb level was significantly increased in the IV iron group compared
with oral iron (WMD, 0.83 g/dL; 95% CI, 0.09 to
1.57) with significant heterogeneity (P 0.001;
I2 89.9%; Fig 2). WMD is the absolute difference in mean values and has the same units as
Hb, meaning this value represents a difference of
0.83g/dL in Hb levels between groups. Metaregression showed significant associations between a larger effect estimate for Hb level response and lower baseline Hb level (0.15
0.054 g/dL of Hb per 1 g/dL of baseline Hb; P
0.004), lower ESA dose (0.006 0.002 g/dL
of Hb per 1 U/kg/wk of ESA; P 0.002), and
greater IV iron dose (0.003 0.0005 g/dL of Hb
per 1 mg/mo of iron; P 0.001; Fig 3). We did
not observe an effect of dialysis duration or
percentage of patients administered ESAs on
effect estimates. Sensitivity analysis did not show
a significant difference between trials reporting
adequate allocation concealment and allocation
generation (WMD, 0.66; 95% CI, 1.08 to 2.39;
2 trials) and trials reporting unclear or inad-

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Rozen-Zvi et al
Table 1. Characteristics of Included Trials

Study
Patients with CKD
Van Wyck et al
200536*

Charytan et al
200533
Agarwal et al
200634
Aggarwal et al
200335
Stoves et al
200138
Spinowitz et al
200637
Dialysis patients
Michael et al
200731
Li et al 200828
Macdougall et al
199630

Fishbane et al
199529
Allegra et al
199027
Svara et al
199632*
Warady et al
200426

Drug and Dose

IV iron sucrose, 1,000 mg, given as 2 doses

of 500 mg d 1 and 14 or 5 doses of 200 mg
over 14 d
Oral iron sulfate, 325 mg 3 d
IV iron sucrose, 200 mg 5 given over 29 d
Oral iron sulfate, 325 mg 3 d
IV iron gluconate, 250 mg 4 given over 22 d
Oral iron sulfate, 325 mg 3 d
IV iron dextran 100 mg 6 over 3 mo
Oral iron sulfate, 200 mg 3 d
IV iron sucrose, 300 mg 6 over 6 mo
Oral iron sulfate, 200 mg 3 d
IV ferumaxitol, 1,020 mg over 1 wk
Oral iron, 200 mg/d (elemental)
IV iron gluconate, 62.5 mg 20 over 20 wk
Oral iron sulfate, 325 mg 3 d
IV iron sucrose, 100 mg 28 over 3 mo
Oral iron succinate, 200 mg 3 d
IV iron dextran, 250 mg 8 over 4 mo

Duration of
Treatment

Intention-toTreat
Efficacy

95

56 d

No

25/300/11

93
48
48
44
45
20
20
22
23
228
76

56 d
29 d
29 d
22 d
32 d
3 mo
3 mo
6 mo
6 mo
1 wk
3 wk

Yes

25/300/10.5

No

20 (or)/100/12 l

No

Hb 8

No

Hb 11

Yes

30/600/11

33
27
70
66
13

5 mo
5 mo
3 mo
3 mo
4 mo

No

TSAT 20/ferritin 100

No

30/500/9

No

Ferritin 100/Hb 8.5

No. of
Patients

Inclusion Criteria TSAT

(%)/Ferritin (ng/mL)/Hb
(g/dL)

Oral iron sulfate, 200 mg 3 d

13

4 mo

IV iron dextran, 100 mg 36 over 4 mo

Oral iron sulfate 325 mg 3 d
IV iron gluconate, 31 mg 72 over 6 mo
Oral iron ferritin 67.5 mg 1 d
IV iron sucrose, 100 mg 6 over 6 wk
Oral iron sulfate, 325 mg 3 d
IV iron dextran, 100 mg 16 over 4 mo
Oral iron fumarate, 4-6 mg/kg/d

25
50
34
22
28
29
17
18

4 mo
4 mo
6 mo

No

TSAT 15/ferritin 100

No

6 wk
4 mo
3 mo

Age (y)

62.3

63.9
62
60
65.5
62.3
Range, 21-66
Range, 23-69
57.3
59.9
65.1
63.7
56.5
56.5
53.6
54.9
47
58

Renal
Failure
Status

CKD

CKD
CKD
CKD
CKD
CKD

HD
HD
HD 4, PD 7,
CKD 1
HD 6, PD 5,
CKD 2
HD

NR

48.7
50.2
NR

HD

No

TSAT 20/ferritin 300

NR

HD

No

TSAT 20

15.1
14.7

HD

(Continued)

equate methods (WMD, 0.90; 95% CI, 0.03 to

1.82; 5 trials).
Secondary Outcomes

Mean end ESA dose or change in ESA dose

from baseline at 2 to 3 months was reported in 5
trials. ESA dose (reported as unit per kilogram
per week) decreased significantly in the IV iron
treated patients (WMD, 28.21 U/kg/wk; 95%
CI, 42.12 to 14.3; 5 trials) without significant
heterogeneity (P 0.1; I2 44.1%; Fig 4).
Ferritin level significantly increased (WMD,
172.34 ng/mL; 95% CI, 111.31 to 233.38; 6
trials) with significant heterogeneity (P 0.001;
I2 97.5%). Transferrin saturation was not
significantly increased (WMD, 12.89%; 95%
CI, 3.9 to 29.7; 6 trials) with significant
heterogeneity among trials (P 0.001; I2
98.7%). There were no data regarding quality
of life.

Patients With CKD

Primary Outcome: Hb Level

Hb level or change in Hb level from baseline

was slightly but significantly greater in the IV
irontreated patients (WMD, 0.31 g/dL; 95% CI,
0.09 to 0.53; 6 trials) without significant heterogeneity (P 0.1; I2 40.6%; Fig 5).
Secondary Outcomes

Ferritin levels increased significantly in the

IV group (WMD, 213.35 ng/mL; 95% CI, 56.5
to 370.2; 3 trials) with significant heterogeneity (P 0.001; I2 97.91%). Transferrin
saturation was significantly increased (WMD,
9.45%; 95% CI, 1.9 to 17.1; 3 trials) with
significant heterogeneity (P 0.001; I2
92.8%). Quality of life assessed by using Kidney Disease Quality of Life (KDQoL) questionnaire was reported in only 1 trial, which showed

Iron Supplementation in Chronic Kidney Disease

901

Table 1 (Contd). Characteristics of Included Trials

Study
Patients with CKD
Van Wyck et al
200536*

Charytan et al
200533
Agarwal et al
200634
Aggarwal et al
200335
Stoves et al
200138
Spinowitz et al
200637
Dialysis patients
Michael et al
200731
Li et al 200828
Macdougall et al
199630

ESA Use
(%)

32.9

16.4/92.6/10.2

40.5

No

NR

B/B

Day 42

37.1
39.6
29.2
44.4
38.5
65
80
45.5
65.2
41.2
31.6

16.7/103.8/10.1
16.6/125/9.8
15.6/103/9.7
17.2/72.5/10.5
17.9/66.4/10.7
59.8/181.4/5.8
63.6/180.3/6.3
NR/100/9.9
NR/74/9.7
11.3/146.1/9.96
10.1/143.5/9.96

37.8
100

No
No

NR
2,000 U SC d 1, 8,
15, 22, 29, 36

B/B

Day 42

None

A/A

Day 43

100

No

2,000 U 2 wk

A/B

2 mo

100

Yes

2,000 U 3 wk

A/A

2 mo

No
No

NR
NR

B/B

Day 35

Yes

142 U/kg/wk
173 U/kg/wk
6,130 U/wk
6,133 U/wk
25 U/kg 3 wk

B/B

5 mo

A/B

3 mo

A/B

4 mo

A/A

1 mo

B/B

3 mo

Men
(%)

GFR 30.4

GFR 28.5
NR
GFR 31.8
GFR 30.4
CCr 13
CCr 18.6
GFR 14
GFR 12
NR

Duration of
Dialysis
(mo)

Baseline TSAT
(%)/Ferritin (ng/
mL)/Hb (g/dL)

Renal Function
(mL/min)

48.5
56.5
44.3
39.4
50

NR
NR
37.6
35.9
NR

28.2/357/12.6
28.7/322/12.2
28.2/192.6/8.1
21.3/194.7/8.2
26/345/7.3

25.9
23.7
100
NR
100

Dose
Change

Yes
Yes

Baseline ESA
Dose

Allocation
Generation/
Concealment

Time of
Included Hb
Measurement

61.5

NR

27/309/7.2

Fishbane et al
199529
Allegra et al
199027

65
56.3
NR

35.6
32.9
57

22.7/191.2/10.8
21.1/178.9/10.6
NR/NR/NR

NR

Yes

None

7,100 U/wk
6,750 U/wk

Svara et al
199632*
Warady et al
200426

NR

NR

NR

No

50 U/kg/wk

A/B

6 wk

41.2
50

15.9
20.3

18/136/8.6
19.8/132/8.9
42.3/138.5/11.4
34.1/138.8/11.6

Yes

234 U/kg/wk
190 U/kg/wk

A/A

4 mo

100

Note: All values expressed as means unless stated otherwise. All studies were unblinded. To convert serum Hb in g/dL to
g/L, multiply by 10; GFR and CCr in mL/min to mL/s, multiply by 0.01667. Ferritin levels expressed in ng/mL and g/L are
equivalent.
Abbreviations: NR, not reported; Hb, hemoglobin; GFR, glomerular filtration rate; IV, intravenous; TSAT, transferrin
saturation; CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; CCr, creatinine clearance; SC, subcutaneous; HD, hemodialysis; PD, peritoneal dialysis; A, adequate; B, not specified; C, inadequate.
*Replied to our contact but did not give additional data.
Replied to our contact and gave additional data.
Median.
These studies did not report exact numbers, but according to the text, most patients were treated with ESAs.
Dosing according to body weight: less than 20 kg, 25 mg/wk; greater than 20 and less than 40 kg, 50 mg/wk; and greater
than 40 kg, 100 mg/wk.

an improvement in patients treated with IV

iron.34
Safety
All-cause mortality for the duration of the
trials did not differ between groups, with a total
of only 3 events, all in the oral iron arm (RR,
0.28; 95% CI, 0.02 to 5.22; 5 trials). Adverse
events were reported in 9 trials, and there was no
difference between groups (RR, 0.80; 95% CI,
0.46 to 1.41).
Twelve trials reported severe adverse events
and adverse events that required discontinuation
of therapy. There was no difference between

groups (RR, 1.31; 95% CI, 0.50 to 3.45). Need

for blood transfusion was reported in 2 trials with
only 5 events and did not differ between groups
(RR, 1.36; 95% CI, 0.21 to 8.73). Number of
hospitalizations was reported in only 1 trial with
few events and no difference between groups.29
There was no difference in number of patients
with CKD who required renal replacement
therapy between the IV-treated group and the
oral group (RR, 0.67; 95% CI, 0.26 to 1.73; 3
trials) without significant heterogeneity (P
0.7; I2 0%). There were no data regarding
cardiovascular morbidity and mortality and bacterial infections.

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Rozen-Zvi et al

Figure 2. Hemoglobin (Hb) level or change from baseline for trials comparing intravenous (IV) iron versus oral iron in
dialysis patients. Studies are identified by name of first author and year of publication and sorted by their weight. Weighted
mean differences (WMD) are pooled using the random-effects model and shown on a scale of 4 to 4 g/dL. The IV iron arm
included 215 patients and the oral iron arm included 205 patients. Serum Hb may be converted from g/dL to g/L by multiplying
by 10. Abbreviation: CI, confidence interval.

DISCUSSION
We compiled all trials comparing oral iron
therapy with IV iron in patients with renal failure.
Our review shows that in hemodialysis patients,
Hb level was greater with IV iron compared with
oral iron (WMD, 0. 83 g/dL; 95% CI, 0.09 to 1.57).

This response was regardless of ESA use and type

of IV iron preparation used. Furthermore, ESA
dose was significantly decreased by the use of IV
compared with oral iron.
In patients with CKD, there was also a benefit
with regard to Hb level in patients treated with
IV iron compared with oral iron (WMD, 0.31

Figure 3. Meta regression of standardized mean

differences in hemoglobin
(Hb) level or change from
baseline in individual studies
on the intravenous iron dose
used in the study in dialysis
patients. Iron dose in milligrams per month.

Iron Supplementation in Chronic Kidney Disease

903

Figure 4. Erythropoiesis-stimulating agent (ESA) dose or change from baseline at end of study for trials comparing
intravenous (IV) iron versus oral iron in dialysis patients. Studies are identified by name of first author and year of publication
and sorted by their weight. Weighted mean differences (WMDs) are pooled using the random-effect model and shown on a
scale of 100 to 100 U/kg/wk. The IV iron arm included 152 patients and the oral iron arm included 156 patients.
Abbreviation: CI, confidence interval.

g/dL; 95% CI, 0.09 to 0.53). However, this

benefit was of a small magnitude and its clinical
significance was not clear.
In both hemodialysis patients and patients
with CKD, ferritin levels were greater in patients treated with IV iron, indicating greater
iron stores.
In patients with CKD, there is no consistent
recommendation for the preferred method of
administration of iron according to the KDOQI
guidelines and EBPGs. However, a recent review
article recommended oral iron as first-line therapy
because of minimal differences between oral and
IV iron in these patients.39 This is in accordance

with our results, which showed only a minor

difference in favor of IV iron.
The difference between dialysis and CKD
populations may be explained by greater blood
losses in hemodialysis patients because of the
hemodialysis procedure itself and probably
gastrointestinal losses. There is also evidence
that gastrointestinal iron absorption is limited
with hemodialysis,40 probably because of coadministration of phosphate binders and a high
level of hepcidin because of a chronic lowgrade inflammatory state.
Results of our analysis are limited by the
significant heterogeneity between trials in hemo-

Figure 5. Hemoglobin (Hb) level or change from baseline for trials comparing intravenous (IV) iron versus oral iron in
patients with chronic kidney disease (CKD) not on dialysis therapy. Studies are identified by name of first author and year of
publication and sorted by their weight. Weighted mean differences (WMDs) are pooled using the random-effect model and
shown on a scale of 1 to 1 g/dL. The IV iron arm included 421 patients and the oral iron arm included 281 patients. Serum
Hb may be converted from g/dL to g/L by multiplying by 10. Abbreviation: CI, confidence interval.

904

dialysis patients. The difference of 0.83 g/dL in

Hb levels between IV and oral iron in hemodialysis patients originated from trials reporting a
difference ranging from 0.24 to 1.99 g/dL. The
heterogeneity may be caused by several factors.
First, various oral and IV preparations were used.
These were administered in different dosages
and schedules. Moreover, in 1 of the trials, the
dosage of oral iron was less than the dose recommended by the KDOQI guidelines.27 Second,
ESA use, dose, and titration methods were inconsistent among trials, and some trials did not
administer ESAs. Third, there was also heterogeneity among trials with regard to basal Hb levels
and iron status of patients, reflected by serum
ferritin level and transferrin saturation. We assessed the effect of these variables on effect
estimates when possible, and the dose of IV iron
used and baseline Hb levels had a significant
effect on Hb level response on linear regression.
In 1 included trial, there was a difference in
patient age between trial arms,30 and patients
who received oral iron were about 10 years older
than those receiving IV iron. This high degree of
heterogeneity may lessen the statistical power of
our analysis.
Our results are also limited by the short-term
follow-up. Most studies in our systemic review
had a short duration of follow-up, and subsequently, our primary outcome was Hb level at
only 2 to 3 months. This limits our ability to
draw conclusions regarding the long-term consequences of the different treatment regimens on
Hb levels and clinical outcomes, such as mortality, cardiovascular outcomes, and quality of life.
Long-term follow-up is especially important because there are studies that raise concerns about
oxidative stress, infection risk, and cardiovascular morbidity and mortality because of free iron
released from the IV preparation to the circulation.12,41-43
Although there was no increase in serious
adverse events in the IV arm, one should keep in
mind that randomized controlled trials probably
are underpowered to assess such serious and rare
adverse events as anaphylaxis. Notwithstanding,
in another recent systematic review of randomized controlled trials that included a diverse
population, there was no significant increase in
severe adverse events.22

Rozen-Zvi et al

Our results are in concert with the common

practice of treating hemodialysis patients with
IV iron, based on a better Hb level response and
lower ESA requirements. This conclusion is based
on a small number of patients, significant heterogeneity between trials, and no assessment of
major clinical outcomes such as cardiovascular
and infectious outcomes.
Nevertheless, one cannot ignore the advantages of IV use in dialysis patients: the convenience of administration during the dialysis, the
good short-term safety profile, and the potential
for cost saving because of ESA dose reduction.
In patients with CKD, the advantage is minimal. This slight advantage in Hb level response
should be weighed against the inconvenience
and cost of IV iron treatment in patients who do
not already have an easy IV access. However, IV
iron should be considered as an alternative in
patients who do not tolerate oral iron or in whom
iron deficiency persists despite an adequate dose
of oral iron.
Because of the heterogeneous body of evidence, additional well-designed large randomized controlled trials comparing IV iron with oral
iron should be conducted in dialysis patients.
The outcomes assessed should include clinical
outcomes and the common hematologic parameters. Because recent evidence shows that some
hemodialysis patients can be managed effectively with oral iron as maintenance therapy,44
subgroup analyses in these trials should be defined according to patient age, comorbidity, and
baseline iron status.
To clarify the long-term consequences of
IV iron, these trials should have a long-term
follow-up.
More randomized controlled trials comparing
oral with IV iron in the predialysis population are
warranted mainly to define subgroups of patients
that may benefit from IV treatment and better
understand the possible influence of iron therapy
on glomerular filtration rate changes in the long
term.
It may be worthwhile to conduct a randomized
controlled trial comparing different modes of
iron therapy in peritoneal dialysis patients because there are no data regarding the best method
of iron supplementation in this unique population.

Iron Supplementation in Chronic Kidney Disease

ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: None.

SUPPLEMENTARY MATERIAL
Item S1: List of excluded studies.
Note: The supplementary material accompanying this
article (doi:10.1053/j.ajkd.2008.05.033) is available at www.
ajkd.org.

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