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32  Management of Anemia in Children Receiving Chronic Dialysis

a

611

Normaxic conditions
Prolyl hydroxylase
domain proteins.
2-Oxoglutarate
Acetate
Iron

Ub

Hydroxylation
and
acetylation
HIF-α

OH
HIF-α

Ub

OH
HIF-α

OAc
OH

Ub

Von Hippel-Lindau
protein (VHL)
binds

VHL

Ubiquitination
HIF-α

OAc VHL
OH

Proteosome
action

OH

Ub

OAc VHL

Ub

Ub

OH

OH

HIF-α
degradation
OAc VHL

Cell
cytoplasm

Oxygen

b

OH

Hypoxic conditions
Prolyl hydroxylase
domain proteins.
2-Oxoglutarate
Acetate
Iron
Translocation
to the nucleus, no
hydroxylation or
acetylation
HIF-α

Proliferation
HIF-α

Coactivators

HIF-α binds
with HIF−β and
coactivators
HIF-α

HIF-α

Transcription
of hypoxiaresponsive
genes

HIF-β

Hypoxia response element

Target genes

HIF-β
Cell
cytoplasm

Low
oxygen

Cell nucleus

Coactivators

Fig. 32.2  Role of hypoxia-inducible factor α (HIF-α) under normoxic and hypoxic conditions. (Modified from Ref.

10)

Decreased EPO production by injured
fibroblast-­
like epithelial cells is not the only
mechanism by which endogenous EPO production is decreased in kidney disease. The kidney
functions as a “critmeter” in that it senses oxygen
tension and then regulates red cell mass by secreting EPO [7]. Diminished oxygen consumption
by diseased renal tissue leads to dysregulation of
EPO production by increasing tissue oxygen
pressure, which in turn leads to decreased HIF
stability [7]. The result is decreased EPO transcription occurring independently of damage to
EPO-producing cells.
The action of EPO is mediated through its
binding to the EPO receptor, which is found on
the cell membrane of erythroid precursors in the
bone marrow. Once the EPO receptor is activated,
a critical cascade of signal transduction results in

increased survival of the red blood cell precursors [1, 13]. Once bound to its receptor, EPO rapidly disappears from the circulation, indicating
likely internalization [1, 13]. The degree of EPO
receptor binding depends on the carbohydrate
content of EPO, with decreased binding affinity
with increasing glycosylation of the EPO molecule; this likely accounts for the prolonged
in vivo half-life of hyper-glycosylated EPO analogues as will be discussed later in this chapter
[9, 14, 15].

I ron Is Required for the Synthesis
of Hemoglobin
Iron is required for many physiologic functions

including oxygen transport and cell growth and


M. A. Atkinson and B. A. Warady

612
Fe
Hepcidin
FpCh
Fe

Hepcidin
FpCh

Macrophage

Fe

Enterocyte

absorption [3]. Transferrin is the glycoprotein
iron transporter that binds tightly but reversibly to
iron in plasma, preventing the oxidative stress that
freely circulating iron would induce. Iron that has
been transported into the circulation bound to
transferrin is released to erythroblasts via the
interaction of transferrin with the transferrin
receptor and receptor-mediated endocytosis [3].

 epcidin Regulates the Ferroportin-­

H
Based Movement of Iron
Fe

Decreased Fe
recycling

Decreased
dietary uptake

Fig. 32.3  Mechanism of action of hepcidin via direct
binding to and downregulation of ferroportin (Contributed
by Cindy N. Roy, PhD, Baltimore, MD; [Modified from
Ref. 19]). Fe iron, FpCh ferroportin channel

survival. The typical adult human body contains
about 3.5  g of iron, and most of that (2.1  g) is
incorporated into hemoglobin [16]. Effective
erythropoiesis depends not only on erythropoietin production, but also on the availability of iron,
and incorporation of iron into erythroblasts is a
rate-limiting step in the maturation of red blood
cells in the bone marrow. Once iron is absorbed,
there is no specific mechanism for its excretion
from the body, and so most iron utilized in erythropoiesis is recycled from iron already present in
hemoglobin.
Iron is essential for hemoglobin synthesis [3].
Hemoglobin consists of four heme groups, each
of which requires the incorporation of one Fe2+
ion for oxygen binding [17]. Each mature red
blood cell contains approximately 300  million

hemoglobin molecules, and two-thirds of total
body iron is located in the erythroid compartment
[17]. To produce billions of erythrocytes daily,
approximately 25 mg of iron must be made available to the bone marrow [3]. The majority of this
iron is supplied by macrophages which recycle
iron from senescent red blood cells, while only
1–2  mg of iron daily comes from intestinal

The iron-regulatory protein hepcidin, a 25-amino
acid antimicrobial peptide encoded by the HAMP
gene and produced by hepatocytes, has emerged
as the key regulator of iron homeostasis [18].
Hepcidin regulates both intestinal iron absorption
and body iron distribution through its posttranslational suppression of cell-membrane expression of ferroportin, which is the sole cellular iron
exporter. Small intestinal ferroportin expression
is upregulated in iron deficiency by HIF-2 [12].
Hepcidin binding to ferroportin causes internalization and lysosomal degradation of ferroportin,
which results in downregulation of dietary iron
absorption via intestinal enterocytes, and inhibits
the release of stored iron from reticuloendothelial
cells [19] (Fig. 32.3).
In this way, hepcidin prevents the utilization
of absorbed or stored iron for erythropoiesis by
the bone marrow, a process which in the short
term may serve as a host-defense mechanism
intended to sequester iron from invading pathogens or malignant cells [20]. A number of pathways have been shown to regulate HAMP gene
expression via mechanisms involving iron status,
erythropoiesis, and inflammation. Iron loading
has been shown to increase the production of
hepcidin, and hepcidin expression is modulated

based on circulating levels of transferrin-bound
iron via a BMP-SMAD signaling pathway [6,
17]. Erythropoietin-stimulated erythroblasts produce erythroferrone, a hormone which acts
directly on hepatocytes to suppress HAMP
mRNA and decrease hepcidin production, with a
resultant increased iron acquisition from
­absorption and storage sites [3, 6, 17]. The reduc-


32  Management of Anemia in Children Receiving Chronic Dialysis

tion in erythroblast number resulting from EPO
deficiency diminishes the production of erythroferrone and prevents it from checking hepcidin
production [6].
Hepcidin expression is induced by inflammation in general and in particular by the inflammatory cytokine IL-6. It is cleared from the
circulation by glomerular filtration, leading to
increased levels in the setting of decreased renal
function [21]. Hepcidin has been found to be elevated in both adults and children with CKD and
on dialysis, and levels are positively correlated
with serum ferritin levels [22, 23]. Hepcidin is
also cleared from the circulation by hemodialysis
[23]. A study in the CKiD cohort found that in
children with mild-to-moderate CKD, higher hepcidin levels were associated with lower hemoglobin and an increased risk for incident anemia [21].

Epidemiology of Anemia
in Children on Dialysis

613

Table 32.1  Definitions of anemia in children with kidney disease

Age group
(years)
1–2
3–5
6–8
9–11
12–14
15–19
Age group
(years)
0.5–5
5–12
12–15
>15 and adult

Age group
(years)
<2
≥2

KDOQI
5th percentile hemoglobin level (g/dL)
Boys
Girls
10.7
10.8
11.2
11.1
11.5
11.5

12.0
11.9
12.4
11.7
13.5
11.5
KDIGO
Hemoglobin level
(g/dL)
<11.0
<11.0
<12.0
<13.0 (males)
<12.0 (females)
RA
Hemoglobin level
(g/dL)
Hb 10.5 g/dL
Hb 11 g/dL

Definition of Anemia
The application of adult normative hemoglobin
thresholds has been shown to substantially underestimate the prevalence of anemia in children with
kidney disease, as normal hemoglobin levels vary
by age and sex [24–27]. In 2006, the National
Kidney Foundation’s Kidney Disease Outcomes
Quality Initiative (KDOQI) published clinical
practice guidelines which utilized National Health
and Nutrition Examination Survey III data from
1988 to 1994 to define anemia, which reports ageand sex-specific 5th percentile values [25].

Subsequently in 2012, the Kidney Disease
Improving Global Outcomes (KDIGO) clinical
practice guideline for anemia utilized World
Health Organization age-specific hemoglobin values to define the level at which an evaluation for
the cause of anemia in patients with CKD should
be initiated [28]. KDIGO also recommends that
hemoglobin should be measured at least every
3 months in those on dialysis and more frequently
for clinical indications. In those patients already
determined to be anemic, the hemoglobin should
be assessed monthly in those patients treated with
an ESA [28]. The most recent clinical practice

guidelines regarding anemia in CKD were published in 2017 by the Renal Association (RA) in
the United Kingdom. The diagnosis of anemia in
pediatric patients was recommended at a hemoglobin level less than10.5  g/dL in children younger
than 2 years old and less than 11 g/dL in children
>2 years old [29] (Table 32.1).

I ncidence, Prevalence, and Risk
Factors
Anemia is one of the most common and clinically
significant complications in children on dialysis,
with many patients requiring treatment with an
ESA starting in later-stage CKD, before the initiation of dialysis. Within the Chronic Kidney Disease
in Children (CKiD) cohort study, the median
hemoglobin declined as the measured glomerular
filtration rate (GFR) decreased below a level of
43  ml/min/1.73  m2 [30]. Data from the North
American Pediatric Renal Trials and Collaborative

Studies (NAPRTCS) cohort has consistently shown
that the risk for anemia increases as the CKD stage
advances, with a prevalence of 73% at stage 3, 87%


614

at stage 4, and >93% at stage 5 [31, 32].
Furthermore, of children prescribed an erythropoiesis-stimulating agent (ESA), over 20% of those
with stage 4 CKD and over 40% of children with
stage 5 CKD demonstrate persistently low hemoglobin levels [31]. In the International Pediatric
Peritoneal Dialysis Network (IPPN) registry, low
serum albumin, increased parathyroid hormone
(PTH) levels, high serum ferritin, and the use of
bio-­
incompatible dialysate were associated with
low hemoglobin levels [33]. Severe anemia in this
registry was also associated with risk factors for
manifestations of fluid overload including low
urine output, high ultrafiltration requirements,
hypertension, left ventricular hypertrophy, and
high transporter state by peritoneal equilibration
test [33]. This suggests that some dialysis patients
with anemia, including apparent ESA-resistant
anemia, may have low hemoglobin levels due to
dilution of red cell mass secondary to volume overload rather than to an impaired erythropoietic
response. Careful attention to volume status and
“challenging” dry weight with increased ultrafiltration in patients with treatment-resistant anemia will
help to clarify the contribution of volume overload
to low hemoglobin concentration.

Race is also a recognized risk factor for anemia. Among children enrolled in the CKiD study,
African-Americans have consistently demonstrated lower hemoglobin levels than Caucasian
children, even after adjusting for the level of kidney function [24]. Normal hemoglobin levels
also vary in healthy children by race, and whereas
differences in the prevalence of hemoglobinopathy traits, iron deficiency, or socioeconomic status do not fully explain this disparity, genetic
polymorphisms may contribute to these differences [34, 35]. Existing anemia management
guidelines do not recommend varying hemoglobin targets or modification of the approach to
treatment by race [34].

Adverse Associations
Risk of Death and Hospitalization
Studies in adults with ESKD have consistently
demonstrated a reduced risk of death and hospi-

M. A. Atkinson and B. A. Warady

talization when hemoglobin levels are ≥11 g/dL. In
children, however, there is less systematic evidence concerning the risks of anemia, and clinical practice recommendations for anemia
management are often based primarily on adult
studies. In observational studies, lower hemoglobin levels in children on dialysis have been
strongly and independently associated with
increased mortality risk. Warady and Ho demonstrated an association between a baseline hematocrit of <33% at 30  days post-initiation of
dialysis and an increased risk of prolonged hospitalization and death in incident ESKD patients
less than 18 years of age from the NAPRTCS registry [36]. Using data from the US Centers for
Medicare and Medicaid Services’ ESRD Clinical
Performance Measures Project linked with the
US Renal Data System hospitalization and mortality records, Amaral et  al. assessed whether
achieving hemoglobin levels of >11 g/dL in 677
adolescents on hemodialysis was associated with
a decreased risk of death. In this retrospective

cohort study, 11.7% of children with a hemoglobin of <11 g/dL at study entry died, compared to
5% of those with an initial hemoglobin of ≥11 g/dL
(P  <  0.0001) [37]. In a multivariate analysis,
hemoglobin of ≥11 g/dL was still associated with
a decreased risk of death. When hemoglobin was
re-categorized into hemoglobin levels of <10,
≥10 to <11, ≥11 to ≤12, and >12 g/dL, the risk
of mortality declined as the hemoglobin level
increased. At hemoglobin levels of 11 to ≤12 g/
dL versus <10 g/dL, the mortality risk decreased
by 70% (HR, 0.30; 95% CI, 0.19–0.74). This
observational study’s findings were consistent
with the experience reported in the adult literature, showing decreased mortality in ESKD
patients who meet hemoglobin targets of >11 g/dL
for adolescents on hemodialysis.
In 2013, Borzych-Duzalka et  al. found that
anemia in children on chronic peritoneal dialysis
was associated with an increased risk for mortality and that the risk for death on dialysis was
independently and inversely associated with
hemoglobin [33]. Survival rates were higher in
children with mean hemoglobin >11 g/dL compared to those with lower values [33]. Examining
the US pediatric peritoneal dialysis population,


32  Management of Anemia in Children Receiving Chronic Dialysis

Dahlinghaus et al. found that hemoglobin ≥11 g/dL
was associated with lower hospitalization risk,
but not with a decrease in mortality risk.
Hemoglobin levels ≥12 g/dL were not associated

with a decreased risk of hospitalization compared
to levels of 11–12 g/dL [38]. Published in 2017, a
40-year retrospective cohort study of children on
dialysis by Adamczuk et al. found that the mean
hemoglobin level was higher among survivors
compared to non-survivors and was a significant
prognostic indicator. The survivors were more
frequently treated with ESAs, suggesting that
treatment of anemia is important in decreasing
mortality in patients on dialysis [39]. Rheault
et  al. found that the hazards for both all-cause
mortality and all-cause hospitalizations were significantly lower in children on hemodialysis with
hemoglobin ≥12  g/dL and that cardiovascular
hospitalizations were significantly higher in
those with hemoglobin <10 g/dL [40].
Quality of Life and Physical and Cognitive
Function
Anemia of CKD has long been associated with a
negative impact on quality of life. Several studies
have revealed that the treatment of anemia in
CKD improves quality of life in adults with CKD
and ESKD [41–43]. A single blinded, placebo-­
controlled crossover study in 11 children with
ESKD showed improvement in exercise tolerance, physical performance, and school attendance with correction of anemia [44]. Treatment
of anemia using recombinant human erythropoietin in a multicenter pediatric study of 44 children with chronic kidney failure undergoing HD
also showed marked improvement in their quality
of life, particularly in activity levels [45]. Another
cross-sectional study by Gerson et al. examined
the link between caregiver-reported QoL and
anemia in a cross-sectional assessment of 116

adolescents with renal insufficiency on dialysis
and post-kidney transplantation. The authors
found that anemia was associated with poorer
quality of life [46]. By caregiver assessment,
adolescents with kidney disease and anemia
(defined as hematocrit of <36%) were less satis-

615

fied with their health, participated in fewer activities at school and with friends, and were less
physically active. These findings mirrored findings of studies examining the correlation between
anemia and quality of life in adults. Correction of
anemia has also been associated with better physical function in children with ESKD. In a small
series, children on chronic PD treated with
rHuEPO with resulting increased hematocrit
demonstrated significantly improved exercise
capacity as measured by peak oxygen consumption and treadmill time [47].
Regarding cognitive function, one multicenter trial of subcutaneous erythropoietin
showed increased Wechsler intelligence scores
in 11 children with chronic kidney failure who
were treated for anemia over a 12-month period
[48]. In the adult literature, several studies have
demonstrated significant improvement in electrophysiological markers of cognitive function
with improvement of anemia in patients with
chronic and end-stage kidney disease, but further study is sorely needed in the pediatric dialysis population [49–54].
Cardiac Function
There is observational evidence of an association
between anemia and left ventricular hypertrophy
in adults, but evidence supporting cardiac benefits of anemia treatment in children is much more
limited [55, 56]. Adverse cardiovascular events

and left ventricular remodeling have both been
associated with anemia in children with CKD
and ESKD [57–59]. A single blinded crossover
trial of 11 children aged 2–12 years on dialysis
demonstrated an improvement in cardiac index
by 6  months and  a significant reduction in left
ventricular (LV) mass by 12  months in those
treated with rHuEPO [60]. Two additional observational studies of patients with severe left ventricular hypertrophy (LVH) demonstrated that
children with lower hemoglobin levels had more
severe LVH and lower LV compliance [61, 62].
Anemia has been identified as an independent
predictor of LVH, even after controlling for blood
pressure, in children with pre-dialysis CKD [63].


616

Clinical Management of Anemia
Symptoms of Anemia
The clinical presentation of anemia depends on
the rate of hemoglobin decline as erythropoietin
production slows and the adaptability of the heart
and lungs to a decreased hemoglobin concentration. In the case of blood loss during hemodialysis, the rate of ultrafiltration will determine
severity of symptoms. Symptoms of anemia may
include fatigue, pallor, somnolence, tachypnea,
tachycardia, depression, impaired cognition or
muscle function, and loss of appetite. If anemia is
more acute from blood loss, patients may experience dyspnea, dizziness, or headache. Patients
with concurrent iron deficiency may have fatigue
and lethargy out of proportion to their degree of

anemia [64].

I nitial Diagnostic Evaluation
of Anemia
Prior to initiating treatment with an ESA in anemic children with kidney disease, other potentially correctable causes of anemia should be
ruled out (Table 32.2).
Because anemia in children on dialysis may
not be associated solely with erythropoietin deficiency, incident anemia should prompt an initial
laboratory evaluation to include assessment of
red cell indices and iron stores and other correctable nutritional deficiencies [28]. Deficiencies of
B12, folate, carnitine, vitamin C, and copper may
also contribute to anemia in CKD.  The B vitamins are water soluble and are removed during
dialysis, and B12 deficiency causes megaloblastic anemia because B12 is needed for DNA synthesis [65]. Folate is also required for DNA
synthesis during erythropoiesis and deficiency is
associated with a macrocytic anemia. In a small
study, when a deficiency in folate was corrected
in 15 children on dialysis, 11 demonstrated
increased hemoglobin with  the mean level
increased by 8%. ESA dose requirements
decreased as well, with  a mean decrease of
20  units/kg [66, 67]. Chronic hemodialysis is a

M. A. Atkinson and B. A. Warady
Table 32.2  Potential causes of anemia in children with
chronic kidney disease
Erythropoietin deficiency and/or dysregulation
Iron-restricted erythropoiesis
 Absolute iron deficiency
 Functional iron deficiency
 Impaired iron trafficking

Inflammation and hepcidin upregulation
Chronic blood loss
 Frequent phlebotomy
 Hemodialysis circuit losses
 GI losses
 Menstrual losses
Acute blood loss
 Surgical losses
 GI losses
Uremia and oxidative stress
Hyperparathyroidism and myelofibrosis
Hypervolemia
Nutritional deficiencies
 B12, folate, carnitine, vitamin C, copper
Medications
 Angiotensin-converting enzyme inhibitors
 Non-adherence with anemia therapies
 Drug toxicity
 Pure red cell aplasia associated with erythropoiesis-­
stimulating agents
Infectious causes
 Parvovirus B19-induced aplastic anemia
 Infection-associated inflammation

leading cause of secondary carnitine deficiency
due to its ready dialyzability [68]. Some studies
have suggested that L-carnitine supplementation
can prolong red blood cell life span and stimulate
erythropoiesis by inhibiting apoptosis, but there
have been no large-scale randomized clinical trials conducted to evaluate whether supplementation is effective as an adjunctive treatment for

anemia in dialysis patients [68]. Vitamin C
enhances absorption of dietary iron, contributes
to the mobilization of intracellular stored iron,
and increases carnitine synthesis, but there have
been no clinical trials to assess the effects of vitamin C supplementation on anemia in dialysis
patients [69]. Caution is also warranted as excessive vitamin C ingestion can be associated with
renal oxalate deposition and acute kidney injury,
both of which could have a negative impact on
residual kidney function [70]. Copper deficiency
is relatively rare, but can arise from excessive