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32  Management of Anemia in Children Receiving Chronic Dialysis

zinc intake and may be associated with a microcytic anemia and leukopenia, and is correctable with supplementation [71]. Anemia with
concurrent lymphopenia or thrombocytopenia
should prompt an evaluation for malignancy,
autoimmune disease, or drug toxicity.
Uremia itself contributes to anemia in children
on dialysis. Accumulated uremic toxins and associated oxidative stress can induce changes in
erythrocyte cell membranes and cytoskeletons
which promote hemolysis and a shortened cell
life span, with red cell survival time decreased by
as much as 50% compared to healthy subjects
[72]. Thus, inadequate dialysis may contribute to
the risk for anemia. In adults on chronic hemodialysis, more hours of dialysis per week have been
associated with higher hemoglobin levels and a
lower required ESA dose [73, 74].

Erythropoietin Levels
EPO deficiency is a diagnosis of exclusion. In the
setting of normal renal function, plasma EPO levels increase exponentially with decreasing hemoglobin, and values may rise from the normal
range of approximately 15 units/liter to as high as
10,000  units/liter [9]. Thus, measuring plasma
levels of EPO in children with kidney disease is
not useful to clarify the contribution of relative
EPO deficiency to anemia, because even if EPO
levels are detectable above the normal range, they
may still be inappropriately low for the degree of
anemia present.

Laboratory Assessment of Iron Status
In clinical practice, the most commonly utilized

biomarkers of stored iron remain serum ferritin
and transferrin saturation (TSAT). KDIGO recommends iron supplementation in children on
dialysis to maintain TSAT >20% and ferritin
>100  ng/mL and recommends IV iron supplementation in children on hemodialysis [28]. Both
ferritin and TSAT have limited sensitivity and
specificity to predict bone marrow iron stores and
erythropoietic response to iron supplementation.

617

Distinguishing hepcidin-mediated impaired iron
trafficking from absolute iron deficiency anemia
presents a clinical challenge, as both disorders
are characterized by a microcytic anemia with
low reticulocyte counts, decreased serum iron
concentration, and low transferrin saturation.
However, serum ferritin levels can be helpful in
distinguishing the disorders; absolute iron deficiency is associated with a low ferritin concentration, while impaired trafficking is characterized
by normal or elevated serum ferritin, reflecting
iron sequestration in the reticuloendothelial system. In contrast, in patients with functional iron
deficiency on ESA therapy, the rate of enteral
iron absorption or release from reticuloendothelial cells is inadequate to meet the demands for
erythropoiesis; these patients often have low
TSAT values with normal or high levels of ferritin, suggesting that patients may benefit from
treatment with intravenous iron [75, 76]. The
limitations of serum ferritin as a marker of accessible stored iron are, however, well established,
including higher ferritin levels being associated
with lower hemoglobin levels and ferritin serving
as an acute phase reactant [33, 77]. Although ferritin is measured in serum, its function is as an
intracellular iron-storage protein. Although we

assume in clinical practice that the serum concentrations reflect some steady-state “leakage” of
intracellular ferritin, the process by which ferritin
enters the circulation is not well understood [76].
TSAT has recognized limitations as well,
including diurnal fluctuations and reduction in
the setting of malnutrition and chronic disease
[78]. There is thus a need for diagnostic tests
which more accurately predict the need for or
response to iron therapy. A study in pediatric
dialysis patients found that the reticulocyte
hemoglobin content (Ret-He), which is not an
acute phase reactant and reflects iron availability
for incorporation into reticulocytes over the previous 2–4  days, performed better than either
­ferritin or TSAT to distinguish between iron deficiency and suboptimal ESA dosing [78]. Thus,
Ret-He may be an attractive alternative indicator
of iron status in clinical practice, although it
remains limited currently as it is only measured
by flow cytometry [78]. Percentage of hypochro-


M. A. Atkinson and B. A. Warady

618

mic red blood cells (% HRC) is another laboratory marker of iron status that can assess iron
availability for incorporation into red cells. %
HRC >6% suggests poor hemoglobin production
due to iron deficiency and may be helpful in distinguishing patients with elevated ferritin levels
who may benefit from additional, potentially
intravenous iron supplementation [79]. %HRC

also requires flow cytometry for measurement,
which may limit its availability in clinical laboratories which measure hemoglobin by electrical
impedance and do not have access to the equipment or software required for testing [80].

 oal Hemoglobin Levels in Children
G
on Dialysis
There have been a series of clinical practice guidelines for the management of anemia in dialysis
patients published over the last 10–15 years, which
have included recommendations for target hemoglobin levels. In 2007, the National Kidney Foundation
Kidney Disease Outcomes Quality Initiative
(KDOQI), in response to data from adult trials in
which the use of ESAs to target higher hemoglobin
levels was associated with adverse outcomes, published a revised recommendation advising that in
patients receiving an  ESA, the hemoglobin target
should generally be in the range of 11–12 g/dL and
should not exceed 13 g/dL [81]. Subsequently, the
KDIGO guidelines were created from systematic
literature searches and supplemental evidence from
October 2010 to March 2012. They did not recommend a hemoglobin threshold for initiation of ESAs
in pediatric patients, but recommended that providers consider all potential benefits and harms prior to
starting ESA therapy. For pediatric patients on
ESAs, the target hemoglobin recommended was
11–12  g/dl [28]. The National Institute for Health
and Care Excellence (NICE) in the United Kingdom
last updated its guidelines in 2015. For patients who
are on ESAs, the recommended hemoglobin target
was 10 to 12 g/dL in children >2 years old and adults
and 9.5–11.5 g/dL in children younger than 2 years
old [82]. In terms of initiation of ESA treatment, a

common threshold in clinical practice is a hemoglobin <10 g/dL.

Recombinant Human
Erythropoietin Therapy
Available Forms of rHuEPO
The human EPO gene was isolated in 1985, with
commercial production of rHuEPO beginning
soon thereafter. Epoetin alfa was approved by the
US Food and Drug Administration in 1989 [8].
The development and widespread use of rHuEPO
in both adults and children eliminated dependence on red blood cell transfusions which could
be complicated by transfusion-associated viral
infections, iron overload, and allosensitization
[83]. Both endogenous and recombinant EPO
have microheterogeneity in carbohydrate structures with variation in sialic acid content, and the
molecules with increased sialic acid content
demonstrate increased in vivo half-life [84]. The
observation that the biologic properties of specific rHuEPO products varied with their molecular structure led to the hypothesis that
reengineering the EPO molecule with the addition of carbohydrate chains, and increasing sialic
acid content, could enhance potency and increase
half-life [85] (Fig.  32.4). Now there are several
types of both short- and long-acting ESAs available worldwide, and new formulations continue
to emerge requiring ongoing attention to the relative safety and efficacy in children compared to
adults.

Epoetin
Epoetin alfa was the first rHuEPO commercialized in the United States, followed by epoetin
beta in Europe. Epoetins alfa and beta, both
­produced in Chinese hamster ovary cells, have
minor structural differences but the same physiological effects [84]. There is no definitive evidence of superiority in patient outcomes for any

particular epoetin brand [28]. As the patents for
the first epoetins expired, biosimilar agents showing only minor differences in clinically inactive
components to those of the licensed products
emerged and were approved in the United States
and Europe; this process will likely continue,


32  Management of Anemia in Children Receiving Chronic Dialysis
Fig. 32.4  Mean in vivo
half-lives of available
erythropoiesis-­
stimulating agents

619

SC
IV
CERA

Darbepoetin alfa

Epotein beta

Epoetin alfa
0

20

40

60
80
Mean half-line (h)

100

120

140

CERA = continuous erythropoietin receptor activator

a

RhEPO

Receptor 1

Carbohydrate
side chains

Receptor 2

b

Darbepoietin alfa
Additional
carbohydrate
side chains

Receptor 1

Receptor 2

Fig. 32.5  Molecular structures of rhEPO (a) and darbepoetin alfa (b). (Modified from Refs. 84, 85)

leading to wider entry of these agents into the
clinical markets [86]. Short-acting epoetin formulations achieve maximum efficacy when
dosed one to three times weekly and demonstrate
a longer half-life when given subcutaneously
(19–24 h) than intravenously (6–8 h) [81].

Darbepoetin Alfa
Darbepoetin alfa is an erythropoietin analogue
with two additional sialic acid-containing carbohydrates resulting in extended in vivo biological
activity. Darbepoetin alfa has been shown to have
equivalent efficacy as rHuEPO to maintain hemo-

globin when dosed weekly or every other week in
children with CKD [28, 66, 87, 88] (Fig. 32.5).
Darbepoetin alfa may be administered intravenously or subcutaneously, and while the drug
clearance, half-life, and bioavailability are similar in adults and children regardless of the route
of administration, absorption when given subcutaneously may be more rapid in children [81].
The longer dosing interval inherent to treatment
with darbepoetin compared to rHuEPO has made
subcutaneous darbepoetin alfa an attractive alternative for anemia management in younger children, with the potential for improving adherence
due to the need for less frequent drug administration. A randomized clinical trial in children with


M. A. Atkinson and B. A. Warady

620

CKD stages 4 and 5 demonstrated that darbepoetin alfa is as safe and effective as rHuEPO for
the correction of anemia [88]. A longitudinal
European registry study similarly demonstrated
that children treated with darbepoetin alfa did not
experience increased rates of adverse events such
as infection or severe hypertension [89]. A potential limitation of darbepoetin alfa in children,
however, is the reported discomfort associated
with injection. In a blinded, randomized, controlled trial, children who received subcutaneous
darbepoetin alfa reported higher levels of post-­
injection pain by a visual analogue scale compared to those who got epoetin beta, consistent
with an increased impression of pain as reported
by their parents and nurses [90]. A potential
explanation is the more physiological pH of the
buffer in the epoetin beta preparation than the
darbepoetin alfa preparation [83]. Other pediatric
studies have, however, not found pain to be more
frequent or severe in patients receiving darbepoetin [88].

CERA
Continuous erythropoietin receptor activator
(CERA) is an EPO analogue that was created by
the integration of a single 30-kDa polymer chain
Epoetin

into the EPO molecule, increasing its molecular
weight to twice that of epoetin and extending its
elimination half-life to around 130  h [91]

(Fig. 32.6).
Unlike endogenous EPO and epoetin, which
are internalized and degraded following binding
to the EPO receptor, CERA escapes degradation
by dissociating from the receptor, allowing sustained in vivo efficacy of the compound [92]. A
study in children on peritoneal dialysis demonstrated that CERA safely and effectively maintained hemoglobin levels when dosed once or
twice monthly, although the doses required to
meet goal hemoglobin levels were higher than
those required in previously published adult studies [93]. A study in 64 children on hemodialysis
aged 6–17 found that CERA given once every
4  weeks was efficacious in maintaining
­hemoglobin levels with a safety profile consistent
with that of adults [94].

ESA Dosing for Children
rHuEPO quantities are traditionally expressed as
units, with 1  unit equaling the erythropoietic
effect of bone marrow stimulation with 5 μmol of
cobalt chloride, an historic treatment for anemia
prior to the rHuEPO era [1]. Darbepoetin alfa

CERA

N-linked glycosylation
chains

30 kDa methoxy-polyethylene
glycol polymer chain

Protein backbone

(165 aminoacids)

Fig. 32.6  Comparison of molecular structures of epoetin and CERA. (Modified from Ref. 91)


32  Management of Anemia in Children Receiving Chronic Dialysis

quantity is expressed in micrograms, with the
biological activity of 1 μg corresponding to that
of 200 units of rHuEPO [9]. The starting dose for
epoetin alfa or beta is generally 20–50  IU/kg
three times weekly (given subcutaneously or
intravenously) [28]. The initial recommended
darbepoetin alfa dose is 0.45  μg/kg subcutaneously or intravenously dosed once weekly or
0.75 μg/kg dosed every 2 weeks [28]. The CERA
dose is measured in micrograms. In the study of
children on chronic hemodialysis performed to
determine the required starting dose of CERA
based on the previous weekly epoetin alfa/beta or
darbepoetin alfa doses, a conversion factor of
4  μg of CERA every 4  weeks for each weekly
dose of 125  IU epoetin alfa or beta, or 0.55  μg
darbepoetin, was found to be most efficacious
[94]. Published CERA dosing recommendations
in children are intended for transition from
another ESA. The goal after ESA initiation is for
a rate of increase in hemoglobin concentration of
no more than 1–2  g/dL per month [28]
(Table 32.3).
ESA dose adjustments after treatment initiation should generally not be made until after the

first 4 weeks of therapy, and no more often than
every 2  weeks in the outpatient setting, as the
effects of therapy are not likely to be seen after
shorter intervals [28]. Decisions on dosing adjustments should be made based on the hemoglobin
rate of rise after initiation and the stability of
hemoglobin during maintenance therapy [21].
Table 32.3 Erythropoiesis stimulating agent dosing
guide for initiation in children
Starting dose
20–50 IU/kg

Interval
Three times
per week

Route
SC or
IV

Darbepoetin
alfa

0.45 μg/kg
0.75 μg/kg

SC or
IV

CERA

4 μg per each
prior weekly
dose of:
 125 IU
epoetin
 0.55 μg
darbepoetin

Weekly
Every
2 weeks
Every
4 weeks

Epoetin alfa/
beta

SC subcutaneously, IV intravenously

SC or
IV

621

When a decrease in hemoglobin is necessary,
ESA dose should be decreased but not necessarily held, as a pattern of holding and reinitiating
ESA therapy can lead to hemoglobin cycling
around the desired target range [95]. Long-acting
ESAs like darbepoetin alfa and CERA, with their
increased half-life and lower binding affinity for

the EPO receptor, stimulate erythropoiesis for
longer periods of time and thus may cause higher-­
than-­intended hemoglobin levels in clinical practice. This can be avoided by using lower starting
doses and making less frequent dose adjustments
than in children treated with short-acting ESAs
[87].

 hildren May Require Higher
C
Absolute ESA Doses than Adults
The dosing requirements of rHuEPO differ
between children and adults. Young children have
been reported to require higher weight-related
rHuEPO doses than adults, ranging from 275–
350 units/kg/week for infants to 200–250 units/kg/
week for older children [96]. Despite their lower
body weight, children and adolescents on chronic
hemodialysis have also been found to require
higher absolute doses of rHuEPO than adults to
maintain hemoglobin in goal range [97, 98]. In
contrast to typical drug dosing in children which
is based on body size to account for a decreased
volume of distribution, rHuEPO dose requirements appear to be independent of weight [97,
99]. The potential mechanisms for increased
rHuEPO dose requirement in children are not
clear, but may include increased presence of non-­
hematopoietic erythropoietin binding sites (e.g.,
endothelial, kidney, brain, and skeletal muscle
cells) resulting in increased drug clearance or
increased erythropoietin demand during periods

of accelerated body growth [9, 96, 99]. Data from
the International Pediatric Peritoneal Dialysis
Network (IPPN) showed that the weekly ESA
dose scaled to body weight was inversely correlated with age, but when normalized to body surface area the dose was independent of age, with a
median (IQR) weekly ESA dose of 4208 (2582,
6863) units per m2 [33]. It has also been shown


622

that an absolute rHuEPO dose of 1000  units
given IV to both adults and children can increase
hemoglobin by 0.4 g/dL, suggesting that dosing
schemes based on hemoglobin deficit rather than
weight may be useful [61, 99]. The doses of
CERA required by children have also been
reported as higher than those required in adults
[93]. Finally, studies in adults with non-dialysis
CKD have shown epoetin alfa administered subcutaneously at higher doses but extended intervals (ranging from 20,000 to 80,000 units every 2
or 4 weeks) to be non-inferior to weekly dosing
regimens in maintaining hemoglobin [100, 101].
This could be an attractive option for allowing
less-frequent ESA dosing in regions where darbepoetin alfa is not readily available, although
extended interval epoetin alfa dosing has not yet
been systematically assessed in children.

Safety of ESA Therapy
Although there are benefits associated with ESA
use, clinical trials in adults have raised concern
about the safety of using escalating ESA doses to

normalize hemoglobin. The CHOIR trial performed in adults with non-dialysis CKD found
that using epoetin alfa to target a higher hemoglobin level was associated with an increased risk
for death, MI, stroke, or CHF [49]. In the 2009
TREAT trial, adults with CKD receiving darbepoetin to achieve hemoglobin >13  g/dL also
demonstrated an increased risk for stroke [102].
Consequently, in 2011 the US FDA changed the
ESA product labeling to recommend the lowest
possible ESA dose to prevent red blood cell
transfusions and that the dose should be reduced
or interrupted for hemoglobin >11  g/dL [103].
However, this label change did not distinguish
between pediatric and adult CKD patients.
Although no such randomized controlled trials
have been conducted in pediatric patients, observational data has demonstrated that higher ESA
doses are associated with an increased risk for
mortality in children on chronic dialysis [33, 38,
104]. No clinical trials in adults have identified
whether the higher hemoglobin level or the
higher ESA dose specifically contributes to the
increased risk for adverse outcomes, but a pro-

M. A. Atkinson and B. A. Warady

spective study in adults on dialysis found that
those with naturally occurring higher hemoglobin levels >12 g/dL were not at increased risk for
mortality [105, 106]. In a similar study conducted
in ESA-treated children on dialysis, Rheault et al.
demonstrated that hemoglobin level >12  g/dL
was not associated with an increased risk for
either mortality or hospitalization [40].

The specific mechanisms for the adverse cardiovascular outcomes observed with ESA use
have yet to be defined, but may include trophic
effects on vascular endothelial or smooth muscle
cells [107]. Greater blood viscosity at higher
hemoglobin concentrations may also contribute by
increasing vascular endothelial wall stress [1].
While exposure to supraphysiologic EPO concentrations may have detrimental off-target effects,
the disparate burden and duration of cardiovascular disease and other comorbidities including diabetes in adults compared to children may result in
the risk for such ESA-associated outcomes being
substantially lower in children on dialysis.
However, given the lack of evidence, similar levels
of caution are applied to ESA use in children.
Other reported side effects of ESAs include hypertension, which seems to be independent of
achieved hemoglobin level, and increased risk for
vascular access thrombosis [108].

Novel Erythropoiesis-Stimulating
Agents
Novel ESA-independent CKD-related anemia
therapies are in varying stages of development.
Small-molecule hypoxia-inducible factor (HIF)
stabilizers/prolyl hydroxylase domain inhibitors
modulate HIF-controlled gene products and are
capable of inducing endogenous erythropoietin
production even in the setting of decreased renal
oxygen consumption, likely by increasing hepatic
erythropoietin production [12]. They have been
shown to increase hemoglobin and decrease hepcidin in adult trials, but trials have not yet been
conducted in children [109–111]. Inhibitors of
HIF can be administered orally in highly bioavailable preparations. Investigational strategies

for direct hepcidin modulation include monoclonal antibodies aimed directly at hepcidin or at the