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32  Management of Anemia in Children Receiving Chronic Dialysis

inflammatory stimuli that induce its production,
including IL-6 [111]. Fully human anti-hepcidin
antibodies have been successfully developed and
applied in animal models [112].

ESA Hyporesponsiveness:
Definition and Risk Factors
There will be patients who, despite iron supplementation combined with escalating ESA dosing,
fail to increase hemoglobin levels above 10  g/
dL. KDIGO defines initial ESA hyporesponsiveness as no increase in hemoglobin concentration
from baseline after the first month of appropriate
weight-based dosing and acquired ESA hyporesponsiveness as a requirement for two increases
in ESA doses up to 50% beyond the dose which
they had previously required to maintain a stable
hemoglobin concentration [28]. An alternative
definition is a persistent hemoglobin deficit after
3 months of high-dose ESA treatment (rHuEPO
in excess of 400 units/kg weekly or darbepoetin
alfa in excess of 1 μg/kg weekly) [67, 113].
In the IPPN registry, ESA resistance and escalated ESA dosing have been associated with
inflammation, fluid retention, and hyperparathyroidism [33]. The observational association
between higher ESA doses and mortality in pediatric patients may, in turn, reflect the impact of
chronic inflammatory processes which negatively
impact patient survival, rather than a direct ESA
effect on the risk for death. While ESA hyporesponsiveness may be chronic, it can also be seen
in the context of shorter-term clinical events such
as infections or surgical procedures which may
negatively impact the response to ESA therapy.
Thus, the potential risks and benefits of escalation in ESA dose vs. administration of intravenous iron vs. red blood cell transfusion in this

setting must be assessed for individual patients
[28]. Attention should also be paid to determining whether affected patients may be suffering
from vitamin or mineral deficiencies resulting
from malnutrition. Other potential causes of ESA
hyporesponsiveness include the following:

623

 one Disease Secondary
B
to Hyperparathyroidism
Severe hyperparathyroidism can contribute to
anemia and ESA hyporesponsiveness due to
decreased bone marrow production of red blood
cells due to myelofibrosis [96, 114, 115].

Medications
There are a variety of medications that can contribute to anemia in dialysis patients including,
but not limited to, ACE inhibitors and anti-­
metabolites causing bone marrow suppression. A
review of the medication list for potential medications contributing to anemia should be undertaken for any dialysis patient with ESA-resistant
anemia.

Aluminum Toxicity
Although aluminum-based compounds are used
far less frequently in the management of hyperphosphatemia than in the past, awareness of aluminum toxicity is important. Chronic use of
aluminum-based antacids and phosphate binders
remains the most common cause of aluminum
toxicity in patients with ESKD. In animal studies, aluminum has been shown to induce partial
resistance to EPO and to increase heme ­oxygenase

activity, which subsequently increases destruction of the heme protein [116, 117].

Hypervolemia
Patients with less residual urine output and who
are clinically judged to be fluid-overloaded demonstrate lower hemoglobin levels, suggesting that
some portion of treatment-resistant anemia may
in fact be due to the chronic dilution of the red
cell mass in an expanded extracellular volume
[33]. This should be addressed with more effective ultrafiltration.


M. A. Atkinson and B. A. Warady

624

Anti-rHuEPO Antibodies

Iron Therapy

ESA-induced pure red cell aplasia (PRCA) is an
increasingly rare hematologic disorder that was
first described in the late 1990s. PRCA is characterized by a severe and progressive normocytic
anemia, reticulocytopenia, and the almost complete absence of erythroid precursors in the bone
marrow, with affected patients becoming transfusion dependent [118]. ESA-induced PRCA is
secondary to the development of neutralizing
antibodies which block the interaction between
an ESA (including epoetin alfa or beta, darbepoetin alfa, or endogenous EPO) and its receptor
[118]. Most initial cases of ESA-induced PRCA
were seen in countries where epoetin alfa formulated with a polysorbate 80 stabilizer was administered to CKD patients subcutaneously;
regulatory advisories have subsequently discouraged this practice [119].

KDIGO recommends iron supplementation in
children on dialysis to maintain TSAT >20% and
ferritin >100  ng/mL and recommends intravenous iron supplementation in children on hemodialysis [28].

Red Blood Cell Transfusion
Despite best efforts in anemia management, and
often in the setting of ESA hyporesponsiveness,
patients sometimes do require packed red blood
cell transfusion. The decision to transfuse
should not be based on an arbitrary hemoglobin
level, but rather guided by symptoms and after
weighing the specific risks and benefits for the
individual patient. Red blood cell transfusions
are associated with an increased risk for the
development of human leukocyte antigen (HLA)
antibodies. In adults, leukoreduction of blood
products is an ineffective means to decrease
HLA sensitization, and red cell transfusions
lead to clinically significant increases in HLA
antibody strength and breadth [120, 121]. These
antibodies serve as a barrier to future transplantation and may adversely affect graft outcomes
[120, 121]. More studies are needed to define
the risks associated with red cell transfusion in
children with regard to HLA sensitization and
graft outcomes.

Oral Iron Supplementation
Most children on dialysis will require iron supplementation as part of their anemia treatment
plan in order to maintain hemoglobin levels and

replete iron stores. Children on hemodialysis in
particular may have chronic blood loss via the
dialysis circuit which exacerbates iron deficiency. Enteral iron supplementation is relatively inexpensive, highly available, and
generally safe and efficacious in children with
chronic kidney disease, although GI side effects
of nausea or constipation are sometimes
reported. Although true intolerance is relatively
rare, it may be a contributing factor to the poor
adherence that may arise to prescribed oral supplementation. In addition, co-administration of
iron with phosphate binders or antacids can
limit absorption due to changes in gastric pH
[64]. The usual dosing range for oral iron supplementation is 3–6  mg/kg/day of elemental
iron, either daily or divided into two daily doses.
The most commonly available oral iron preparations come in ferrous (Fe2+) or ferric (Fe3+)
forms, including ferrous sulfate and ferric iron
polymaltose complexes [16]. Ferrous sulfate has
better bioavailability (10–15%) than ferric iron
and is available in prolonged release forms [16].
Some ferric polymaltose complex formulations
are available with added vitamins C, B12, and
folic acid to enhance iron absorption and replete
other vitamins associated with red blood cell
production. However, there is no evidence that
ferric iron formulations are superior to ferrous
preparations for oral supplementation in children on dialysis.


32  Management of Anemia in Children Receiving Chronic Dialysis

Intravenous Iron Supplementation

Children on dialysis often benefit from iron preparations administered intravenously due to the
poor enteral absorption or poor tolerance associated with oral administration. There are an
increasing number of available iron preparations
for clinicians opting for intravenous therapy
(Table 32.4).
Early IV iron compounds were formulated as
inorganic iron oxyhydroxide complexes, which
could result in the release of labile iron directly
into the plasma leading to the formation of highly
reactive free radicals associated with severe toxicity, including hypotension. Newer preparations
surround the iron oxyhydroxide core with carbohydrate shells of different sizes and polysaccharide branch characteristics [123]. The shell
characteristics determine how long the iron
remains circulating, with larger molecular weight
formulations such as iron dextran resulting in
longer plasma residence, while products with
smaller shells are more labile and likely to release
iron directly into the plasma before it can be
metabolized in the reticuloendothelial system
[124–126]. Intravenous iron therapy can be delivered as a loading phase, using consecutive doses

625

to replete iron stores, or as smaller maintenance
doses given weekly.
IV iron has been shown to be effective in
repleting iron stores in children. In 2005,
Gillespie and Wolf published a meta-analysis that
combined clinical data on IV iron use in children
on HD [127]. They evaluated nine studies including eight cohort studies and one prospective trial
with historical controls, and they showed

increased hemoglobin, ferritin, and transferrin
saturation levels and reduced use of ESAs with
IV iron use. In 2004, Warady et al. performed an
RCT to examine the preferential route of iron
administration for children. The authors prospectively randomized 35 iron-replete children
<20  years old with ESKD on hemodialysis to
receive either IV iron dextran with each dialysis
session (n = 18) or oral iron daily (n = 17) for up
to 16 weeks. In both groups the hemoglobin was
stable, but the IV iron group experienced a significant increase in serum ferritin and the oral
iron group did not. There was no statistically significant difference in ESA dosing detected
between the two groups [128]. Sodium ferric gluconate complex has also been shown in pediatric
studies to safely and effectively increase and
maintain iron parameters in children undergoing

Table 32.4  Physiochemical characteristics and pharmacokinetics of iron formulations for intravenous administration
(with permission [122])
Properties
Molecular mass (D)
Carbohydrate shell

Ferumoxytol
731,000
Polyglucose
sorbitol
carboxymethylether

Median shell/
particle diameter
(nm)

Relative catalytic
iron release
Relative stability of
elemental iron
within the
carbohydrate shell
Relative osmolality
Administration (iv
push) rates
t1/2 (h)

26.3

Ferric carboxy
maltose
150,000
Carboxymaltose

Iron dextran
410,000
Dextran
polysaccharide

Iron sucrose
252,000
Sucrose

23.1

12.2

8.3

Ferric gluconate
200,000
Gluconate,
loosely
associated
sucrose
8.6

+

+

++

+++

+++

High

High

High

Medium

Low

Isotonic
30 mg/s

Isotonic
Bolus push
7–12

Hypertonic
Approximately
20 mg/min
6

Hypertonic
12.5 mg/min

Approximately 15

Isotonic
50 mg (1 ml)/
min
5–20

Approximately 1


626

hemodialysis, with pharmacokinetic data demonstrating that mean serum iron concentrations
increase in a dose-dependent manner after intravenous administration [129–131].

Iron Safety
Given trial evidence in adults that higher ESA
doses are associated with adverse cardiovascular
outcomes, using IV iron to reduce ESA dose
requirements is an attractive treatment option.
However, the administration of IV iron, even
with new formulations, is not without risk.
Concerns about potential adverse effects of IV
iron supplementation include iron overload,
adverse reactions including anaphylaxis, and
increased risk when administered in the context
of active infections. There have not been any
pediatric studies focused on the long-term effects
of IV iron supplementation in patients on chronic
dialysis. The DRIVE trial, conducted in adults on
dialysis, demonstrated that IV ferric gluconate
was effective at raising hemoglobin and decreasing ESA dose requirements in patients with ferritin levels 500–1200 ng/mL and TSATs ≤25%,
dispelling the widely held belief that patients
with ferritin levels in this range were unlikely to
benefit from IV iron [132]. However, further
study is needed to determine whether IV iron
supplementation is effective and safe in children
with higher ferritin levels. KDIGO recommends
avoidance of IV iron in patients with active systemic infections [28]. There is biologic plausibility to this, as iron may impair neutrophil and
T-cell function and serve as a growth factor for
pathogens [133]. However, there have been few
studies testing this hypothesis. Ishida et  al.
showed, using observational data, that adults on
hemodialysis who received IV iron within

14  days of hospitalization for a bacterial infection had no increased risk for 30-day or 1-year
mortality or readmission or death within 30 days,
but no comparable studies have been conducted
in children [133]. Goldstein et  al. conducted a
RCT in 145 children with CKD to compare the
safety and efficacy of varying doses of iron
sucrose. They showed that a 0.5 mg/kg dose was

M. A. Atkinson and B. A. Warady

non-inferior to higher-dosing regimens (1  mg/kg
and 2  mg/kg) in terms of reaching a composite
endpoint of hemoglobin in the range of 10.5–
14 g/dL, TSAT 20–50%, and a stable ESA dose,
supporting the practice of utilizing the lowest
effective dose of IV iron in children [134].
Dialysis contributes to oxidative stress, the
result of pro-oxidant molecules overwhelming
the antioxidant defense mechanisms [135].
Studies performed in adults on hemodialysis
have demonstrated that IV iron infusions are
associated with an increased accumulation of
biomarkers of oxidative stress [135]. Bolus or
rapid IV infusion may be more likely to trigger
an oxidative response and slow IV intradialytic
infusion may be preferable in minimizing inflammatory or oxidative response, but no studies have
specifically examined this in children [136–138].
There is a shortage of research to evaluate the
effect of differences in formulation and pharmacokinetics of such agents and to determine
whether repeated induction of oxidative stress

has longer-term sequelae in terms of inflammation and cellular and tissue iron deposition.

 ovel Routes of Iron
N
Supplementation
Ferric pyrophosphate citrate (FPC, Triferic®) was
approved by the US FDA in April 2016 for the
replacement of iron to maintain hemoglobin in
adults on hemodialysis [139]. FPC is dissolved in
dialysate and administered via dialysis. In contrast to the IV iron administration of other iron
preparations which can lead to the presence of
non-transferrin-bound iron in the circulation and
potentially trigger the generation of pro-oxidant
and atherogenic molecules, FPC is quickly transferrin bound and removed from the circulation
[140]. Pratt et al. conducted a pediatric study in
which FPC was administered via the dialysate
(added to bicarbonate concentrate) or intravenously (via the venous blood return line) to 22
hemodialysis patients <18  years of age during
dialysis treatment and found it was well tolerated
[141]. The mean serum total iron concentrations
peaked 3–4 h after administration, and iron expo-


32  Management of Anemia in Children Receiving Chronic Dialysis

sure based on maximum serum concentration
was greater after dialysate administration compared to the intravenous route [141]. Serum iron
concentrations were also higher in 12–<18-year-­
old subjects after dosing compared to <12-year-­
olds [141]. Ferric citrate is a novel oral phosphate

binder which also supplies elemental iron and
has the potential benefit of providing therapy for
at least two CKD comorbidities in a single agent,
a potentially adherence-enhancing strategy. The
ferric ion in ferric citrate combines with dietary
phosphorus in the GI tract, but the excess ferric
ions are reduced by the bowel mucosa to ferrous
iron and absorbed into the systemic circulation
[142]. Although ferric pyrophosphate citrate and
oral ferric citrate have been approved for use in
adults, the safety and efficacy of these agents
have yet to be systematically assessed in children
with CKD.

Future Directions
Anemia remains one of the most common comorbidities affecting children on dialysis, with dysregulated erythropoietin production and
iron-restricted erythropoiesis the mechanisms
targeted by most currently available clinical therapies. An ongoing treatment challenge is identifying the optimal target hemoglobin levels for
children in terms of promoting survival, growth,
cognitive function, and overall health, as the recommendations for “target” hemoglobin levels in
dialysis patients are largely based on data extrapolated from adult studies. It is critical that emerging anemia therapies continue to have their safety
and efficacy assessed in pediatric dialysis populations so that our patients can benefit from
advances in treatment strategies.

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