Original Article

Therapy with Erythropoietin‑alpha and Erythropoietin‑beta for

Anemia of Chronic Kidney Disease in Children on Maintenance
Hemodialysis
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Phoebe Anne Mateo Diño‑Santos, Rachelle C. Dela Cruz1, Caridad M. Santos, Angelo Martin B. Catacutan2
Clinical Research Department, Philippine Children’s Medical Center, 1Section of Pediatric Nephrology, Philippine Children’s Medical Center, Hemodialysis Unit,
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2
Philippine Children’s Medical Center, Quezon City, Philippines

Abstract
Background and Aims: Anemia is a common complication of chronic kidney disease which can be treated with erythropoietin (EPO). We
compared the outcomes of EPO‑alpha and EPO‑beta in children on maintenance hemodialysis. Settings and Design: This was a retrospective
cohort study. Methods: Hemodialysis patients aged 12 to <19 years with hemoglobin ≥8 to <11 g/dL were grouped according to the type of
EPO they received. Successful treatment was defined as achievement of hemoglobin ≥11g/dL within 3 months of treatment and successful
maintenance as hemoglobin ≥11g/dL for ≥3 months after successful treatment. The effectiveness and treatment cost using EPO‑A and EPO‑B
were compared. Standard statistical tests were used, including Chi‑square, Fisher’s exact, Student’s t‑test, Mann–Whitney U‑test, and multiple
regression. Results: Thirty‑two subjects were included with 16 patients in each group. Patients receiving EPO‑B, compared to EPO‑A, more
often achieved successful treatment (75% vs. 31.2%, P = 0.03; EPO-A adjusted odds ratio, 0.07; 95% confidence interval, 0.01–0.71) and
maintenance (50% vs. 40%, P = 0.99). EPO‑B required lower doses than EPO‑A for successful treatment (208 ± 151 vs. 393 ± 140 U/kg/week;
P = 0.03) and maintenance (P = 0.99). The median increase of hemoglobin using EPO‑B was higher (P = 0.002) beyond the first month.
Hypertensive episodes were similar in both groups. Therapy costs were lower with EPO‑B than EPO‑A during treatment (P = 0.04) and
maintenance (P = 0.32) phases. Conclusions: This is the first study that directly compares EPO‑A and EPO‑B in children on maintenance
hemodialysis. EPO‑B was more effective than EPO‑A in the management of anemia in children on maintenance hemodialysis. Both agents
had comparable safety profiles. Prospective large studies are required to confirm these findings.

Keywords: Anemia, children, chronic kidney disease, epoetin‑alpha, epoetin‑beta, erythropoiesis‑stimulating agents, hemodialysis,
pediatric

Introduction week.[6] In the Philippines, around 75% of the total dialysis

population was receiving EPO.[7] The most widely used
Anemia, a common complication of chronic kidney
EPO preparations in our institution are EPO‑alpha (A) and
disease (CKD) in children, has adverse clinical consequences,
EPO‑beta (B). While the costs of outpatient hemodialysis
including poor quality of life,[1,2] depressed neurocognitive
sessions are shouldered by Philippine Health Insurance
ability, reduced exercise capacity, and progression of
cardiovascular (CV) risk factors, e.g., left ventricular
Address for correspondence: Dr. Phoebe Anne Mateo Diño‑Santos,
hypertrophy, independent of elevation in blood pressure.[3,4]
Clinical Research Department, Philippine Children’s Medical Center, Quezon
Low hemoglobin levels strongly and independently predict Ave Corner Agham Rd, Quezon City, Philippines.
mortality and are associated with increased risk of E‑mail: phoebeanne18@yahoo.com
hospitalization among adolescent patients on maintenance
hemodialysis.[3] Anemia affects more than 93% of children Submitted: 03‑Jan‑2023 Revised: 28‑Mar‑2023
Accepted: 13‑May‑2023 Published: 26-Jun-2023
with CKD stage 5[5] and requires therapy with human
recombinant erythropoietin (EPO) vials 2–3 times each
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How to cite this article: Mateo Diño-Santos PA, Dela Cruz RC, Santos CM,
DOI: B. Catacutan AM. Therapy with erythropoietin‑alpha and erythropoietin‑beta
10.4103/ajpn.ajpn_1_23 for anemia of chronic kidney disease in children on maintenance
hemodialysis. Asian J Pediatr Nephrol 2023;6:2-10.

2 © 2023 Asian Journal of Pediatric Nephrology | Published by Wolters Kluwer - Medknow

 Diño‑Santos, et al.: Erythropoietin therapy for anemia of chronic kidney disease
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Figure 1: Flow diagram of methodology
Corporation (PhilHealth),[8] the high cost of maintenance
medications, including EPO vials, precludes 100% coverage.
Determining the dose requirement and its impact on costs of
management of anemia with EPO to achieve and maintain the
target hemoglobin can guide treatment protocols for patients
on hemodialysis and help identify ways to allocate the
financial provision from the different government agencies.
While EPO‑A and EPO-B appear to have similar
pharmacokinetics and efficacy in the management of
anemia, adult studies have shown conflicting results.[9‑12]
Moreover, few studies have examined the effects of
EPO administration in children, [13,14] and none have
directly compared the alpha and beta preparations.
A meta‑analysis [15] which compared the efficacy and
safety of erythrocyte‑stimulating agents against each
other, placebo, or no treatment to manage anemia in
adults with CKD did not include direct comparisons of
the efficacy of EPO‑A and EPO‑B in raising hemoglobin
to target levels.
Therapy with EPO is typically begun at 100 units/kg in
adults, and 50 units/kg in pediatric patients, by intravenous
or subcutaneous route, thrice a week.[13] In order to achieve
and maintain target hemoglobin levels, young children
require higher EPO doses than adults, ranging from 275
to 350 U/kg/week for infants, to 200–250 U/kg/week for
Asian Journal of Pediatric Nephrology ¦ Volume 6 ¦ Issue 1 ¦ January‑June 2023
older children.[16] Halstenson et al.[9] reported higher dose
requirements for EPO‑A than EPO‑B due to differences
in the pharmacokinetics and function, possibly related to
glycosylation. On the contrary, Sörgel et al.[10] found that
EPO‑A (HX575) and EPO‑beta were bioequivalent with
similar pharmacokinetics and pharmacodynamic actions.
While these results indicate similar efficacy for EPO‑alpha
and EPO‑beta preparations, these were conducted in
healthy adult volunteers. While two reports in patients
on hemodialysis[11,12] suggest no significant differences
between the two agents in maintaining hemoglobin levels,
one study each in patients with CKD reported a higher
increase in hemoglobin during therapy with EPO‑alpha
and EPO‑beta.[17,18] While the two agents do not appear
to differ significantly in their dosage and route of
administration.[11,12,18]
The use of EPO in children relies on these studies among
adults, since pediatric‑specific evidence is lacking.
However, reliance on and direct extrapolation from the
adult studies appears inappropriate since age‑specific
variations of normal hemoglobin concentration, causes
of CKD, comorbidities, and developmental differences
between children and adults, could influence EPO
response,[6] dose requirements, and therefore, the costs of
care. Therefore, this study was planned to compare the
effectiveness, safety, and cost of EPO‑A and EPO‑B for
3
 Diño‑Santos, et al.: Erythropoietin therapy for anemia of chronic kidney disease
the treatment of anemia among children with CKD on
maintenance hemodialysis.
Methods
This retrospective cohort study was conducted in a pediatric
tertiary hospital. The technical aspects of the study were
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approved by the Clinical Trial and Research Division and
the Institutional Review Board before the start of the study.
Medical records of all children with CKD registered in the
database of the hemodialysis unit, since its inception in
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January 2018, until June 2022, were reviewed.
Patient eligibility
Patients aged 12 to <19 years, undergoing hemodialysis
on an outpatient basis for ≥3 months, with a baseline
hemoglobin ≥8 g/dL to <11 g/dL, were screened [Figure 1].
Those receiving EPO for at least 3 months were included
in the study, while critically ill patients and those with
hematologic disorders were excluded from the study. The
subjects who met the inclusion criteria were selected for
the study and were placed into two comparison groups
according to the type of EPO used: Group A: EPO‑A and
Group B: EPO‑B.
Therapy
The EPO products used for all dialysis patients in
this unit were human recombinant EPO‑A (Repoitin®,
India) at 4,000 IU/vial, and human recombinant EPO‑B
(Recormon® Roche, Malaysia) at 2000 IU/vial, administered
subcutaneously 2–3 times a week by the trained hemodialysis
nurses after each dialysis session. The pediatric nephrologist
on duty at the hemodialysis unit determined which type of
EPO the patient would receive based on clinical judgment
and the supply of EPO. Each subject received 50–250 U/kg
of EPO each week. The medicine was charged as one vial
whether a fraction or full dose is given.
The dose of EPO was adjusted only beyond the first 4 weeks
after EPO initiation, and according to KDIGO guidelines.[6]
The frequency of EPO dose adjustment was determined
by the rate of increase in hemoglobin concentration during
initial EPO therapy, the stability of these levels during
maintenance EPO therapy, and the frequency of hemoglobin
testing. The EPO dose was decreased or withheld when
hemoglobin was high. When the hemoglobin approached
11.5 g/dL, the dose was reduced by approximately 25%.
If the hemoglobin continued to rise, EPO was temporarily
withheld until hemoglobin showed a decline, after which
therapy was restarted at a dose approximately 25% below
the previous dose.[6]
Iron was supplemented in patients with poor response to
therapy, assuming inadequate iron availability. However,
baseline mean levels of serum iron, ferritin, and transferrin
saturation were lacking in the majority of patients.
4 Asian Journal of Pediatric Nephrology ¦ Volume 6 ¦ Issue 1 ¦ January‑June 2023
Definitions
The body mass index (BMI), calculated by dividing
the weight (kg) by height (m) squared (kg/m 2), was
classified by the Centers for Disease Control and
Prevention definition to indicate nutritional status[19] as
follows: BMI‑for‑age ≥95th percentile was termed obesity,
≥85th to <95th percentile as overweight, ≥5th to <85th percentile
as normal, and <5th percentile as underweight.
Vascular access was recorded as central venous catheter,
arteriovenous fistula, or arteriovenous graft. Maintenance
hemodialysis was defined as hemodialysis for ≥3 months.
Hemodialysis adequacy was estimated by computing the
parameter Kt/V, which refers to the clearance K of a specific
solute during treatment time t in a given patient with volume
of distribution V for the solute. A Kt/V of ≥1.2 indicated
dialysis adequacy.[20]
The target hemoglobin level was ≥11 g/dL, according to
the KDIGO guidelines.[6] Successful treatment was defined
as achievement of hemoglobin level ≥11 g/dL within
3 months of treatment, and successful maintenance as
monthly hemoglobin level ≥11 g/dL for at least 3 months
after successful treatment. EPO‑induced hypertension was
defined as an increase in diastolic blood pressure by at least
10 mmHg or requiring an increase in antihypertensive drug
requirements after 12 weeks of therapy with EPO.[21]
Outcomes
The effectiveness of EPO‑A treatment was compared
with that of EPO‑B based on the following primary
outcomes: (i) the proportion of patients who achieved
successful treatment and successful maintenance, (ii) the
dose requirement for successful treatment and successful
maintenance, and (iii) the duration of therapy required to
achieve target hemoglobin level. The secondary outcomes
included (i) changes in hemoglobin level per 100 units
of EPO per kg body weight per week, (ii) occurrence of
adverse events, and (iii) cost of treatment based on the
number of monthly vials consumed.
Collection of data on baseline and outcome variables
Information collected from the charts of the patients
included demographic data, duration of hemodialysis and
CKD, primary diagnosis, comorbidities (CV, neurologic,
and others), nutrition status according to BMI (as defined
above), type of vascular access, and baseline and monthly
levels of hemoglobin, white blood cell (WBC) count, EPO
dose, and Kt/V. Data were collected for as long as the patient
was receiving hemodialysis treatment in this institution
and until breakthrough anemia (hemoglobin <11 g/dL after
successful treatment and/or successful maintenance).
Statistical analysis
Data were analyzed using DATAtab: Online Statistics
Calculator (2022). Categorical variables are presented as
 Diño‑Santos, et al.: Erythropoietin therapy for anemia of chronic kidney disease

numbers and percentages, while continuous variables are
presented as mean and standard deviation (SD) or median
and interquartile range, based on their distribution.
Categorical variables were compared with the Chi‑square
or Fisher’s exact test, as appropriate. Continuous variables
were compared using the Student’s t‑test or the Mann–
Whitney U‑test for normal and nonnormal distribution,
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and Zar, 1984),[22,23] a total of 32 patients (16 subjects per
group) were required to achieve 80% power to detect a
difference of −1.1 g/dL between the groups of patients
treated with either EPO‑A or EPO‑B to raise and maintain
the hemoglobin of ≥11 g/dL. A purposive sampling
technique was utilized until the minimum sample size for
each group was achieved.

respectively. Multiple regression was performed to

control for the following predictor variables: (i) baseline Results
hemoglobin level; (ii) comorbidities; (iii) elevated WBC
Thirty‑two subjects who fulfilled the eligibility criteria
>12,000/mm3 (as a marker of acute inflammation, known
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were included. Seventeen were initiated on therapy with

to impact response to EPO;[6] (iv) type of vascular access;
and (v) nutritional status. A two‑tailed P < 0.05 was
considered statistically significant.
Sample size
Sample size was computed for a two‑sample t‑test using
PASS 2008 (NCSS, LLC. Kaysville, Utah, USA). Based
on the study by Ahsan et al.,[18] among 94 CKD patients
on EPO treatment, the null hypothesis was that both the
group means are 10.25 g/dL and the alternative hypothesis
that the mean of group 2 is 11.34 g/dL with estimated
group SDs of 1.1. With a significance level (alpha) of
0.05 using a two‑sided two‑sample t‑test (Machin, 1997
EPO‑A (Group 1), while EPO‑B was the initial drug in
15 patients (Group 2). To complete the computed sample
size, one patient initially given EPO‑A was included
in Group 2 after shifting to EPO‑B. Most patients had
breakthrough anemia, except for two patients (one from
each group) who were followed until transfer to adult care.
The average duration of observation was 3.7 months. Age,
sex, and other baseline characteristics were comparable
in the two groups [Table 1]. The most common causes
of CKD were chronic glomerulonephritis, followed by
systemic lupus erythematosus and congenital anomalies
of the kidney and urinary tract. Information on Kt/V was

Table 1: Baseline characteristics of children on maintenance hemodialysis treated with erythropoietin‑A or erythropoietin‑B
Total (n=32) EPO‑A (n=16) EPO‑B (n=16) P
Age (years) 5.9±1.8 15.75±2.9 16±1.3 0.69
Boys 19 (59.3) 12 (75) 7 (43.7) 0.19
Primary diagnosis
Chronic glomerulonephritis 20 (62.5) 10 (62.5) 10 (62.5) 0.99
Congenital anomalies of the kidneys and urinary tract 7 (21.9) 4 (25) 3 (18.8)
Systemic lupus erythematosus 3 (9.4) 1 (6.25) 2 (12.5)
Alport syndrome 1 (3.1) 1 (6.25) 0
Metabolic syndrome 1 (3.1) 0 1 (6.25)
Weight (kg) 42.0±16.9 39.5±8.6 42.0±16.9 0.59
Duration of disease (years) 0.8 (0.3–2.0) 1.38 (0.5–2.2) 1.6 (0.3–1.3) 0.97
Duration of hemodialysis (months) 7.0 (3.5–14.5) 8.0 (3.7–15.2) 7 (3–18.5) 0.73
Comorbidities
Neurologic 3 (9.4) 1 (6.2) 2* (12.5) 0.99
Cardiovascular* 11 (34.3) 6 (37.5) 5* (31.2)
None 19 (59.4) 9 (56.2) 10 (62.5)
Nutritional status (based on BMI)
Underweight 12 (37.5) 4 (25) 8 (50) 0.2
Normal 18 (56.2) 12 (75) 6 (37.5) 0.07
Overweight 2 (6.2) 0 2 (12.5) 0.48
Vascular access
Central venous catheter 21 (65.6) 10 (62.5) 11 (68.7) 0.99
Arteriovenous fistula 11 (34.4) 6 (37.5) 5 (31.2)
Hemoglobin (g/dL) 9.8±0.9 10.0±0.7 9.6±1.0 0.17
Elevated total leukocyte count (>12,000/mm3) 9 (28.1) 5 (31.2) 4 (25) 0.99
Initial EPO dose (U/kg/week) 249.4±102.6 166.8±64.1 0.01
Dialysis adequacy (n) 12 5 7 0.22
Kt/V ≥1.2 7 (58.3) 3 (60) 4 (57.1)
*One patient had both neurologic and cardiac pathology. Continuous variables are presented as mean±standard deviation or median (interquartile range),
and categorical as n (%), P<0.05 was considered statistically significant. BMI: Body mass index, EPO: Erythropoietin

Asian Journal of Pediatric Nephrology ¦ Volume 6 ¦ Issue 1 ¦ January‑June 2023 5

 Diño‑Santos, et al.: Erythropoietin therapy for anemia of chronic kidney disease

limited to 12 of 32 patients, including 5 and 7 patients
in groups 1 and 2, respectively. Of seven patients with
Kt/V ≥1.2, 3 were treated with EPO‐A, while 4 received
EPO-B.
Patients receiving EPO‑A required higher doses
initially than those receiving EPO‑B (249.4 ± 102.6 vs.
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the target hemoglobin and prevent increase above the target
range. Beyond 3 months of therapy, the majority of patients
receiving EPO‑A showed a decrease in hemoglobin levels,
while those receiving EPO‑B had increased or decreased
hemoglobin levels.
The probability of successful treatment was significantly

166.8 ± 64.1 U/kg/week), likely due to an intent to utilize
the entire vial, the dose within which was higher for the
former agent (4000 vs. 2000 units/vial). Despite the higher
initial dose, fewer patients receiving EPO‑A had successful
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higher in the EPO‑B group versus EPO‑A group (EPO-A
adjusted odds ratio [AOR], 0.07; 95%, confidence
interval [CI]: 0.01–0.71). Among patients with data on Kt/V,
upon adjusting for inadequate hemodialysis (Kt/V <1.2),

treatment compared to therapy with EPO‑B.
Table 2 compares the outcomes of therapy with EPO‑A
versus EPO‑B. Seventeen (53.1%) patients had successful
treatment, and eight (47%) of these achieved successful
maintenance. Treatment was less often successful in patients
receiving EPO‑A compared to EPO‑B (12% vs. 75%;
P = 0.03). Therapy success was achieved by 1 month more
often with EPO‑B (10 of 12; 83%) than with EPO‑A (1 of
5; 20%). The average dose to achieve successful treatment
was significantly lower for therapy with EPO‑B compared
to EPO‑A.
After successful treatment, 8 of 17 patients achieved
successful maintenance. The average dose to maintain
hemoglobin levels in six patients receiving EPO‑B was half
of that in the two patients treated with EPO‑A. Figure 2
indicates the changes in hemoglobin level/100 units of
EPO dose/kg/week after 1 month (A), 2 months (B),
and 3 months (C) of treatment. While the median levels
increased in both the groups at 1 month, the median increase
was significantly higher in patients receiving EPO‑B.
Hemoglobin levels continued to increase after 2 months in
the EPO‑A limb, while levels decreased in the majority of
patients in the EPO‑B limb. This was because doses were
usually adjusted downward in the second month to maintain
the probability of success remained higher, but only
insignificantly, in patients in the EPO‑B versus EPO‑A
group (EPO-A AOR 0.07; 95% CI, 0-7.3), it did not reach
significance. Hypertensive episodes were similar in patients
treated with EPO‑A and EPO‑B (56.2% vs. 50%; relative
risk: 1.12; 95% CI, 0.59–2.16; P = 0.99). No other adverse
events were recorded, such as hypersensitivity reactions.
Table 3 compares the median cost of treatment with EPO‑A
versus EPO‑B. Patients who received EPO‑B consumed
fewer vials to achieve successful treatment compared to
those who received EPO‑A (12 vs. 24 vials), leading to
lower cost of treatment using the former. There were no
significant differences in the number of vials consumed
per month and in the monthly cost of EPO‑A and EPO‑B
during the maintenance period. While the overall cost of
EPO‑B therapy was 27% lower than that of EPO‑A, the
difference in the overall cost per month using either type of
EPO from successful treatment to successful maintenance
was not statistically significant.
Discussion
This study shows that EPO‑B is more effective than EPO‑A
in the treatment of anemia among pediatric CKD patients
on maintenance hemodialysis. The initial doses for patients

Table 2: Comparison of outcomes of treatment in patients receiving erythropoietin‑A and erythropoietin‑B in children on
maintenance hemodialysis
Total (n=32) EPO‑A (n=16) EPO‑B (n=16) P
Treatment phase, n treated 32 16 16
Successful treatment 17 (53.1) 5 (31.2) 12 (75) 0.03
Success of therapy at various time points (months) n=17 n=5 n=12
1 11 (64.7) 1 (20) 10 (83.3) 0.013
2 5 (29.4) 4 (80) 1 (8.3)
3 1 (5.9) 0 1 (8.3)
EPO dose (U/kg/week) 393±140 208±151 0.03
Maintenance phase, n treated 17 5 12
Successful treatment 8 (47) 2 (40) 6 (50) 0.99
Duration of successful maintenance (months) n=8 n=2 n=6 0.99
3 4 (23.5) 1 (50) 3 (50)
≥4 4 (23.5) 1 (50) 3 (50)
EPO dose (U/kg/week) 254±101 124±44 0.03
Continuous variables are presented as mean±SD and categorical as n (%). P<0.05 was considered statistically significant. EPO: Erythropoietin, SD: Standard
deviation

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 Diño‑Santos, et al.: Erythropoietin therapy for anemia of chronic kidney disease
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a b
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c
Figure 2: Comparison of changes in Hb level (g/dL)/100 units/kg week among patients who had successful treatment in the EPO‑A and EPO‑B groups
after 1 month (a), 2 months (b), and 3 months (c) of treatment

Table 3: Comparison of costs of therapy with erythropoietin‑A and erythropoietin‑B in children on maintenance
hemodialysis
Erythropoietin‑A (n=5) Erythropoietin‑B (n=12)*,a P
Cost to achieve successful treatment n=5*,a n=12*,a 0.03*
Number of vials consumed 24 (24–24) 12 (8–17) 0.05*
Cost (Php, ₱) 11,448 (11,448–11,448) 5580 (3720–14,880) 0.04*
Monthly cost to achieve successful maintenance 2*,b 6*,b 0.99
Number of vials consumed 13 (12–15) 11 (8–14) 0.50
Cost (Php, ₱) 6916.5 (6659.00–7274) 4650 (3434–6510) 0.32
Overall monthly cost from successful treatment to successful maintenance n=2*,c n=6*,c 0.99
Number of vials consumed 14 (12–15) 10 (8–13) 0.50
Cost (Php, ₱) 6360 (5724–6996) 4650 (3434–6510) 0.50
*Significant P-value <0.05. n=Number of patients who achieved aSuccessful treatment, bSuccessful maintenance, and cBoth successful treatment and
maintenance, continuous variables are presented as median (IQR), P<0.05 was considered statistically significant. IQR: Interquartile range

who receive EPO‑A are significantly higher than those who
are given EPO‑B. The inclination to provide larger doses
to patients may result from the desire to use up the entire
vial before discarding it after opening. Although there is a
significant difference, the initial doses given are based on
the recommendation from the KDIGO guidelines to start
EPO at 50–250 U/kg/week for children 12 to <19 years old.
Our results show that more patients using EPO‑B achieve
successful treatment of anemia within 3 months of treatment,
similar to the findings of Ahsan et al., 2021.[18] This is in
contrast to most adult studies claiming that both agents are
equally effective in achieving hemoglobin levels of ≥11 g/dL
within 3 months of treatment.[11,12,17] Sörgel et al., 2009,[10]
showed that the two agents were bioequivalent with regard to
steady‑state pharmacokinetic profile and pharmacodynamic
action in healthy adults. With declining creatinine clearance,
however, residual renal function modulates the response to
EPO and differs from healthy individuals.[13]

Asian Journal of Pediatric Nephrology ¦ Volume 6 ¦ Issue 1 ¦ January‑June 2023 7

 Diño‑Santos, et al.: Erythropoietin therapy for anemia of chronic kidney disease
In addition, this study shows that more patients who received
EPO‑B achieve treatment success within 1 month compared
to those who received EPO‑A. According to De Nicola et al.,
2007,[24] the median time required to reach target hemoglobin
with EPO was 1.5 (0.2–10.7) months. Singh et al., 2006,
demonstrated that the median time for patients in the low
hemoglobin group to reach the target of 11.3 g/dL using
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EPO‑A is 36 days (95% CI, 29–43; P < 0.001).[25]
Our findings show that the dose required for successful
treatment using EPO‑B is markedly lower compared with
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that required for EPO‑A, and the difference is larger during
the initial treatment. In children with CKD, the maintenance
of hemoglobin level correlates with better renal survival.[5]
In this study, only half of the subjects were able to maintain
hemoglobin of ≥11 g/dL after successful treatment of anemia
(8 out of 17, 53%). The percentage of patients who had
successful maintenance did not significantly differ between
the two groups, similar to the findings of Azmandian et al.,
2018, and Ostrvica et al., 2010.[11,12] Observational studies
in adult patients on hemodialysis have demonstrated that
hemoglobin levels during EPO therapy show marked
intrapatient variability over time.[26] Similarly, significant
fluctuations in hemoglobin level are also demonstrated in
nondialyzed patients with CKD.[17] De Nicola et al., 2007,[24]
observed that only 24.3% of patients have a hemoglobin
at desired level after starting EPO therapy and only 33.6%
of these maintain target hemoglobin for merely 3.2 (0–6.2)
months. In this study, breakthrough anemia was associated
with acute infections. Notwithstanding, patients were able to
maintain a hemoglobin level of ≥11 g/dL after a maximum
of 4 and 5 months with continuous therapy with EPO‑A
and EPO‑B, respectively.
This study also shows a lower dose requirement for EPO‑B
than EPO‑A to achieve successful maintenance. Although
not statistically significant, this is consistent with the results
of Halstenson et al., 1991,[9] and Loughnan et al., 2011,[27]
showing increased doses of EPO‑A required to maintain
target hemoglobin levels. The recommended lower dose
requirements of EPO‑B may be due to differences in the
pharmacokinetics and functions between the two types of
EPO, possibly caused by glycosylation.[27]
Our results show that the median increase in hemoglobin per
100 units of EPO/Kg/week after 1 month of treatment is higher
in EPO‑B than in EPO‑A. This is in contrast with the previous
study (Prasetya et al., 2019)[17] comparing the effectivity of
the two types of EPO among adult hemodialysis patients,
wherein the mean increase of hemoglobin level for the EPO‑A
group was higher than in the EPO‑B group (1.28 ± 0.80 vs.
0.37 ± 0.95 g/dL; P = 0.001 vs. P = 0.25).
Insight into factors that influence sensitivity and response
to EPO is essential for the adequate management of
8 Asian Journal of Pediatric Nephrology ¦ Volume 6 ¦ Issue 1 ¦ January‑June 2023
anemia. However, due to the nonuniformity of data
collected, we were not able to explore important
variables that may influence EPO treatment response
such as hemodialysis adequacy and iron stores. [6]
Studies among adults have shown that factors that can
affect response to EPO are the severity of anemia,
comorbidity and its severity, type of vascular access
used for dialysis, acute infection, nutritional status, and
inadequate dialysis (Kt/V <1.2). A catheter may be a
limiting factor for appropriate dialysis, in addition to
acting as a source of infection or chronic inflammation
which can trigger the release of inflammatory cytokines,
partially blocking erythropoiesis. Malnutrition is closely
related to inflammation and arteriosclerosis, and through
common mediators such as interleukin‑6 or tumor
necrosis factor‑alpha, it may play a relevant role in EPO
resistance; on the other hand, obese patients have the
lowest EPO resistance index.[28] In this study, we have
seen that patients who are overweight/obese achieve
successful treatment and successful maintenance. Even
when these confounding variables are controlled, the
probability of successful treatment remains higher in
patients who received EPO‑B compared with those who
were given EPO‑A. However, the result is not significant
in the subanalysis of patients with inadequate dialysis
(Kt/V <1.2) which may be due to a very limited number
of subjects who had data on Kt/V.
In our study, hypertension is the only recorded adverse event.
It is seen in both EPO‑A and EPO‑B groups and in all levels of
hemoglobin. As in the previous study, there is no significant
difference between treatment groups regarding the incidence
of adverse effects.[11,17] EPO‑induced hypertension is mainly
due to enhanced vascular responsiveness to constrictors and
impaired action of vasodilators.[29] A meta‑analysis[15] on
EPO demonstrates that targeting higher hemoglobin levels
in CKD increases risks for stroke, hypertension, vascular
access thrombosis, death, serious CV events, and end‑stage
kidney disease (ESKD). The mechanisms for harm were
not yet established and a systematic review of patients’
individual data and trials on fixed doses are recommended
to explain its mechanisms.
Since a lower dose of EPO‑B is required to achieve
successful treatment, the number of EPO‑B vials consumed
is two times less than that of EPO‑A, consequently a
marked reduction in the cost of treatment. The monthly
cost of EPO to achieve successful maintenance is also
lower with the use of EPO‑B. Likewise, the overall cost per
month from successful treatment to successful maintenance
is lower in EPO‑B compared with that of EPO‑A. Based
on our findings, the estimated annual cost of treatment of
anemia in CKD using EPO‑B is 27% lower than that of
 Diño‑Santos, et al.: Erythropoietin therapy for anemia of chronic kidney disease
EPO‑A (Php 55,800.00 or 1,001.35 USD, vs. Php 76,320
or 1370.00 USD, respectively). This is similar to the
study demonstrating that the annual cost of treatment for 5.
anemia among ESKD adult patients in Iran using EPO‑A
is 2.5 times the cost of using EPO‑B.[11] Even though our 6.
results are not statistically significant, the lower cost of
EPO‑B, mainly during the treatment period, may have
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7.
a considerable impact on our financially incapacitated
patients and, to a large extent, on the allocation of
government funds. 8.
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 09/24/2023
Conclusions
9.
This study shows that EPO‑B is more effective than
EPO‑A in the management of anemia of CKD stage 5 in
pediatric patients on maintenance hemodialysis. EPO‑B
10.
achieved the target hemoglobin level within 1 month of
treatment at lower doses and lower cost than EPO‑A.
Both agents had comparable safety profiles. This is the
11.
first study among pediatric patients on hemodialysis that
directly compares the effectiveness and treatment costs
of the two therapies. However, prospectively controlled
comparisons are necessary to confirm the findings of 12.
this retrospective comparison in pediatric patients on
maintenance hemodialysis.
13.
Ethical statement
This study was approved by the Institutional Research-Ethics
Committee of the Philippine Children’s Medical Center with IR- 14.
EC Protocol Number: 2022-013.
Acknowledgment 15.
We thank the CRD research consultants, Dr. Ma. Lucila Perez, Dr.
Maria Luz Del Rosario, and Dr. Paul Matthew Pasco for technical
help and assistance with writing and editing this manuscript, Mr. 16.
Ruel Guirindola for his contribution to statistical analysis, and
Dr. Ma. Norma Zamora, head of the Section of Nephrology for 17.
her support in conducting this study.
Financial support and sponsorship
18.
Nil.
Conflicts of interest
There are no conflicts of interest. 19.
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10 Asian Journal of Pediatric Nephrology ¦ Volume 6 ¦ Issue 1 ¦ January‑June 2023