APME-345; No.

of Pages 6

apollo medicine xxx (2016) xxx–xxx

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.elsevier.com/locate/apme

Review Article

A review on pharmacological use of recombinant

human erythropoietin in renal and nonrenal
anemia and other potential applications in clinical
practice

G.K. Thilaka, S. Vijaya Kumar *

PG and Research Department of Botany and Microbiology, A.V.V.M. Sri Pushpam College (Autonomous), Poondi,
Thanjavur 613503, Tamil Nadu, India

article info abstract

Article history: The introduction of recombinant human erythropoietin (rHuEPO) has revolutionized the
Received 5 August 2014 treatment of patients with anemia of chronic renal disease. Clinical studies have demon-
Accepted 27 January 2016 strated that rHuEPO is also useful in various nonuremic conditions, including hematological
Available online xxx and oncological disorders, prematurity, HIV infection, and perioperative therapies. Since the
cloning and first clinical introduction of recombinant erythropoietin (epoetin) in the late
Keywords: 1980s, indications and usage of epoetin have expanded significantly. It is estimated that as
Recombinant erythropoietin many as one-third of patients with substantial anemia (hemoglobin less than 10.0 g/dl)
Anemia resulting from chemotherapy for cancer are treated with epoetin. Research suggests there is
Clinical applications considerable variation in epoetin usage in practice. This review highlights the applications
of rHuEPO in clinical practice and also addresses the usage of recombinant erythropoietin
in situations where benefit is substantiated by high-quality studies.
# 2016 Indraprastha Medical Corporation Ltd. Published by Elsevier B.V. All rights
reserved.

day. Anemic people suffer from tissue hypoxia. Severe cases

1. Introduction
Erythropoietin is an endogenous hormone produced in the
kidney that regulates red blood cell production within
the body. The human gene for erythropoietin was closed
in the early 1980s,1,2 and the recombinant form was
developed shortly thereafter. Hematocrit and the concentra-
tion of hemoglobin in blood are normally maintained
constant. About 1% of the red cell mass is renewed each
can require transfusion of red cells from blood donors.
Transfusion therapy with allogenic blood components may
cause immunologic reactions and infections. In addition,
repeated red blood cell transfusions can lead to iron
overload. Therefore, the availability of recombinant human
erythropoietin (rHuEPO) as an antianemic drug has been an
important medical progress.
Initial trails of the replacement therapy with rHuEPO to
restore the hematocrit in patients with end-stage renal failure

* Corresponding author. Tel.: +91 9003311921.

E-mail address: svijaya_kumar2579@rediff.com (S.V. Kumar).
Abbreviations: rHuEPO, recombinant human erythropoietin.
http://dx.doi.org/10.1016/j.apme.2016.01.004
0976-0016/# 2016 Indraprastha Medical Corporation Ltd. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Thilaka GK, Kumar SV. A review on pharmacological use of recombinant human erythropoietin in renal
and nonrenal anemia and other potential applications in clinical practice, Apollo Med. (2016), http://dx.doi.org/10.1016/j.apme.2016.01.004
APME-345; No. of Pages 6

2 apollo medicine xxx (2016) xxx–xxx

were reported 20 years ago,3,4 which then lent a new impetus

to studies of the pathophysiology and pharmacology of EPO.5
As soon as rHuEPO was made available for human trial, a series
of clinical studies were promptly conducted to assess its
effectiveness in correcting anemia of chronic renal disease.
The initial results demonstrated that rHuEPO could restore the
packed cell volume, abrogate the necessity of regular blood
transfusion in patients requiring dialysis, and improve the
overall well-being.3,4,6 This review provides an overview of
pharmacologic use of recombinant erythropoietin in various
nonuremic conditions and other potential applications of
recombinant erythropoietin in clinical practice.

2. rHuEPO

2.1. Production and biological characteristics

The preparation of pure human urinary EPO enabled the
identification of the amino acid sequence of a tryptic fragment
of the protein and synthesis of EPO DNA probes for the
isolation and cloning of the EPO gene. Mammalian cells
transferred with the EPO gene linked to an expression vector
(‘‘recombinant DNA’’) produce rHuEPO in vitro. Chinese
hamster ovary (CHO) cells deficient in the dihydrofolate
reductase gene are most commonly used for the large-scale
manufacture of the drug, because in such cells EPO gene
amplification can be achieved by coselection in the metho-
trexate.7–9 The extent of microhetergeneity of CHO cell
expressed rHuEPO has been studied by mass spectroscopy
and NMR spectroscopy.
Human urinary EPO and rHuEPO are identical with regard to
their amino acid sequence, position of the a-disulfide bridges
and 4 glycosylation sites, and their secondary structure. The
peptide consists of 165 amino acids. The molecular mass of the
glycoprotein entity is 30 kDa. The carbohydrate portion (40%)
is essential for molecular stability and full in vivo biological
activity. There are quantitative differences in glycosylation,
which may also explain the fact that the specific in vivo
biological activity of purified human urinary EPO is lower
(70,000 IU/mg peptide) than that of the purified recombinant
product (about 200,000 IU/mg peptide).
Two brands of CHO cell-derived EPOs, termed epoetin alfa
and epoetin beta, are currently used for treatment of EPO-
deficiency anemia and for support in autologous blood
collection programs. Both of these types of rHuEPO are
produced in CHO cultures and act on the same erythropoietin
receptor, and there are some variations on the degree of
glycosylation,10 which lead to the differences in the pharma-
cokinetics and pharmacodynamics among the rHuEPOs.
As the N-glycosylation confers the biological activity of
RHuEPO, an increase in the number of glycosylation sites may
enhance its activity. A hyperglycosylated rHuEPO, known as
NESP (Novel Erythropoiesis Stimulating Protein; Darbepoetin-
alfa), has recently been introduced.11
Compared with the rHuEPOs, NESP has a higher negative
charge and a threefold longer half-life and requires a less
frequent dosing schedule and produces a similar clinical
outcome and safety profile as rHuEPOs in treating anemia of
chronic renal disease and of malignancy.12–14
Fig. 1 – Hematopoiesis.
2.2. Mechanism of action
Erythropoietin is essential for the proliferation, differentiation,
and maturation of RBCs in bone marrow (Fig. 1). Erythropoietin
is critical for the survival of RBC progenitors in bone marrow
and may also have immune modulatory activity.15,16 Erythro-
poietin functions by binding to the erythropoietin receptor,
which is a member of the superfamily of cytokine receptors.17
The number of erythropoietin receptors varies during RBC
differentiation, with its peak presentation at the colony-
forming unit erythroid/proerythroblastic stage and the level
being undetectable at the reticulocytes (Fig. 2). The binding of
erythropoietin to its receptor results in homodimerization of
the receptor, followed by activation of several signal trans-
duction pathways: JAK2/STAT5 system, G-protein (RAS),
calcium channel, and kinases.
rHuEPO has revolutionized the treatment of patients with
anemia of chronic renal failure. Moreover, rHuEPO has been
shown to be effective in connecting anemia associated with
various nonuremic conditions (Table 1).
3. rHuEPO therapy in renal failure
rHuEPO as an antianemic drug for treatment of patients
suffering from chronic renal failure was introduced 20 years
ago.3,4 Given intravenously or subcutaneously,18 it is now
routinely used in patients on regular hemodialysis or continu-
ous ambulatory peritoneal dialysis (CAPD), as well as in many
predialysis patients.19,20 rHuEPO raises hematocrit and blood
hemoglobin concentration in a dose-dependent and predictable
way, and it abolishes the need for red cell transfusions with its
risks of incompatibility reactions, viral infections, and iron
overload. In previously anemic patients, rHuEPO therapy
reverses the hyperdynamic cardiac state and restores the
impaired brain function. The well-being and exercise tolerance
of the patients are greatly increased (Table 2).
rHuEPO can correct the anemia in practically patients with
renal failure, but the dose needed is variable (Table 3). The

Please cite this article in press as: Thilaka GK, Kumar SV. A review on pharmacological use of recombinant human erythropoietin in renal
and nonrenal anemia and other potential applications in clinical practice, Apollo Med. (2016), http://dx.doi.org/10.1016/j.apme.2016.01.004
APME-345; No. of Pages 6

apollo medicine xxx (2016) xxx–xxx 3

Fig. 2 – Erythropoietin functions by binding to the erythropoietin receptor.

Table 1 – Clinical applications of rHuEPO.

Replacement therapy Supportive therapy Augmentative therapy Other potential therapeutic
(in anemia associated (to accelerate (increase Hb above applications
with) erythropoiesis) physiological level)
Chronic renal failure Post-chemotherapy Surgery Acute renal failure
Malignancy Post-radio therapy Situation where blood Anemia associated with auto
transfusion is refused or immune diseases, acute hemolysis
disallowed
Prematurity Post-transplantation Hemoglobinopahty
HIV infection Critically ill patients
Neuroprotection
Congestive cardiac failure

main reason for rHuEPO hyporesponsiveness in clinical

4. rHuEPO therapy in cancer-related anemia
practice is failure to provide sufficient iron, which is reflected
by a serum ferritin concentration <100 mg/l, a transferrin
saturation <20%, and a proportion of hypochronic red cells Anemia is a complication commonly encountered in malig-
>10%.21 Intravenous iron is recommended for hemodialysis nancy, especially of hematological origin, either at presenta-
patients (10–20 mg/hemodialysis treatment). Oral iron supple- tion or during the course of treatment. Anemia of chronic
mentation is appropriate for CAPD and predialysis patients
with serum ferritin >100 mg/l.22 The potential toxicity of
chronic iron exposure has been discussed recently.23
Table 3 – rHuEPO therapy in chronic renal failure.
1 Practice 30% predialysis patients
60% dialysis patients
Table 2 – Positive effects of rHuEPO in patients with
2 Application S.C. (2–3 week) predialysis and
chronic renal failure.
CAPD
(1) Stimulation of erythropoiesis. S.C./i.v. (3 week) hemodialysis
(2) Elimination of the need for – and risks of transfusion of 3 Dose 50–150 IV/kg and week
allogenic red blood cells. 4 Targets Hemoglobin – 120 g/l
(3) Increase in physical exercise tolerance. Hematocrit – 0.33–0.36
(4) Prevention of anemia-induced hyperdynamic cardiac state. 5 Iron deficiency if Serum ferritin
(5) Improvement of cognitive and psycho-osmotic functions of Transferrin – <100 mg/l
the brain. Saturation – <20%
(6) Relief of pruritus. Hypochromic red cells – >10%

Please cite this article in press as: Thilaka GK, Kumar SV. A review on pharmacological use of recombinant human erythropoietin in renal
and nonrenal anemia and other potential applications in clinical practice, Apollo Med. (2016), http://dx.doi.org/10.1016/j.apme.2016.01.004
APME-345; No. of Pages 6
4 apollo medicine xxx (2016) xxx–xxx
disease, a condition characterized by disordered iron metabo-
lism, shortened RBC half-life and inefficient erythropoiesis is
the major contributor to cancer anemia.24
More than half of the cancer patients have a low serum
level of erythropoietin.25 rHuEPO has been employed in
correcting the anemia, either as supportive or preventive
treatment, with an excellent safety profile. rHuEPO has
recently been shown to be capable to induce apoptosis in
myeloma cell culture, suggesting its antitumor activity.26
When rHuEPO is applied before chemotherapy, it prevents
the decline in hemoglobin and decreases the requirement of
blood transfusion during the course of chemotherapy.27,28 In a
large prospective community study, the use of rHuEPO
increased the functional capacity and the quality of life of
patients.29
Recent clinical studies have demonstrated that a normal
level of hemoglobin before radiotherapy with or without
chemotherapy could improve the treatment outcome.30
Analysis of two large-scale studies involving 4382 patients
has revealed that patients with solid tumors receiving rHuEPO
had a significant improvement in quality of life occurring
between hemoglobin levels of 80 and 140 g/l.31
5. Hemotological malignancy/preleukemic
stem cell disorder
Multiple myeloma and lymphoproliferative leukemia are
those hematological disorders that benefit significantly from
rHuEPO therapy, with an average response rate of 60%.
Whether rHuEPO is given as supportive, preventive, or
maintenance therapy, it increases the hemoglobin and
minimizes the requirement for blood transfusions.32–35
6. Anemia associated with bone marrow/stem
cell transplantation
‘‘Conditioning’’ using intensive chemotherapy with or without
radiotherapy before transplantation induces the state of
pancytopenia, which requires regular blood product support
until bone marrow/stem cells have been fully engrafted. The
frequency of blood transfusion requirement has been estimated
at 11/patient/50 kg body weight within the first 2 months after
transplant. 17 clinical trials of bone marrow/stem cell trans-
plantation were using intravenous rHuEPO (range 500/kg 3 times
a day to 500 U/kg once a day for a 28–30-day period), with
or without G-CSF/granulocyte-macrophage-CSF.36 The patient
receiving an allogenic transplant could expedite erythroid
engraftment and augment the level of hemoglobin. The efficacy
of rHuEPO was also observed in late-onset anemia due to graft-
versus-host disease or infection and immune hemolysis
secondary to bone marrow/stem cell ABO incompatibility.
7. Efficacy of rHuEPO in anemia associated
with
(i) Surgery: There is increasing evidence that rHuEPO can
minimize blood transfusion in patients whose surgical
Please cite this article in press as: Thilaka GK, Kumar SV. A review on pharmacological use of recombinant human erythropoietin in renal
and nonrenal anemia and other potential applications in clinical practice, Apollo Med. (2016), http://dx.doi.org/10.1016/j.apme.2016.01.004
procedure, for example cardiothoracic surgery or orthope-
dic surgery, may cause up to a 20% loss of total blood
volume.37,38 Furthermore, a study has demonstrated that
in patients who were not eligible for autologous donation, a
low dose of rHuEPO (150 IU/kg/week) given 3–4 weeks
before surgery reduced the blood transfusion requirement
by nearly 50%.39
(ii) HIV infection: Up to two-thirds of patients suffering from
AIDS have anemia, particularly those who are receiving
Zidovudine therapy. Treatment with rHuEPO, given either
as a weekly dose (24,000–48,000 U) or as a thrice weekly
administration (100–2000/kg), corrects anemia, improves
the patients quality of life when baseline serum erythro-
poietin is <500 mU/ml, and improves survival.40–42
It has been suggested that the target hemoglobin should be
maintained at 120 g/l and 110 g/l in males and females,
respectively.43
8. Other potential applications of rHuEPO
(i) Autoimmune diseases
Anemia is common in rheumatologic disorders, in
particular rheumatoid arthritis. This is usually due to
anemia of chronic disease. Other complications, such as
chronic blood loss and malabsorption, are particularly
prominent in inflammatory bowel disease. The rHuEPO
therapy has been shown to be effective in controlling
these immune-associated conditions.44–46
(ii) Hemolysis
The fall of hemoglobin as a result of RBC disorders,
such as hereditary spherocytosis and hemoglobinopa-
thies, or due to mechanical damage, such as cardiac valve
dysfunction, can be controlled, at least temporarily, by the
use of rHuEPO.47–49
(iii) Acute renal failure
In murine model of ischemic acute renal failure,
rHuEPO has been found to be capable of rapidly reversing
the associated anemia, accelerating functional recovery of
the kidneys, and reducing mortality.50,51 Furthermore,
rHuEPO may offer renoprotection in cisplatin-induced
acute renal failure and accelerates renal recovery.52,53
(iv) Critically ill patients
Patients in intensive care regularly require blood
transfusion. Patients who are anemic have an inappropri-
ately low endogenous serum erythropoietin.54 A prospec-
tive, multicentre, randomized study has demonstrated
that rHuEPO therapy (initiated on 300 U/kg subcutaneous-
ly from day 3 for 5 consecutive days followed by an
alternate day administration until the packed cell volume
reached 38%) reduced the requirement of blood transfu-
sion by 50%. Furthermore, there were no significant
differences in both mortality and frequency of adverse
events when compared with the control groups.55
(v) Neuroprotection
Based on the results from murine model, the use of
rHuEPO has been shown to limit the degree of ischemic
cerebral damage and spinal cord injury, together with
expediting neurological recovery.56,57 Intravenous rHuEPO
APME-345; No. of Pages 6
apollo medicine xxx (2016) xxx–xxx
(33,000 IU daily for 3 days) was associated with a
significant improvement in both functional activity and
clinical outcome.
(vi) Congestive cardiac failure
The anemia in congestive cardiac failure could be
safely corrected by subcutaneous rHuEPO and intrave-
nous iron, which results in ameliorating congestive
cardiac failure, preventing the progression of chronic
renal failure, reducing diuretic doses, and hospitaliza-
tion, together with improving the quality of life.58 Finally,
the authors have emphasized that the treatment of
anemia should be initiated early and the success of
treatment requires a close cooperation between cardiol-
ogists and nephrologists.
Conflicts of interest
The authors have none to declare.
Acknowledgment
The authors are thankful to the management of A.V.V.M. Sri
Pushpam College (Autonomous), Poondi, Thanjavur, for their
constant support throughout this work.
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