Peritoneal Dialysis International, Vol. 37, pp. 6–13
00
www.PDIConnect.com
ANEMIA IN PERITONEAL DIALYSIS PATIENTS; IRON REPLETION, CURRENT
AND FUTURE THERAPIES
Ahmed Zeidan and Sunil Bhandari
Department of Academic Renal Research, Hull and East Yorkshire Hospital Trust and Hull York Medical School,
Kingston Upon Hull, UK
Iron deficiency, both functional and absolute, is common in
patients with chronic kidney disease (CKD), especially those
requiring dialysis. Guidelines advocate treatment of iron-
deficiency anemia in patients with CKD and those on peritoneal
dialysis (PD). Oral iron is often insufficient and slow to improve
hemoglobin concentrations because of high hepcidin levels caus-
ing impaired absorption and mobilization, while intravenous (IV)
supplementation replenishes and maintains iron stores more
effectively and is now standard practice (Kidney Disease Improv-
ing Global Outcomes [KDIGO] 2012 guidelines). However, there
still remain concerns about the effects of labile iron and possible
increased risk of infections for this group of patients.
To date, the majority of published studies have focused on
hemodialysis (HD) patients; very limited data are available regard-
ing patients on PD. This review summarizes the rationale for iron
therapy, methods of treatment, potential adverse effects, and
long-term concerns in PD patients. In addition we highlight some
interesting potential future therapies under study.
Perit Dial Int 2017; 37(1):6–13
https://doi.org/10.3747/pdi.2016.00193
KEY WORDS: Anemia; hemodialysis; hepcidin; intravenous;
iron deficiency; oxidative stress; peritoneal dialysis.
C hronic kidney disease (CKD) affects approximately 4 – 6% of
the UK adult population and between 8 – 13% of the popu-
lation in the USA (1). This population has a high incidence of
both absolute (depleted iron stores) and functional (depleted
available circulating iron) iron deficiency anemia (IDA). In PD
patients, it accounts for 11% of the dialysis population (2).
The Renal National Service Framework and National
Institute for Health and Care Excellence (NICE) advocate
treatment of anemia in patients with CKD, including those
on PD (3). Oral iron is often insufficient and slow to improve
hemoglobin levels because of high hepcidin levels, while
intravenous (IV) supplementation replenishes and maintains
iron stores more effectively. This is caused by poor dietary
iron intake due to anorexia as a result of uremia and dietary
protein restriction, and may be compounded by impaired iron
Correspondence to: Sunil Bhandari, Department of Nephrology,
Hull Royal Infirmary,
 Anlaby Road,
Hull, HU3 2JZ United Kingdom
sunil.bhandari@hey.nhs.uk
Received 13 July 2016; accepted 24 July 2016.
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0896-8608/17 $3.00 + .
Copyright © 2017 International Society for Peritoneal Dialysis
absorption and mobilization, which is mediated by hepcidin
in the setting of inflammation. Peritoneal dialysis patients,
like non-dialysis (ND)-CKD patients and unlike HD patients, do
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not always need IV iron. In addition, the iron requirements in
both PD patients and ND-CKD patients are less than those of
HD patients, so oral iron supplements have traditionally been
tried before IV iron is used in patients receiving PD (Figure 1).
Intravenous iron however is now standard practice (Kidney
Disease Improving Global Outcomes [KDIGO] 2012 guidelines),
but there still remain concerns about the effects of labile iron
and the possible increased risk of infections for this group of
patients (4).
To date, the majority of published studies have focused on
hemodialysis patients (HD); very limited data are available
regarding patients on PD. This review summarizes the rationale
for iron therapy, methods of treatment and potential adverse
effects, and long-term concerns in PD patients. In addition,
we highlight some interesting potential future therapies
under study.
WHY TREAT IRON DEFICIENCY ANEMIA OF CKD IN PATIENTS
RECEIVING PD
The aim of treating anemia and iron deficiency in patients
receiving PD is to improve their symptoms and quality of
life and potentially reduce their cardiovascular risk. Studies
have demonstrated a direct link between IDA and both qual-
ity of life and mortality (5). Patients experience a reduction
in symptomatic restless legs; improved cognition, physical
performance, exercise tolerance and immune function with
iron repletion (6). Cardiovascular disease in patients with
CKD is complex, with macrovascular disease, abnormalities
in calcium/phosphate metabolism, hypertension, volume
overload and, importantly, both anemia and iron deficiency
contributing to the cardiovascular risk and mortality in this
patient group (7). In PD patients, iron repletion allows more
effective erythropoiesis, which improves hemoglobin (Hb)
and oxygen carrying potential (8). An observational study of
14,958 PD patients and 221,866 HD patients found that PD
patients required a lower dose of erythropoietin stimulating
agent (ESA) to reach target Hb levels (9). The mean adjusted
ESA dose decreased by 76.5% and 58.4% in PD and HD patients,
respectively. However, IV iron use increased in both groups by
PDI JANUARY  2017 - VOL. 37, NO. 1 ANEMIA IN PD PATIENTS

Iron deficiency Anemia

TS% ≤ 20%
and/or
SF ≤ 100 µg/L

NOT on an ESA On an ESA

Consider a trial of Standard Practice: IV iron Consider a trial of oral iron

Standard Practice: IV iron
1–3 months oral therapy especially if a therapy for patients who
therapy to maintain

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iron therapy more rapid increase in Hb are not receiving iron
iron repletion
(Limited by GI side effects) concentration is desired. supplementation

Figure 1 — Iron use in PD patients. The above algorithm is a recommendation only, from the guidelines, and according to our local practice, all
PD patients who are iron-deficient should be considered for intravenous iron (500 mg – 1,500 mg iron isomaltositde 100 [Monofer] depending
on body weight) without subjecting them to the oral iron therapy trial. TS = transferrin saturation; SF = serum ferritin; ESA = erythropoietin
stimulating agent; GI = gastrointestinal; IV = intravenous; Hb = hemoglobin; PD = peritoneal dialysis.

39.3% and 80.5% for PD and HD patients, respectively, which
may account for this reduced ESA dose.
A second retrospective study of 79 PD patients showed
that the cyclical fluctuations in Hb levels using standard cur-
rent practice in ESA administration (87.8% fluctuation) was
reduced by using the longer-acting continuous erythropoietin
receptor activator (CERA), presumably in part due to fewer
dose changes per patient (10). There was also a reduction in IV
iron requirements (30.2% to 8.3%) and better outcomes, but,
given the limitations of this small study, these results need to
be viewed with caution.
WHEN TO TREAT IRON DEFICIENCY IN PD
Various guidelines cite different targets for Hb. The KDIGO
2012 Guidelines have a conservative upper limit that Hb should
not exceed 115 g/L, whether or not on ESA therapy, while NICE
has a target upper limit of 120 g/L (3,4). All guidelines advise
that both absolute and functional iron deficiency require cor-
rection before subsequent effective use of ESA therapy. This is
especially relevant with the increasing emerging concerns of
stroke, thrombosis, and cancer risk with the liberal use of ESAs
(11). However, use of parenteral iron reduces platelet count
and theoretically may reduce thrombotic risk (12) in addition
to reducing ESA doses.
In ND-CKD and PD patients, iron therapy should be con-
sidered when the serum ferritin (SF) is less than 100 μg/L
or transferrin saturation (TS%) is less than 20%. However,
the predictive value of these measures is poor and relatively
unreliable despite their use over the last 3 decades (13).
Hypochromic red cells (HRC) greater than 6% or a mean hemo-
globin content of reticulocytes (CHr) of less than 29 g/L offer
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a potentially more reliable assessment of iron deficiency and
are currently recommended by NICE (3). Several other promis-
ing novel markers are under study but not yet used in routine
clinical practice (14).
HOW TO TREAT IRON DEFICIENCY IN PD PATIENTS
The effectiveness of oral iron supplements is limited by
poor bioavailability, poor patient compliance due to its gas-
trointestinal side effects, the need to time the medication
away from meals, and the magnitude of the iron deficiency
in PD. In patients treated with ESAs, even normal TS% and
SF levels are inadequate to support effective erythropoiesis
since the enhanced level of red blood cell production con-
sumes circulating iron faster than the reticuloendothelial
stores can release it (“functional” iron deficiency). Despite the
availability of numerous oral iron preparations, there is little
evidence in the literature to substantiate any additional gain
over standard ferrous sulphate or ferrous fumarate therapy in
PD patients (15).
Newer oral irons have been studied to improve tolerability
(ferric maltol and liposomal iron). Ferric maltol is effective in
correcting IDA in patients with inflammatory bowel disease,
and the results from those patients intolerant to standard oral
iron and given ferric maltol as an alternative are promising,
while the data on liposomal iron seem less promising (16,17).
Most methods to circumvent the hepcidin pathway have been
disappointing (18). The observed lack of efficacy of oral iron
is, in part, due to the increased iron requirements and per-
sistent low-grade chronic inflammatory effect of CKD on iron
utilization. There is an increase in both cytokine release (e.g.
interleukin-6) and upregulation of the regulatory protein
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ZEIDEN and BHANDARI JANUARY  2017 - VOL. 37, NO. 1 PDI

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Figure 2 — Possible strategies to target iron deficiency and modulate pathways to promote iron egress from the reticuloendothelial system and
the absorption of dietary iron from the duodenum by targeting the biological activity of the key regulator hepcidin and/or cytokines to increase
iron release from macrophages and to relocate it for erythropoiesis. HIF = hypoxia induced transcription factor; IP = intraperitoneal; ERFE =
erythroferrone; ESA = erythropoietin stimulating agent; Fe-TF = iron-loaded transferrin; IV = intravenous; RES = reticuloendothelial system.

hepcidin, which is synthesized in the liver (19). Hepcidin acts
on the ferroportin transporter to block iron absorption via the
gastrointestinal tract and mobilization of stored iron from the
liver and reticuloendothelial system (Figure 2).
Heme iron polypeptides (HIP) represent a promising,
novel oral iron supplementation to circumvent the hepcidin
pathway. A multicenter randomized controlled trial to deter-
mine the ability of HIP administration to augment iron stores
in 32 darbepoetin (DPO)-treated PD patients compared with
30 patients given conventional oral iron supplementation
demonstrated that the median TS% was 22% (inter-quartile
range [IQR] 16,29) in the HIP group compared with 20% (IQR
17,26) in controls (p = 0.65). Heme iron polypeptide treatment
was not significantly associated with TS% at 6 months on
multivariable analysis (p = 0.95) (20). Serum ferritin levels at
6 months were significantly lower in the HIP group (p = 0.003).
Hence the agent is unlikely to have a significant role in iron
supplementation in PD patients (20).
Intravenous iron therapy, however, does effectively circum-
vent the hepcidin pathway and leads to more rapid repletion of
iron stores (21). A randomized controlled trial comparing 26
PD patients given IV iron sucrose (200 mg iron once per week
for 4 weeks then once every other week for a further 4 weeks)
versus 20 PD patients given oral ferrous succinate (200 mg
3 times per day, for 8 weeks) demonstrated that Hb in the IV
group was significantly higher than in the oral group (34 vs
22% rise at 8 weeks of IV vs oral). Levels of SF and TS% were
also significantly increased in the IV group, and significantly
higher than in the oral group (326 vs 170% and 94 vs 34%
rise at 8 weeks, respectively). Finally the mean erythropoietin
(EPO) dose was significantly lower in the IV group than in the
oral group. These data demonstrate that although IV iron was
most effective, oral iron did have a significant effect on Hb and
iron at 8 weeks, suggesting it may be useful in some patients
(Figure 2) (22).
Ferric citrate, primarily developed as a non-calcium based
phosphate binder, has shown promise in replacing iron and
avoiding the potential effects of labile iron from IV iron prepa-
rations; however the published studies show that an average
dose of 8 tablets per day was required (23). This is equivalent
to 1,680 mg of elemental iron, a dose that would completely
saturate the iron absorption system and perhaps, in part,
circumvent the effects of raised hepcidin levels. Whether
this will be tolerable and beneficial in the long term in PD
patients remains to be confirmed. The study from Umanath
et al. of 441 subjects receiving renal replacement therapy,
which contained a proportion of PD patients, also showed
improvements in TS%, SF, and reduced IV iron and ESA use with
maintained Hb after a follow-up period of 52 weeks with use of
ferric citrate (23).
A Japanese phase-3, multicenter, open-label study inves-
tigated the efficacy and oral safety of ferric citrate in 56 PD
patients, with serum phosphate ≥ 5.6 and < 10.0 mg/dL. The
dose of ferric citrate hydrate was adjusted according to the tar-
get range of serum phosphate (3.5 – 5.5 mg/dL) for 12 weeks.
Serum phosphate was significantly reduced by 2.26 mg/dL

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PDI JANUARY  2017 - VOL. 37, NO. 1 ANEMIA IN PD PATIENTS
(p < 0.001). Treatment resulted in significant increases in
serum ferritin and transferrin saturation (p < 0.001) (24).
METHOD OF ADMINISTRATION – TOTAL DOSE INFUSIONS IN
PD PATIENTS
Used in isolation, IV iron leads to a 6 – 27 g/L rise in Hb con-
centration (25). Infrequent high dosing of IV iron to replenish
stores (usually 4 – 6 monthly doses) maintains iron status and
reduces regular attendances for iron therapy, resulting in less
disruption to patients’ lifestyle, especially those who work, and
greater convenience for healthcare professionals (26,27). From
a practical clinical perspective, target Hb and ferritin levels
may be achieved more rapidly, allowing hematinic levels to
achieve stability earlier than when using multiple small doses
of parenteral iron. The revised NICE guidelines have endorsed
this view of total dose infusions of iron (3), and we favor the
use of IV iron in PD patients as first-line therapy.
A recent multicenter trial of patients who had anemia,
PD-dependent CKD, stable ESA therapy, and variable iron
status (SF ≤ 500 μg/L, TS% ≤ 25%) were randomly assigned
to receive either 1 g of iron sucrose intravenously in 3 divided
doses (300 mg over 1.5 h on days 1 and 15, 400 mg over 2.5 h
on day 29) or no supplemental iron. The primary end point,
peak Hb increase, was higher (1.3 ± 1.1 versus 0.7 ± 1.1, mean ±
standard deviation [SD]; p = 0.0028), and anemia intervention
(transfusion, increase in ESA dose, or IV iron therapy outside
the protocol) occurred later (p = 0.0137) and less often in IV
iron-treated patients compared with untreated control subjects
(1 of 66 [1.3%] versus 5 of 30 [16.7%]). Among patients who
did not require intervention, iron-treated patients showed a
calculated net ESA dose decrease compared with untreated
control subjects. Therefore 1 g of IV iron sucrose in divided
doses appears to also be effective in iron repletion (28).
Currently, in our unit, PD patients are given a single dose of
1 – 1.5 g of IV iron isomaltoside 1000 (Monofer) over 15 – 30
minutes, respectively, for iron repletion.
Absorption of iron from the peritoneal cavity possibly occurs
via the capillary network of blood vessels surrounding the
intestinal mucosa (29). This process might depend on simple
diffusion along a concentration gradient, convective forces
during solute drag, or possibly via as yet unclassified channels,
such as aquaporins. However, from previous studies in our lab,
there was no measurable benefit of administering iron via this
route (30). In the current issue, Shetty A et al. (31) describe
a pilot animal study to determine the absorption of soluble
ferric pyrophosphate (SFP) iron from the peritoneal cavity and
its toxicity to the peritoneum in 7 New Zealand white rabbits
subjected to single PD exchanges with 4.25% Dianeal (Baxter
Healthcare, Deerfield, IL, USA) containing 5 mg/L iron on
days 14, 21, and 28. They found significant increases in serum
iron levels and TS% 30 and 120 minutes after instillation of PD
solution on day 21. Histological examination in all but 1 case
showed no significant serosal iron deposition or inflammation
of the parietal and visceral peritoneum. This study is intriguing
as a concept of iron repletion but needs to be replicated in a
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larger study and translated to the clinical setting. The longer-
term exposure of the peritoneal membrane to repeated iron
doses will also require careful evaluation.
POTENTIAL ADVERSE EFFECTS OF IRON
The formulation of iron is usually based on local recom-
mendations and clinician preferences. Safety is critical and has
been demonstrated in several studies for the current therapies
(32). There are 5 areas of potential risk with parenteral iron
preparations: in the short term, there are acute anaphylactic
and labile iron reactions (Fishbane effect), while longer-term
effects include effects of oxidative stress, possible increased
risk of infections, and risk of iron overload, all of which were
the subject of a KDIGO conference meeting in 2014 (33).
However, the data on potential adverse effects are limited in
PD patients. In a prospective observational study to determine
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whether a single dose of iron dextran can correct iron defi-
ciency during a period of 4 months in patients receiving PD,
no clinically significant adverse event was reported during the
infusion. Four months after the iron dextran infusion, there
was a significant increase of the mean Hb, SF levels, and TS%.
Almost all patients had a SF level higher than 100 μg/L and
TS% higher than 20%. They suggested that, in PD, patients
with IDA, a single infusion of iron dextran is usually enough
for a period of 4 months (34).
Comparable safety of low-molecular weight iron dextran
(LMW-ID) in varying doses over that of iron sucrose in PD
patients was shown in a retrospective review of 167 PD patients,
of whom 92 received LMW-ID and 75 received iron sucrose. Only
1 adverse event was reported in a patient who was administered
500 mg iron sucrose in a single infusion (35).
Wysowski et al. analyzed the US Food and Drug Administration
reports on side effects of 4 iron preparations and concluded
that the mortality possibly associated with iron was approxi-
mately 0.06 – 0.32 per million doses sold of each formulation
(36). Chertow et al. have eloquently summarized that serious
adverse effects associated with iron are relatively rare and
these side effects, including anaphylactoid reactions, can occur
with all iron preparations (32). Feldman et al., in an obser-
vational study of 32,566 HD patients who received 6 months
of a cumulative dose of iron, found that, after 2 years, there
was no increased all-cause mortality (37). However, Kalantar-
Zadeh et al., in another observational study, have suggested
that > 400 mg of iron per month may lead to an increase in
cardiovascular mortality (38). One would expect to see similar
findings in a PD population.
INFECTION RISK
It is advised to avoid administering IV iron to patients with
an active systemic infection, as there is a concern that IV iron
increases infection risk. In-vitro studies have indicated that
iron sucrose and iron gluconate cause significant inhibition
of transendothelial migration of polymorphonuclear neu-
trophrils and may depress phagocytosis. These findings are
9
ZEIDEN and BHANDARI JANUARY  2017 - VOL. 37, NO. 1 PDI
supported by a number of clinical studies (39). Comparative
toxicological analysis in animals after injection of IV iron
have confirmed that iron sucrose appears to cause cell death,
perhaps via induction of monocyte chemoattractant protein
(MCP)-1 generation in renal and extra-renal tissues leading
to inflammation in addition to toxic effects on monocytes and
macrophage (40). In contrast to HD (41), there are no data
to suggest increased risk of peritonitis or other infections in
PD patients.
OXIDATIVE STRESS
The majority of IV iron when administrated is taken up by
the reticuloendothelial system where it combines to ferritin or
transferrin for Hb production and storage. However, up to 2%
is released as labile iron, a potential catalyst for the production
of oxidant complexes and subsequent lipid peroxidation and
cell damage. Animal models have demonstrated that labile iron
causes glomerular dysfunction from oxidative stress and cell
cytotoxicity (mesangial and endothelial cells). Clinical stud-
ies suggest that labile iron may be higher after iron sucrose
compared with LMW-ID and ferric gluconate, but there are few
studies in PD patients (42). Ferric gluconate appears to reduce
creatinine clearance and increase proteinuria while both ferric
gluconate and iron dextran, but not carboxymaltose, increase
tissue markers of oxidative stress. In a further study aimed
at evaluating the effect of IV iron sucrose on intraperitoneal
homeostasis in PD patients, Breborowicz et al. (43) analyzed
blood and peritoneal dialysate samples from 10 patients who
received 100 mg of IV iron sucrose. Systemic and peritoneal
permeability, as well as transperitoneal transport, were studied
along with in-vitro tests conducted on human peritoneal meso-
thelial cells (MCs). They found that intravenous iron sucrose
caused inflammation and oxidative stress within peritoneal
MCs, which may impair viability of the peritoneum (43).
The potential for long-term harm from repeated total dose
infusion of iron is unknown. There is a growing wealth of clinical
data to reassure, but this remains the most critical element for
the future use of newer iron preparations in PD.
FUTURE THERAPIES FOR ANEMIA IN PD PATIENTS
Use of hypoxia-induced transcription (HIF) stabilizers are
currently under study. Orally active inhibitors of propyl hydrox-
ylase enzyme (PHD inhibitors) have been synthesized and lead
to increased HIF concentrations and hence more endogenous
erythropoietin production. Hypoxia-induced transcription
is involved in erythropoiesis, as it promotes erythropoietin
production in the kidney, upregulates erythropoietin recep-
tors in the bone marrow but also increases iron mobilization
from gut and macrophages in both hepcidin-dependent and
hepcidin-independent pathways. Propyl hydroxylase enzyme
inhibitors produce effects in the body that are similar to those
that occur at high altitude in response to hypoxia, essentially
causing the body to make more red blood cells. In addition to
stimulating erythropoiesis, PHD inhibitors have been shown
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to reduce circulating levels of hepcidin, which is upregulated
in CKD and limits iron absorption in the gut. Besarab and col-
leagues found that 12 weeks of roxadustat treatment, with or
without oral or IV iron, increased Hb levels (mean Hb increased
by ≥ 2.0 g/dL within 7 weeks regardless of dialysis modality)
in an open-label study of 60 anemic patients on incident HD
or PD who had never received ESA analogues (44). Roxadustat
treatment also significantly reduced mean serum hepcidin
levels 4 weeks into the study: by 80% in HD patients receiving
no iron (n = 22); 52% in HD and PD patients receiving oral iron
(n = 21); and 41% in HD patients receiving IV iron (n = 9). This
is currently the most promising therapy effectively manipulat-
ing the physiological response to anemia in CKD.
Newer and potentially more physiological therapies are
under study as summarized in Table 1. These consist of strat-
egies modulating pathways to promote iron egress from the
reticuloendothelial system and the absorption of dietary iron
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from the duodenum by targeting the biological activity of
the key regulator hepcidin and/or cytokines to increase iron
release from macrophages and to relocate it for erythropoiesis.
Early studies in animal models of anemia of chronic disease
have confirmed that different anti-hepcidin strategies amelio-
rate anemia and reverse hypoferremia (45). The possible use of
anti-cytokine therapies has been shown to improve anemia in
rheumatic disease via effects on IL-6 and hepcidin expression
and increase availability of iron originating from macrophages
for erythropoiesis (46).
Several companies are investigating small hairpin RNA
(shRNA), short/small interfering RNA (siRNA) and antisense
oligonucleotide systems to target transcription and translation
of hepcidin directly in the liver, to reduce hepcidin expres-
sion and increase serum iron levels in different inflammation
mouse models (47). Others have developed a hepcidin-specific
spiegelmer (NOX-H94) (48). This chelates serum hepcidin via
use of synthetic single-stranded oligonucleotides that bind
ligands with high affinity (Spiegelmers).
Anti-ferroportin antibodies which inhibit ferroportin deg-
radation by specifically binding to ferroportin are also under
development. Although chelating hepcidin directly is a very
specific method to influence iron metabolism in anemia of
chronic disease, this method has its limitations due to the high
rate of hepcidin production. Therefore, in parallel with hepcidin
binding strategies, companies have developed strategies to
inhibit hepcidin production.
Anti-bone morphogenetic protein 6 (BMP6) monoclonal
antibody treatment decreases serum hepcidin expression and
increases serum iron levels in healthy and Hfe transgenic mice
(49). Like anti-BMP antibodies, heparins have been reported
to present BMP sequestering activity, leading to decreased
hepcidin levels (50). Patients who have been treated with
heparins because of vein thrombosis present with significant
lower hepcidin levels as compared with control patients.
In animal studies using different rodent models of acute
and chronic anemia of inflammation, Dorsomorphin and its
derivate LDN-193189, both BMP receptor Type I kinase inhibi-
tors, show marked effects on elevated hepcidin levels. They
PDI JANUARY  2017 - VOL. 37, NO. 1 ANEMIA IN PD PATIENTS

TABLE 1
Summary of Recent Molecules for Treatment of Anemia of Chronic Disease

Molecule
(pharmaceutical company) Mode of action Effect

mAb2.7 (Amgen) Anti-hepcidin antibody Decreases hepcidin expression

Increases iron availability from macrophages

LY2787106 (Eli Lilly) Anti-hepcidin antibody Decreases hepcidin expression

Increases iron availability from macrophages

Short hairpin RNA (Amgen) Halts transcription of hepcidin directly Decreases hepcidin expression
in the liver (in vitro)

siRNA (Alnylam Pharmaceuticals) Halts translation of hepcidin in the liver Decreases hepcidin expression
(in vitro)

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Antisense oligonucleotide systems Halts transcription of hepcidin directly Decreases hepcidin expression
  (Xenon pharmaceuticals) in the liver (in vitro)

Spiegelmer NOX-H94 (Noxxon) Synthetic single-stranded oligonucleotide Chelates serum hepcidin

that binds ligands

Anti-ferroportin antibody (Eli Lilly) Anti-ferroportin hepcidin interaction Inhibits ferroportin degradation

Tocilicumab (Hoffmann–La Roche Anti-IL-6R antibody Lowers CRP and hepcidin

  and Chugai) Increases hemoglobin levels
Reverses anemia in patients with MCD

Momelotinib (invivogen) Jak1/Jak2 inhibitor Ameliorates anemia in myelofibrosis

Anti-BMP6 BMP sequestering activity Decreases hepcidin levels

Dorsomorphin/LDN-193189 BMP receptor Type I kinase inhibitors Inhibit liver and serum hepcidin expression

HJV.Fc (Ferrumax Pharmaceuticals) BMP receptor Type I kinase inhibitors Increase serum iron levels
Ameliorate anemia in vitro

PHD inhibitors Increases HIF concentration Promotes EPO production

Stimulates erythropoiesis
Upregulates EPO receptor in the bone marrow
Increases iron mobilization from gut and macrophages
Reduces circulating levels of hepcidin

siRNA = short/small interfering RNA; IL = interleukin; CRP = c-reactive protein; MCD = Multicentric Castleman Disease; BMP = bone morphogenetic
protein; LDN = LDN 193189 derived from structure activity relationship studies of Dorsomorphin, a BMP inhibitor; HJV = hemojuvelin; PHD =
propyl hydroxylase enzyme; HIF = hypoxia-induced transcription; EPO = erythropoietin.

completely inhibit liver and serum hepcidin expression, leading supplementation remains the cornerstone of initial treatment
to increased hemoglobin levels. However, the inhibition profile in most PD patients to a target Hb of 115 – 120g/L. The drivers
of both kinase inhibitors may be non-specific for safe use in a of this practice include overall cost reduction, improved patient
future clinical setting. convenience (especially as a home based therapy), improved
compliance, preservation of venous access, and reduced blood
SUMMARY transfusions. Larger and longer-term studies are required to
confirm long-term safety of IV therapy in this population with
The benefits of improving anemia are well established. their associated high comorbidity and examine effects on the
Many questions, however, remain unanswered from the peritoneal membrane. The use of HIF stabilizers is promising
limited clinical data, but results from those studies avail- but too early to institute into routine clinical practice, while
able have directed clinical management. Intravenous iron newer oral irons and those molecules acting on the hepcidin
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ZEIDEN and BHANDARI JANUARY  2017 - VOL. 37, NO. 1 PDI
pathway may prove successful. The role of iron and the need
to establish adequate iron repletion prior to commencing an
ESA is now explicit in published guidelines, but the method of
correction may change in the future.
REFERENCES
1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al.
Prevalence of chronic kidney disease in the United States. JAMA 2007;
298(17):2038–47.
2. Jain AK, Blake P, Cordy P, Garg AX. Global trends in rates of peritoneal
dialysis. J Am Soc Nephrol 2012; 23(3):533–44.
3. National Institute of Health and Care Excellence. Chronic kidney disease:
managing anaemia. NICE Guideline NG8. 2015.
4. Locatelli F, Barany P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D,
et al. Kidney Disease: Improving Global Outcomes guidelines on anaemia
management in chronic kidney disease: a European Renal Best Practice
position statement. Nephrol Dial Transplant 2013; 28(6):1346–59.
5. Bhandari S. Iron therapy in patients with chronic kidney disease. Transfus
Alt Transfus Med 2012; 12:115–21.
6. Agarwal R. Nonhematological benefits of iron. Am J Nephrol 2007;
27(6):565–71.
7. Bhandari S. Risk factors and metabolic mechanisms in the pathogenesis
of uraemic cardiac disease. Front Biosci (Landmark ed) 2011; 16:1364–87.
8. Li H, Wang SX. Intravenous iron sucrose in peritoneal dialysis patients
with renal anemia. Perit Dial Int 2008; 28(2):149–54.
9. Wetmore B, Peng Y, Monda L, Kats M, Kim H, Bradbury BD, et al. Trends
in anemia management practices in patients receiving hemodialysis and
peritoneal dialysis: a retrospective cohort analysis. Am J Nephrol 2015;
41(4–5):354–61.
10. Selby N, Fonseca S, Fluck R, Taal M. Hemoglobin variability with epoetin
beta and continuous erythropoietin receptor activator in patients on
peritoneal dialysis. Perit Dial Int 2011; 32(2):177–82.
11. Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al. Eryth-
ropoietic response and outcomes in kidney disease and type 2 diabetes.
N Engl J Med 2010; 363(12):1146–55.
12. Hazara A, Bhandari S. Intravenous iron infusion reduces platelet counts
in patients with chronic kidney disease. J Clin Pharm Ther 2015; 40:20–3.
13. Ferrari P, Kulkarni H, Dheda S, Betti S, Harrison C, St Pierre TG, et al. Serum
iron markers are inadequate for guiding iron repletion in chronic kidney
disease. Clin J Am Soc Nephrol 2011; 6(1):77–83.
14. Chinnappa S, Bhandari S. Influence of intravenous iron therapy on novel
markers of iron deficiency. Int J Artif Org 2010; 33(5):297–301.
15. Bhandari S. Oral iron properties and current place in the treatment of
anaemia. Drug Profile. Prescriber 2012:12–28.
16. Gasche C, Ahmad T, Tulassay Z, Baumgart DC, Bokemeyer B, Buning C, et al.
Ferric maltol is effective in correcting iron deficiency anemia in patients
with inflammatory bowel disease: results from a phase-3 clinical trial
program. Inflamm Bowel Dis 2015, 21(3):579–88.
17. Pisani A, Riccio E, Sabbatini M, Andreucci M, Del Rio A, Visciano B. Effect of
oral liposomal iron versus intravenous iron for treatment of iron deficiency
anaemia in CKD patients: a randomized trial. Nephrol Dial Transplant 2015;
30(4):645–52.
18. Nagaraju SP, Cohn A, Akbari A, Davis JL, Zimmerman DL. Heme iron poly-
peptide for the treatment of iron deficiency anemia in non-dialysis chronic
kidney disease patients: a randomized controlled trial. BMC Nephrol 2013;
14:64.
19. Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annual
Review of Medicine 2011, 62:347–60.
20. Barraclough K, Brown F, Hawley C, Leary D, Noble E, Campbell SB,
et al. A randomized controlled trial of oral heme iron polypeptide
versus oral iron supplementation for the treatment of anaemia in peri-
toneal dialysis patients: HEMATOCRIT trial. Nephrol Dial Transplant 2012;
27(11):4146–53.
21. Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovici L, Shpilberg O, Gafter U.
Intravenous versus oral iron supplementation for the treatment of anemia
This single copy is for your personal, non-commercial use only.
12 For permission to reprint multiple copies or to order presentation-ready
copies for distribution, contact Multimed Inc. at marketing@multi-med.com
in CKD: systematic review and meta-analysis. Am J Kidney Dis 2008;
52(5):897–906.
22. Li H, Wang SX. Intravenous iron sucrose in peritoneal dialysis patients
with renal anemia. Perit Dial Int 2008; 28(2):149–54.
23. Umanath K, Jalal DI, Greco BA, Umeukeje EM, Reisin E, Manley J, et al.
Ferric citrate reduces intravenous iron and erythropoiesis-stimulating
agent use in ESRD. J Am Soc Nephrol 2015; 26(10):2578–87.
24. Yokoyama K, Akiba T, Fukagawa M, Nakayama M, Hirakata H. JTT-751 for
treatment of patients with hyperphosphatemia on peritoneal dialysis.
Nephron Clin Pract 2014; 128(1–2):135–40.
25. Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, et
al. Anemia management and outcomes from 12 countries in the Dialysis
Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004;
44(1):94–111.
26. Bhandari S, Naudeer S. Improving efficiency and value in health care.
Intravenous iron management for anaemia associated with chronic kidney
disease: linking treatment to an outpatient clinic, optimizing service
provision and patient choice. J Eval Clin Pract 2008; 14(6):996–1001.
27. Cooke M, Lamplugh A, Naudeer S, Edey M, Bhandari S. Efficacy and toler-
ability of accelerated-dose low-molecular-weight iron dextran (Cosmofer)
Downloaded from http://www.pdiconnect.com/ at HINARI BAND 1 on February 15, 2017
in patients with chronic kidney disease. Am J Nephrol 2012; 35(1):69–74.
28. Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich
K, et al. Roxadustat (FG-4592): correction of anemia in incident dialysis
patients. J Am Soc Nephrol 2016; 27(4):1225–33.
29. Thirayothin P, Crosby WH. The distribution of iron injected intraperitone-
ally. Evidence of serosal “absorption” by the small intestine. J Clin Invest
1962; 41:1206–10.
30. Moniem KA, Bhandari S. Bolus intraperitoneal iron versus intravenous iron
in peritoneal dialysis patients; a prospective study. Transfus Alt Transfus
Med 2007; 9:101–7.
31. Shetty A, Hawkins JV, Gupta A. Peritoneal dialysis using soluble ferric
pyrophosphate as an iron supplement in rabbits. Perit Dial Int 2017;
37(1):121–2.
32. Chertow GM, Winkelmayer WC. On the relative safety of intravenous
iron formulations: new answers, new questions. Am J Hematol 2010;
85(9):643–4.
33. Macdougall IC, Bircher AJ, Eckardt KU, Obrador GT, Pollock CA, Stenvinkel
P, et al. Iron management in chronic kidney disease: conclusions from
a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies
Conference. Kidney Int 2016; 89(1):28–39.
34. Ficheux M, Cuny P, Lecouf A, Ryckelynck JP, Hurault de Ligny B, Lobbedez
T. Treatment of iron deficiency by a bolus intravenous iron dextran in
peritoneal dialysis. Nephrol Ther 2011; 7(7):558–61.
35. Solak Y, Atalay H, Guney I, Turkmen K, Kaya E, Turk S. Comparison of
adverse event profiles of intravenous low-molecular-weight iron dex-
tran and iron sucrose in peritoneal dialysis patients. Ren Fail 2011;
33(3):307–11.
36. Wysowski DK, Swartz L, Borders-Hemphill BV, Goulding MR, Dormitzer C.
Use of parenteral iron products and serious anaphylactic-type reactions.
Am J Hematol 2010; 85(9):650–4.
37. Feldman HI, Joffe M, Robinson B, Knauss J, Cizman B, Guo W, et al. Admin-
istration of parenteral iron and mortality among hemodialysis patients.
J Am Soc Nephrol 2004; 15(6):1623–32.
38. Kalantar-Zadeh K, Regidor DL, McAllister CJ, Michael B, Warnock DG.
Time-dependent associations between iron and mortality in hemodialysis
patients. J Am Soc Nephrol 2005; 16(10):3070–80.
39. Gupta A, Zhuo J, Zha J, Reddy S, Olp J, Pai A. Effect of different intravenous
iron preparations on lymphocyte intracellular reactive oxygen species
generation and subpopulation survival. BMC Nephrol 2010; 11:16.
40. Johnson AC, Becker K, Zager RA. Parenteral iron formulations differentially
affect MCP-1, HO-1, and NGAL gene expression and renal responses to
injury. Am J Physiol Ren Physiol 2010; 299(2):F426–35.
41. Brookhart MA, Freburger JK, Ellis AR, Wang L, Winkelmayer WC, Kshirsagar
AV. Infection risk with bolus versus maintenance iron supplementation in
hemodialysis patients. J Am Soc Nephrol 2013; 24(7):1151–8.
42. Stefansson BV, Haraldsson B, Nilsson U. Acute oxidative stress follow-
ing intravenous iron injection in patients on chronic hemodialysis: a
PDI JANUARY  2017 - VOL. 37, NO. 1 ANEMIA IN PD PATIENTS

comparison of iron-sucrose and iron-dextran. Nephron Clin Pract 2011;
118(3):c249–56.
43. Breborowicz A, Połubinska A, Kupczyk M, Wanic-Kossowka M, Oreopoulos
DG. Intravenous iron sucrose changes the intraperitoneal homeostasis.
Blood Purif 2009; 28(1):53–8.
44. Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich
K, et al. Roxadustat (FG-4592): correction of anemia in incident dialysis
patients. J Am Soc Nephrol 2016; 27(4):1225–33.
45. Theurl I, Schroll A, Sonnweber T, Nairz M, Theurl M, Willenbacher W, et
al. Pharmacologic inhibition of hepcidin expression reverses anemia of
chronic inflammation in rats. Blood 2011; 118(18):4977–84.
46. Weiss G, Schett G. Anaemia in inflammatory rheumatic diseases. Nat Rev
Rheumatol 2013; 9(4):205–15.
47. Sasu BJ, Cooke KS, Arvedson TL, Plewa C, Ellison AR, Sheng J, et al.
Antihepcidin antibody treatment modulates iron metabolism and is
effective in a mouse model of inflammation-induced anemia. Blood 2010;
115(17):3616–24.
48. Schwoebel F, van Eijk LT, Zboralski D, Sell S, Buchner K, Maasch C, et al.
The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-
induced anemia in cynomolgus monkeys. Blood 2013; 121(12):2311–5.
49. Andriopoulos B, Jr., Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, et
al. BMP6 is a key endogenous regulator of hepcidin expression and iron
metabolism. Nat Genet 2009; 41(4):482–7.
50. Poli M, Girelli D, Campostrini N, Maccarinelli F, Finazzi D, Luscieti S, et
al. Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo.
Blood 2011; 117(3):997–1004.

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