Open Access Review

Article DOI: 10.7759/cureus.10358

Erythropoietin Administration for Anemia

Due to Chronic Kidney Disease -
Subcutaneous OR Intravenous, What Do We
Know So Far?
Muhammad Hasan Shahab 1, 2 , Shahzeen Saifullah Khan 3, 2

1. Internal Medicine, Memon Medical Institute Hospital, Karachi, PAK 2. Paediatrics, Dr Ruth K.M. Pfau
Civil Hospital Karachi / Dow Medical College, Karachi, PAK 3. Accident and Emergency, Memon Medical
Institute Hospital, Karachi, PAK

Corresponding author: Muhammad Hasan Shahab, hasan.s_1993@hotmail.com

Abstract
The prevalence of anemia in chronic kidney disease (CKD) patients is almost twice that of the
normal population and its severity increases exponentially as the disease worsens, dramatically
affecting the quality of an individual’s life. The advent of erythropoiesis stimulating agents
(ESA) in the 1980s saw a revolutionary change in the treatment of anemia in CKD patients,
drastically improving quality of life (QoL), overall health and reducing the need for blood
transfusions. Numerous ESAs have been developed ever since and are in current use, with the
primary routes of administration being intravenous (IV) and subcutaneous (SC) injections.
Their use, however, has stirred significant controversy over the last two decades. Additionally,
despite numerous studies and trials, the latest international recommendations for their use do
not provide clear cut guidance with well-grounded evidence on the recommended route of
administration for different sets of patients. Instead, this decision has mainly been left up
to the physician’s discretion, whilst keeping certain key factors in mind. This review shall
summarize, discuss and compare the findings of previous studies on various factors governing
the two aforementioned routes of administration and identify areas that need further
exploration.

Categories: Internal Medicine, Nephrology

Keywords: chronic kidney disease, esrd, subcutaneous, intravenous, erythropoietin, dialysis, cost,
efficacy, frequency, anemia

Introduction And Background

Received 08/26/2020 Anemia, defined as serum haemoglobin (Hb) levels ≤12 gm/dL in women and ≤13 gm/dL in
Review began 09/01/2020 men, is a common complication of chronic kidney disease (CKD), being prevalent twice as much
Review ended 09/02/2020
in the affected adult population (15.4%) as opposed to the general population (7.4%). The
Published 09/10/2020
prevalence of anemia tends to be correlated with the severity of underlying kidney disease,
© Copyright 2020 prevailing in 8.1% of patients with stage 1 CKD to 53.4% in stage 5 CKD [1]. It is frequently
Shahab et al. This is an open access
associated with a poorer quality of life (QoL) that deteriorates further as the disease progresses,
article distributed under the terms of
and commonly results in cognitive impairment, reduced exercise capacity, worsening of cardiac
the Creative Commons Attribution
License CC-BY 4.0., which permits function, increased cardiovascular morbidity and ultimately contributes to an increased overall
unrestricted use, distribution, and mortality rate [1,2].
reproduction in any medium, provided
the original author and source are
credited.
Poor kidney function and accumulation of uremic toxins is a known cause of anemia in CKD
patients in addition to reduced erythropoietin (EPO) production due to loss of functioning renal

How to cite this article

Shahab M, Saifullah Khan S (September 10, 2020) Erythropoietin Administration for Anemia Due to
Chronic Kidney Disease - Subcutaneous OR Intravenous, What Do We Know So Far?. Cureus 12(9):
e10358. DOI 10.7759/cureus.10358
 parenchyma, hyporesponsiveness to EPO, iron deficiency, chronic inflammation, and
shortened red blood cell survival [1-3].

If left untreated, it has a significant detrimental impact on the patient’s QoL, their overall
health and healthcare costs. A study in pre-dialysis CKD patients found a significant increase (p
< 0.0001) in monthly treatment costs between CKD patients who had untreated anemia against
those without anemia. In a similar study involving patients with end-stage renal disease
(ESRD), who were undergoing dialysis, medical costs were found to be 8.9% higher for every
month of treatment when Serum Hb was less than 11 gm/dL [2].

While the treatment of anemia in CKD involves managing multiple causative factors as
highlighted above, the most significant factor is the deficiency of EPO. As a result, the use of
erythropoiesis stimulating agents (ESAs) since 1989 has significantly improved the
management of anemia [4]. The need for blood transfusions in CKD patients has gone down
significantly, whilst improving QoL and exercise capacity [5,6]. A study conducted in the United
States in 2005 indicated almost 99% of in-center haemodialysis (HD) patients receiving ESA.
The magnitude of the revolutionary change brought by these agents can also be estimated from
the fact that in 2004, EPO therapy totaled $1.8 billion - the single largest Medicare drug
expenditure in the United States [4,7].

The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines regarding anemia in
CKD present evidence and recommendations of varying strength. With regards to ESA therapy
in adult CKD patients, they strongly recommend against intentionally increasing Hb > 13.0
gm/dl, backed by high quality evidence. They suggest that ESA therapy should be initiated in
ESRD patients when Hb is between 9-10.0 gm/dl with an aim to keep it above 10 gm/dl but not
above 11.5 gm/dl, backed by low to moderate quality evidence [8]. In patients with non-dialysis
dependent, advanced CKD with Hb < 10.0 gm/dl, they suggest that the decision to treat using
ESAs should be weighed against various other factors but this is supported by low quality
evidence. These guidelines however, exhibit low to very low quality evidence when it comes to
recommendations about the type of ESA, dosing frequency, and their route of administration,
the last of which is the main focus of this review [8].

Since their inception, ESAs have undergone significant development and innovation, in line
with associated healthcare costs, pharmacokinetics, drug efficacy, side effect profiles and
dosing frequency as well as the route of administration. The ones commonly used include the
first generation erythropoietin-alfa and beta and the second generation agent Darbepoetin [4].
Their use, however, has come under serious scrutiny over the last two decades owing to certain
studies that showed an increase in overall mortality and adverse cardiovascular as well as
cerebrovascular events [9].

Target Hb levels secondary to ESA therapy remain a matter of controversy worldwide, with
higher Hb targets (>11.0 gm/dl) being tied to an increased risk of adverse events and no
significant improvement in QoL against that of partially corrected anemia, i.e., Hb (9.5 - 11.0)
gm/dl [8,10]. One rare outcome that gained significant attention was that of ESA-induced pure
red cell aplasia (PRCA) between 1998 and 2004, mainly associated with the subcutaneous (SC)
route of administration, and the exact cause of which is thought to be the production of anti-
EPO antibodies. However, this was found to be associated with one specific product of epoetin-
alfa “Eprex/Erypo” in Europe and was not associated at the same scale with other
subcutaneously administered epoetin products. This was appropriately dealt with by the
formulation of ESAs with a new structure [11,12].

Review

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 Method
For this review, we performed a literature search on the PubMed database (1988 - Present date)
using combinations of multiple keywords and Medical Subject Heading (MeSH) terms - anemia,
ESRD, erythropoietin, dialysis, chronic kidney disease, patient satisfaction, etc. The study types
that were reviewed included review articles, meta-analyses, systematic reviews, multicenter
studies, randomized clinical trials, excerpts from various journals and documents, and clinical
trials. To meet the criteria for inclusion, articles also needed to involve human subjects only
and be published in English. Case reports, editorials, commentaries, opinions and animal
studies were not included in this review. The most important point for inclusion was individual
article relevance to the scope of this review. However, this was carried out manually after
screening articles on the basis of their titles and abstracts.

Results
Using the aforementioned searching strategy, we found a total of 41,271 articles, of which
35,419 were found to be duplicated (see Table 1). A total of 5,852 articles were therefore found
after the initial search.

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 Search number Query Results

1 Erythropoietin AND Quality Of Life 1,302

2 Erythropoietin AND ESRD 3,519

3 Erythropoietin AND Safety AND ESRD 229

4 Erythropoietin AND Pure Cell Red Aplasia 272

5 ESRD AND Pure Cell Aplasia 86

6 Erythropoietin AND Cost AND Subcutaneous 109

7 Anemia AND Chronic Kidney Disease 7,353

8 Anemia AND ESRD 5,322

9 Erythropoietin AND Anemia 8,941

10 Erythropoietin AND Dialysis 4,158

11 Erythropoietin AND Haemodialysis 4,162

12 Erythropoietin AND Health Cost 361

13 Erythropoietin AND Treatment Adherence And Compliance 140

14 Erythropoietin AND Patient Satisfaction AND Quality Of Life 20

15 Erythropoietin AND Chronic Kidney Disease AND Dialysis 2,829

16 Erythropoietin AND ESRD AND Dialysis 2,468

TOTAL SEARCH COUNT 41,271

DUPLICATED ARTICLES 35,419

TOTAL ARTICLES FILTERED (EXLCUDING

5852
DUPLICATES)

TABLE 1: Results of the initial literature search, carried out on 15th August 2020, on
the PubMed Database using combinations of different MeSH terms and regular
keywords
ESRD: End-stage renal disease; MeSH: Medical Subject Heading

These were then further filtered for articles that were pertinent to the confines of this review by
another search carried out using “EndNote X9 ®”, a citation management software, by utilizing
a comprehensive list of relevant MeSH terms and regular keywords (see Table 2). Ultimately we
were able to narrow down our search to 160 articles that we felt were pertinent to the scope of
this review. Out of 160 articles, 38 full-text publications were then chosen for discussion in this
literature review, with the merit of selection being individual article relevance and
comprehensiveness.

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 MeSH Terms Regular Keywords

Erythropoietin Chronic renal disease

Erythropoietin / adverse effects Costs

Erythropoietin / pharmacokinetics Patient preference

Kidney failure, chronic Anemia

Chronic kidney disease ESRD

ESRD Erythropoietin

Renal dialysis Convenience

Health cost Haemodialysis

Epoetin alfa Chronic kidney disease

Erythropoietin / administration & dosage Injection

Kidney failure, chronic / complications Preference

Injections, intravenous Subcutaneous

Injections, subcutaneous Intravenous

Quality of life Haemodialysis

Patient compliance Administration route

Treatment adherence and compliance Pain

Patient satisfaction Efficacy

Patient preference Safety and tolerance

TABLE 2: A comprehensive list of various MeSH terms and regular keywords used for
filtering relevant articles after the initial search, using “EndNote X9 ®”
ESRD: End-stage renal disease; MeSH: Medical Subject Heading

Discussion
The major factors that govern the route of ESA administration include the patient’s stage of
CKD, efficacy considerations, the type of ESA used, dosing frequency, convenience, healthcare
costs, and drug safety and tolerability [8,12]. This literature review aims to discuss the existing,
relevant literature for these factors with respect to the route of ESA administration and to
define areas that need further exploration.

Dosing Frequency

Numerous studies and trials have documented evidence strongly suggestive of the advantages

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 that the SC route of erythropoietin administration has, in terms of requiring a lower dose and
frequency of administration, over the IV route (see Table 3).

Serial Study
Author/Year Population Relevant Conclusive Points
Number Design

128 adult HD patients selected from five Mean dose at stabilization of Hb levels, time
Muirhead et dialysis centers, 45 patients withdrew due to achieve target Hb levels and time to
1 al. / 1992 Clinical Trial to various reasons. 45 patients were in the stabilization of Hb levels of rHuEPO were all
[13] subcutaneous group (SC) and 38 in the significantly lower in the SC compared to the
intravenous (IV) group. IV group.

62,710 adult HD patients enrolled in the IV epoetin doses were on average 25%
Centers for Medicare and Medicaid higher than the SC dose for achieving
Comparative
Services ESRD Clinical Performance equivalent haemoglobin responses in study
Wright et al. Study
2 Measures Project from 1997 to 2005 were patients. Adverse outcomes on follow-up
/ 2015 [14] (retrospective
treated with epoetin, of which 57,602 were also found to be significantly more
cohort)
patients received IV and 5108 received SC likely in HD patients receiving IV rather than
epoetin. SC epoetin.

98 adult HD patients already on IV Epoetin requirements increased by 35%,

maintenance SC epoetin therapy enrolled on average, compared to previous SC
Vercaigne et into study and all patients were shifted to dosage whilst also resulting in a significantly
3 al. / 2005 Clinical Trial IV epoetin simultaneously for the lower mean Hb level. Similarly at the end of
[15] prospective study of anemia. 34 patients the IV epoetin evaluation period, 52%
withdrew at different stages due to various patients needed more frequent dosing than
reasons. 64 patients took part in study. at the time of SC to IV epoetin conversion.

414 adult HD patients participated in this The mean weekly, weight-adjusted dose of
study, which was essentially a wide-scale IV epoetin was found to be 20.2% higher, on
Comparative policy implementation for a change from average, than the baseline SC dosage. This
Moist et al. / Study the maintenance SC epoetin was most pronounced at 6 and 12 months of
4
2006 [16] (prospective administration route to the IV route. All follow-up. Patients receiving epoetin 3 times
cohort) patients were shifted simultaneously to the per week increased from 19.6% at baseline,
IV route. 111 patients withdrew from the with SC administration, to 79.5% at 12
study due to various reasons. months of IV epoetin.

Hb levels fell significantly in the first two

86 adult HD patients were studied on a
Comparative months after the switch from SC epoetin-alfa
Galliford et monthly basis for 6 months before and
Study to IV epoetin-alfa administration. This effect
5 al. / after a change in the route of
(prospective was partially offset at 6 months by an
2005 [17] administration from SC epoetin-alfa to IV
cohort) increase of IV epoetin-alfa dose by 32%
epoetin-alfa.
along with an increase in costs.

145 adult HD patients, already on SC

Epoetin, were randomized to one of two
Randomized epoetin treatment groups. The groups
Controlled either involved treatment with IV epoetin Provided that iron stores are optimal, there
Steffensen
Trial (Open, for 4 months followed by SC is no significant difference in mean Hb levels
6 et al. / 2011
multicentre administration for 4 months or vice versa. and mean EPO doses between IV and SC
[18]
Crossover Routine iron studies were carried out administration of epoetin-beta.
study) during study and supplemented as

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 needed.

44 adult chronic HD patients from a The outcomes showed that most chronic,
dialysis unit, already on IV Epogen (r- stable HD patients can maintain stable
HuEPO, Epoetin-alfa), were selected for hematocrit and Hb concentrations at once
this study and subjected to an approved weekly SC EPO doses that are one-third of
treatment protocol comprised of 3 phases the required weekly IV dose thereby lending
Parker et al.
7 Clinical Trial with different routes and doses of Epogen support to its safety and efficacy. Patient
/ 1997 [19]
administration. 27 patients completed the safety, serum biochemistry, blood pressure
protocol over 22 months. 135 “control” and red blood cell indices were also
subjects were matched during the protocol monitored during the study, with no
from another group of dialysis patients significant differences in any variable
refusing to opt for SC r-HuEPO. between the control and experimental group.

TABLE 3: A summary of studies comparing dosing frequency between intravenous

and subcutaneous routes of administration of erythropoietin
HD: Haemodialysis, SC: Subcutaneous, IV: Intravenous, Hb: Haemoglobin, r-HuEPO: Recombinant Human Erythropoietin, ESRD:
End-stage Renal Disease.

Drug Safety and Tolerability

As with any other drug, recombinant Human EPO (r-HuEPO) or epoetin carries with it a certain
set of side effects. While both IV and SC share some of these adverse effects, the extent and
frequency differ between the two (see Table 4). Common to both routes include injection site
pain sensation, the development of hypertension, arteriovenous fistulae thrombosis, an
increased overall risk of thrombotic and cardiovascular as well as cerebrovascular events,
hyperkalemia, depletion of iron stores, flu-like symptoms, a prolonged duration of dialysis and
rarely, PRCA and seizures [9,11,12,20].

Serial Study
Author/Year Population Relevant Conclusive Points
Number Design

78 adult HD patients were randomly Patients in the SC therapy group exhibited a

assigned to either receive IV or SC significantly higher rate (12.0%/patient year) of
Randomized
Lee et al. / epoetin. The time to Vascular access access failure as compared to the IV epoetin
1 Controlled
2009 [21] failure was analysed. Seven patients group (4.7%/patient year). The study was
Trial
were withdrawn from evaluation due limited, however, by a small sample size and
to various reasons. asymmetry between the two groups.

Adverse events (AE) were recorded in the two

groups, as serious and non-serious. AE were
362 adult HD patients from 16
higher in the SC therapy group
European dialysis centers entered
(55.9%) compared to the control group (44.1%),
the study with half of the patients
with serious AE being slightly higher in the
receiving r-HuEPO during the first
therapy group. Statistically however, there was
Clinical Trial year (first phase) of the trial and then
no significant difference between the two
Klinkmann et (Prospective, serving as the control group during
2 groups in terms of serious AE like
al. / 1992 [22] Multi-center the second year (second phase) and
hypertension, loss of vascular site access,
study) the other half followed the opposite

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 respiratory and gastrointestinal system-related
treatment plan. These patients were
issues. Death due to cardiac issues was higher
monitored for the drug safety of SC
in the control group. NO anti-EPO antibodies
administered EPO. A total of 73
were detected in either group. SC EPO
patients dropped out from the study.
administration has demonstrated a better safety
profile than IV EPO.

30% of all treated patients exhibited

hypertensive reactions. During the Hb and
hematocrit correction phase, there were more
90 adult HD patients already
Clinical Trial patients becoming hypertensive with SC EPO
suffering from ESRD, were enrolled
(Randomized, therapy than with IV EPO. This was not the
and randomly assigned to 4 different
Schaller et al. double-blind, case during the maintenance phase of
3 groups, 2 of which comprised of IV
/ 1994 [23] Prospective, treatment, however, SC EPO-treated patients
EPO therapy and the other 2 SC EPO
Multi-center did not complain about injection site pain and
therapy. The study involved 4
study) adverse reactions. The relationship between
different phases of treatment.
EPO treatment, development of hypertension
and route of EPO administration is complex and
multifactorial.

EPO hyporesponsiveness has numerous

causes, prominently infection, inflammation and
depletion of iron stores. 57 patients were found
Existing patient data and serum
to be EPO hyporesponsive, an estimated
samples from 1677 patients
incidence of 16.7/1000 patient years on EPO
participating in The Netherlands
while on dialysis. Only one patient among the
Cooperative Study on the Adequacy
above 57 patients was found to have clinical
of Dialysis-2 (NECOSAD-2) were
Kharagjitsingh PRCA, an estimated incidence of 0.29/1000
Multi-center used in this study. Data was collected
4 et al. / 2005 patient years on EPO while on dialysis. The
Cohort study at 6-month intervals between April
[24] incidence of EPO antibodies stood at 1.27/1000
1997 and September 2002. The
patient-years since the start of dialysis. Out of
study was performed to detect EPO
these 57 patients found to be EPO
hyporesponsive patients, EPO
hyporesponsive, 6 were treated with EPO IV,
antibodies and PRCA in dialysis
while all others used EPO SC. anti-EPO
patients.
antibodies and PRCA remain a rare cause of
EPO hyporesponsiveness, though it may be
tied to SC EPO administration.

13 chronic haemodialysis patients, At the end of the first month of the switch to SC
who remained hypertensive after rHuEPO, there was a significant drop in pre-
being on long term (>12 months), dialysis mean arterial pressure as opposed to
thrice weekly, post HD IV rHuEPO baseline pressures, prior to the switch. The
therapy were selected for this study, number of hypertensive patients reduced from
with hypertension being defined as 13 at the time of baseline recording to 8 at the
elevated blood pressure that end of the six-month trial. In the remaining 8
necessitated the use of anti- hypertensive patients, the severity dropped
Navarro et al. hypertensive medications. These significantly as was measured by a
5 Clinical Trial
/ 1995 [25] patients were switched to SC EPO “therapeutical score” that assessed
thrice weekly for 6 months, whilst hypertensive severity from the antihypertensive
keeping the total weekly SC dose at power of the drugs used to control it. This study
two-third of the weekly IV rHuEPO shows better control of hypertension with the
dose. Their blood pressure was SC route of administration in ESRD patients
monitored prior to each HD session.

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 and that SC rHuEPO doesn’t prevent
Patient’s hypertensive therapy and
hypertension in ESRD patients, rather only
red blood cell indices were also
reduces its severity compared to the IV route.
analysed regularly.

TABLE 4: A summary of studies comparing erythropoietin safety profile and tolerance

between intravenous and subcutaneous administration
HD: Haemodialysis, SC: Subcutaneous, IV: Intravenous, Hb: Haemoglobin, rHuEPO: Recombinant Human Erythropoietin, ESRD: End-
stage Renal Disease, AE: Adverse events, EPO: Erythropoietin, PRCA: Pure Red Cell Aplasia

Drug-associated Costs

Patients with severe anemia secondary to CKD < Hb 9.0 gm/dl and those with advanced CKD,
for example those on regular HD, need prolonged periods of ESA therapy to improve their QoL,
to prevent anemia-related symptoms, and to minimize the need for blood transfusion [8]. This
can incur significant recurring costs on individuals and on healthcare systems. Dealing with
this by employing a cost effective yet efficacious means of ESA therapy is therefore crucial (see
Table 5).

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 Serial Study
Author/date Population Main points
Number design

The switch from IV to SC

Patients were chosen from 4 in-centre Haemodialysis Units
EPO across 4
in Winnipeg, Manitoba, Canada. Patients were treated with
haemodialysis units,
Epoetin-alfa in two separate treatment regimes in two
Retrospective resulted in a 12.6% dose
Wazny et al. separate time periods - each lasting 6 months. 622
1 Multicenter reduction and saved 98%
/ 2013 [26] individuals were subject to on IV EPO (period 1), and 609
Study of the patients receiving
individuals to SC EPO (period 2). Costs were analysed
SC epoetin alpha, about
retrospectively from available patient data and monthly
1125 USD per person per
inventory billing records.
year.

Transitioning from SC to
86 adult HD patients, already on SC EPO-alfa treatment, IV EPO alpha in HD
Comparative
Galliford et were switched simultaneously to IV EPO-alfa, at the same patients requires a dose
Study
2 al. / 2005 weekly dose as their SC administration, for a period of 6 increase of around one-
(prospective
[17] months. Monthly Red cell indices, weekly EPO dosages and third, possibly resulting in
cohort)
other parameters were monitored during the study. an annual increase in
cost of £ 1500 per patient.

The cost of anemia

therapy rose significantly
6 months post-switch to
158 adult, chronic, HD patients, already on IV EPO therapy,
McFarlane IV EPO therapy. The
Controlled were studied for 1 year prior to the trial. In the study that
3 et al. / 2007 median rise in costs over
Clinical Trial spanned 12 months, patients were collectively shifted to SC
[27] the whole 6-month period
EPO therapy.
was estimated at 13.1%
(CAD 665/patient-year; p
< 0.01).

Administering epoetin
Two hundred and fifteen patients aged more than 18 years,
alpha subcutaneously
receiving in-center HD for at least 6 months at 4 HD centers.
resulted in a dose
Patients suffering from anemia of CKD requiring epoetin alfa
Retrospective reduction from IV to SC of
Prasad et al. therapy, and on IV epoetin alfa therapy for at least 6 months,
4 Observational 30.51% and 25%
/ 2020 [28] were switched to SC EPO-alfa. Data was collected from 6
Study reduction in EPO costs,
months prior to 12 months after the switch. Primary outcome
being equally effecting at
was the assessment of epoetin-alfa cost per patient per
maintaining Hb levels in
month before and after the policy change.
patients on HD.

TABLE 5: A summary of studies comparing healthcare costs between intravenous and

subcutaneous EPO administration
HD: Haemodialysis, SC: Subcutaneous, IV: Intravenous, EPO: Erythropoietin, CKD: Chronic Kidney Disease, CAD: Canadian Dollars

Drug Efficacy

There are various factors that underpin ESA efficacy, i.e., the dose needed to attain a certain

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 target Hb concentration or hematocrit level, which can be adequately summarized under the
umbrella of individual ESA pharmacokinetics and pharmacodynamics [12]. Discussed further
are factors that have been found relevant to ESA efficacy (see Table 6). Numerous studies have
provided support to the SC route of administration due to multiple advantages over the IV
route, most notably a lower overall dose to achieve a similar target Hb concentration as well as
hematocrit levels and a reduced dosing frequency, i.e., the SC route offers more efficacy for
administration of r-HuEPO [13-17,19]. Although the SC route offers a much lower level of
bioavailability as compared to the IV route, it results in a significantly longer half-life,
attaining peak plasma levels that are substantially lower than the IV route but persist for a
much longer period of time. The reasons theorized behind this low bioavailability but a
paradoxically prolonged maintenance of modest serum plasma levels can be attributed to a
multiple injection site, drug inherent and systemic factors. This persistence and delayed
absorption of EPO from SC administration has been pivotal in the explanation for this route’s
effectiveness over the IV route. As erythropoiesis is not as dependent on peak plasma EPO
levels as it is on the maintenance of EPO levels above a critical threshold for a prolonged time
duration, the SC route offers an advantage. IV EPO dosing results in a fall in serum r-HuEPO
levels during the interdialytic period and ultimately in the apoptosis of EPO-dependent
erythrocyte precursor cells in the bone marrow. SC EPO dosing prevents this apoptosis due to
maintenance of plasma EPO levels for a longer duration therefore enabling a more protracted,
efficient and effective process of erythropoiesis [29,30].

Serial Author / Study

Population Relevant Conclusive points
Number Year Type

12 adult, chronic, stable HD After first dosing with IV EPO, plasma EPO levels
patients, already under treatment were found to have a mean (±S.D.) half-life of 5.4 ±
with a thrice weekly IV rcEPO, were 1.70 hours compared to initial SC EPO administration
subjected to treatment scheme using with a mean(± S.D) absorption time being 22 ± 11
regimes of IV and SC rcEPO and an average bioavailability of 44% (28-100%).
Brockmöller
Prospective recombinant human EPO (rcEPO) With continuous long-term treatment with IV EPO,
1 et al. / 1992
study injections in discrete phases to elimination half-life reduced by 15% to around 5
[31]
assess pharmacokinetics and hours, possibly a reflection of an increase in
therapeutic response to both routes. hematocrit. The study suggests that the SC route be
Serum analyses were carried out at more effective due to prolonged plasma rcEPO
specific time intervals for achieving elevation following SC administration, with the exact
the goals of this study. mechanism being unclear.

Two groups of adult, chronic, and After IV rhEPO injections at the lower dose, the mean
stable HD patients were enrolled. half-life was found to be 5.4 ± 0.90 hrs, while at the
Group 1 was already under higher dose it was around 7.60 hrs. Peak serum EPO
maintenance treatment with IV levels (Cmax ) after IV dosing were found to be 20
recombinant human EPO (rhEPO)
times that of SC Cmax. Peak serum EPO levels after
thrice weekly. Group 2 included
Nielsen / Clinical ESRD patients not previously SC dosing were reached on an average of 27.3 ± 8.6
2 hrs. Mean bioavailability was also found to be a
1990 [32] Trial treated with rhEPO. Both groups
were subjected to IV and SC rhEPO meager 14.1% after SC dosing. Despite the data, the

administration at different dosages – protracted maintenance of rhEPO levels after SC

50 U/kg for group 1 and 150 U/kg for administration may be more efficacious than IV

group 2. Pharmacokinetic studies dosing though more work is needed in this area and

were then carried out using serum patients with SC administration need to be closely

analytics. monitored for anti-EPO antibodies.

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 29 adult, chronic, and stable HD
patients, were enrolled and split into Peak plasma levels after IV dosing were seen within

3 groups. Group I comprised of 19 5 minutes of administration and were not significantly

patients who were treated with IV different between Group I and II. IV rhEPO

rhEPO initially, then kept on elimination half-life was found to be an average of

maintenance therapy for 3 months 8.75 (7.29 - 11.68) hours, in Group I, but fell

and thereafter 10 patients from this significantly after 3 months, i.e. in Group II, to 6.80
Neumayer group, making up group II, were hours. SC rhEPO peak levels, though 5% that of IV
Clinical
3 et al. / 1989 subject to another bolus dose of IV levels, were attained between 18-24 hours after
Trial
[33] rhEPO at the end of these 3 months. administration, with a mean half-life of 11.2 (7.0-13.9)

Group III was made up of 9 hrs. SC bioavailability was also low at around 25%.

additional patients who were treated The study questions the benefit of reaching high peak

with a single SC rhEPO dose. serum levels immediately after IV administration and

Pharmacokinetic profiles of these provides support to a relatively low dose SC

two administration routes at different administration as mimicking EPO physiological levels

stages of treatment was then in augmenting erythropoiesis.

assessed using serum studies.

Cmax for the IP and SC routes are almost identical but

8 stable peritoneal dialysis (PD) only 5% of the IV route. Peak plasma concentrations
patients participated in a (C max) were attained at a mean of 9.4 ± 1.90 hrs for
randomized, single-dose, three-way the IP route, compared to a much slower time for SC,
cross-over study with Continuous at 17.1 ± 5.0 hours. However, SC bioavailability,
Ambulatory PD (CAPH) being 22.81%, was twice that of IP EPO, 11.4%. Compared
Ateshkadi carried throughout the study. to the IP route, the SC route had a significantly higher
Clinical
4 et al. / 1993 Patients were already using EPO or area-under-the-curve (AUC) between 0 and 96 hours
Trial
[34] candidates for it. They were given a after administration. The study also found the
single average dose of 99.1 U/kg of potential effect of EPO administration into a “dry” or
intraperitoneal (IP), IV, and SC empty peritoneum for greater efficacy via this route,
rhEPO. Pharmacokinetics of the albeit significantly lesser than the SC route.
three routes were compared using Administration strategies involving a more prolonged
serum analysis studies. EPO absorption with a relatively low Cmax may
enable more efficacy of rhEPO.

IV administration exhibited a serum peak level being

attained at 15 minutes post administration, with a
mean half-life (t 1/2 ) of 8.20 (6.20 - 10.20) hrs. IP
administration saw Cmax at 12 hours and an average

bioavailability of 2.90% (1.2 - 6.8%). Cmax for SC

8 adult, stable, chronic CAPD administration was at 18 hours and had a mean

patients were enrolled. Each patient bioavailability of 21.5% (11.3 - 36.0%). The study
Macdougall found that t1/2 for IV EPO in CAPD patients was not
Clinical was administered intraperitoneal
5 et al. / 1989
Trial (IP), IV, and SC rhEPO at a set dose significantly different from those on HD. The findings
[35]
for each route. The doses were of the study also suggest that high serum peaks of
spaced by 4 weeks. EPO are of little therapeutic value for effective
erythropoiesis. As a result, it suggests that SC route
of administration may be more beneficial in both
CAPD and HD patients. The bioavailability of this
route, however, is governed by a complex interplay
of injection site, drug composition and systemic
factors.

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 TABLE 6: A brief summary of studies comparing erythropoietin pharmacokinetics
between intravenous and subcutaneous administration
HD: Haemodialysis, PD: Peritoneal Dialysis, CAPD: Continuous Ambulatory Peritoneal Dialysis, SC: Subcutaneous, IV: Intravenous,
IP: Intra-peritoneal, Hb: Haemoglobin, EPO: Erythropoietin, rHuEPO: Recombinant Human Erythropoietin, ESRD: End-stage Renal
Disease, rcEPO: Recombinant Human Erythropoietin, Cmax: Peak serum drug concentration, t1/2 : drug half-life, S.D.: Standard
Deviation

Route of Administration and Stage of CKD (Non-Dialysis Dependent and Patients on Peritoneal
Dialysis vs Haemodialysis Patients)

Non-dialysis CKD patients with preserved GFR, or those undergoing peritoneal dialysis, benefit
from SC administration of ESAs, considering that it's least invasive and can be carried out
without any monitoring. Furthermore, intraperitoneal administration in patients on
continuous ambulatory peritoneal dialysis (CAPD), can dilute ESA concentration, limiting its
use [34,35]. The advantage of IV administration lies in the fact that it can be conveniently
administered during the process of haemodialysis. Numerous studies have shown that SC doses
of ESAs in non-dialysis dependent and patients on peritoneal dialysis, were found to effectively
increase Hb concentrations and were well-tolerated and may even be more efficacious than IV
EPO formulations in HD patients as well [36,37]. However, more work needs to be done
comparing the efficacy of SC versus IV EPO administration in non-dialysis and patients on
continuous ambulatory peritoneal dialysis (see Table 7). The use of EPO in HD patients has
been covered under other sections.

Serial Study
Author/date Population Main Points
Number Design

15 adult ESRD patients, on

Thrice weekly administration of r-HuEPO to subjects on
CAPD for the treatment of
peritoneal dialysis effectively corrected renal anemia. A
ESRD were enrolled in this
reduction in ineffective erythropoiesis and much more
study. They were subjected
Hughes et Randomized importantly, an increase in erythroid activity was thought
to treatment with r-HuEPO
1 al. / 1990 Controlled to be the major factor in increasing red cell volumes. The
thrice weekly SC, with two
[36] Trial findings of this study also suggested that prolonged,
separate target Hb levels in
moderate increase in serum EPO concentration is more
two discrete phases – the
important than a sudden rise in EPO as would be
correction phase and the
observed with IV EPO administration.
maintenance phase.

24 children, suffering from

Eighteen patients experienced increased Hb levels after
anemia secondary to ESRD
24 weeks of treatment from a mean of 6.5 (4.7-7.9) gm/dl
and on peritoneal dialysis,
to 9.4 ± 1.7 gm/dl. The IV route of administration is less
Montini et al. Multi-center aged 3 months to 18 years,
2 convenient in patients on peritoneal dialysis because of
/ 1993 [37] Study were treated with SC r-
lack of vascular access and difficult self-treatment, while
HuEPO, in varying doses,
the intraperitoneal route of administration compromises
depending on the Hb levels
bioavailability significantly.
achieved with each dose.

The mean hematocrit increased from a baseline value of

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 28.4 ± 2.7 to 33.6 ± 3.4% after an average of 6 weeks of
31 pre-dialysis CKD patients'
treatment and to 37.7 ± 4.5% after about 3 months of
medical record was
treatment. By analyzing a variety of other parameters as
assessed. These patients
well, the study importantly concluded that pre-dialysis
Trivedi Comparative had been treated with EPO
CKD patients exhibited significant response to EPO
3 and Brooks / Study between 1996 and 2001.
therapy without parenteral iron therapy. It was also
2003 [38] (retrospective) Various parameters were
evident that pre-dialysis CKD patients had lower overall
assessed including renal
EPO dosage requirements than ESRD patients. However,
function, red cell indices,
it is important to note that these findings are similar to the
and iron profiles.
ones in ESRD patients. More work is specifically needed
in pre-dialysis patients for analyzing dose requirements
among the two routes.

Sixteen anemic patients with

an Hb < 9 gm/dl, maintained
on chronic continuous 15 patients responded to treatment with a rise in Hb
ambulatory peritoneal concentration of more than 2 gm/dl. SC administration
dialysis (CAPD), were given was found to be acceptable, convenient more effective in
SC epoetin-alfa thrice treating anemia in CAPD patients. It was also associated
Stevens et
weekly, in two different with an improved QoL and can very well be thought of as
4 al. / 1991 Clinical Trial
phases – each with a higher an optimal route of EPO administration in CAPD patients.
[39]
Hb level target than the Additionally, in the same dialysis unit, it was found that
previous one. The dose of CAPD patients required a lower dose via the SC route
SC EPO was changed than HD patients did via the IV route for maintaining
periodically, depending upon target Hb levels.
the results of red-cell indices
and target Hb levels.

TABLE 7: A comparison of the different routes of ESA administration with the stage of
CKD (Non-dialysis dependent AND Patients on Peritoneal Dialysis vs Haemodialysis
patients)
HD: Haemodialysis, PD: Peritoneal Dialysis, CAPD: Continuous Ambulatory Peritoneal Dialysis, SC: Subcutaneous, IV: Intravenous,
Hb: Haemoglobin, EPO: Erythropoietin, r-HuEPO: Recombinant Human Erythropoietin, ESRD: End-stage Renal Disease, CKD:
Chronic Kidney Disease, QoL: Quality of Life

Convenience of Drug Administration

Between the two routes, convenience depends on factors like the stage of CKD, the dose and
dosage frequency, the type of ESA being used, ease-of-use, the type of dialysis being utilized,
the associated healthcare costs, and patient satisfaction.

For non-HD patients, the SC route may be more generally convenient due to the lack of a
continuous IV access, the ease of self administration, comparatively lower dosage, less frequent
hospital visits, a reduced dosing frequency and ultimately reduced costs. Even in HD patients,
the SC route has been tied to similar advantages and may therefore be more beneficial overall as
compared to the IV route, despite the obvious convenience that an arteriovenous fistula
confers to IV EPO administration [13-17, 19, 26-28, 31-35]. This may be particularly beneficial
in low-income countries where affordability and access to newer, longer acting ESAs may be
difficult [40]. Evidence lending support to the efficacy, cost effectiveness and safety of the SC

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 route of ESA administration has been presented in earlier sections.

A multicenter study, non-randomized, open-label study conducted by Grzeszczak et al. in 128

stable, chronic PD patients already on once to thrice-weekly SC EPO administration who were
enrolled in a study where the effect of shifting them to once-weekly and once-fortnightly
administration of SC Epoetin-beta in maintaining their Hb concentrations, was
investigated. The findings concluded that shifting patients to SC Epoetin-beta once-weekly did
not result in a significant change in mean Hb levels over a period of 25 weeks. In the once-
fortnightly group, the dose needed to be increased slightly and even then, more than 50% of
patients could still be maintained on baseline EPO-beta doses or lower. This study paves way
for a means of ESA administration that could result in greater convenience, compliance,
patient satisfaction, reduced dosage frequency and greater cost savings [41].

The convenience of use for the IV formulation in HD has its possible roots in the preference for
its use by HD Staff. This may be due to the routine use of the IV route by HD staff [16] as well as
the issue of pain or ‘stinging’ or discomfort at the injection site associated with the initial use
of SC epoetin-alfa which some studies have cited in the past [42]. The KDIGO guidelines have
also cited ‘pain’ secondary to SC administration, in terms of using short-acting ESAs, as a
reason to prefer IV EPO administration, referring to the results of a single centre trial of 30
patients [8, 26]. In a randomized, un-blinded trial carried out by Kaufman et al. among 208
patients, 86% of the 107 candidates who received SC epoetin injections reported experiencing
pain as none to mild [43]. Similar findings were found in a multi-center randomized, double-
blind, prospective study among 90 ESRD patients already on HD, who were subjected to
different regimes of IV and SC EPO treatment. None of the patients treated SC complained of
injection site pain nor were there any identifiable local adverse reactions [23]. Nonetheless the
pain reported in previous studies has mainly been tied to the citrate component of the epoetin-
alfa buffered solution that is administered SC to patients [44]. However, it has largely been
controlled by replacement of the citrate preservative with Benzyl Alcohol saline and other
newly developed stabilizer solutions, using large gauge needles, and smaller volume doses, all
of which were highly effective in reducing pain whilst maintaining drug efficacy [43, 45, 46].

Type of ESA Formulation Used

ESA can generally be classified as short-acting or long-acting. The former usually refers to the
1st generation ESAs like Epoetin-alfa and beta while the latter normally refers to 2nd
generation ESAs and beyond, including formulations like Darbepoetin-alfa and continuous
erythropoietin receptor activator (C.E.R.A) [4]. The choice of ESA depends on factors like drug
availability, affordability, patient preference, and local policies. Each of these agents also has
its own unique pharmacokinetic and pharmacodynamic profiles [4, 8]. In this review we shall
only discuss common ESA types from the first and second generations (see Table 8).

Serial Author /
Study Type Population Relevant Conclusive Points
Number Year

139 adult, chronic HD patients on Eprex

Darbepoetin alfa given weekly or once in two
(epoetin-alfa) for the last 3 months were
weeks proved to be more effective (64.8% of all
Bernieh randomized to three groups: Group-A-1
Randomized patients in Group-A) in achieving target Hb levels
et al. / receiving long-acting ESA Darbepoetin-
1 Controlled than epoetin-alfa (59.7% of all patients in Group-
2014 alfa once weekly, Group-A-2 receiving
Trial B), with significantly less dose changes and
[47] Darbepoetin-alfa once in two weeks and
vascular site thrombosis in the former group
Group-B representing patients continued
compared to the latter.
on Eprex treatment.

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 Clinical Trial
Adult anemic, chronic HD dependent
(a
patients already on EPO-alfa, were Darbepoetin-alfa, when administered at a reduced
prospective
started on an EPO regime comprised of frequency and comparatively lower dose, is similar
phase III,
Sinha et Darbepoetin-alfa, in two phases: to epoetin-alfa in terms of achieving and
randomized,
al. / correction phase (12-24 weeks) and maintaining target Hb levels. Darbepoetin-alfa
2 open label,
2019 maintenance phase (24-36 weeks). 126 also has a slightly better safety profile. This may
two-arm,
[48] patients in both phases were randomized pave way for achieving methods of treating renal
parallel
in 1:1 ratio to receive either Darbepoetin- anemia that are simpler and with mutual benefits
group, multi-
alfa once weekly or EPO-alfa thrice for patients and healthcare staff.
center
weekly.
study)

As opposed to the significant changes in dosage,

Randomized 126 adult, chronic, stable HD patients at 9
dose frequency and incurred costs that one
Controlled German dialysis centres, already on
Bommer encounters in changing EPO-alfa from SC to IV
Trial Darbepoetin-alfa for at least 6 months,
et al. / administration, Darbepoetin-alfa does not exhibit
3 (prospective, were randomized to either continue with
2008 such a trend. Instead, it exhibits a similar
randomized, their previous treatment plan or to IV
[49] pharmacokinetic profile for both the IV and SC
multicentre Darbepoetin-alfa in the same dose and
route. Therefore it presents a better cost-benefit
study) frequency.
profile and an easier to use choice among ESAs.

IV Darbepoetin alfa has a t1/2 that is 2 - 3 times

47 adult, chronic, stable HD patients,
longer and a clearance 4 times slower than that of
already being treated with IV epoetin
Clinical Trial epoetin alfa. The data gathered showed no
Allon et since at least 2 months, were randomized
(multicenter, changes in Darbepoetin pharmacokinetics with
al. / to 3 treatment groups for 6 months – one
4 randomized, dose frequency or amount, as compared to
2002 to receive IV Darbepoetin alfa once
open-label epoetin alfa. The results lend support to the use of
[50] weekly, one to receive IV Darbepoetin
study) Darbepoetin alfa by healthcare staff owing to its
alfa thrice weekly and the last to receive
flexible safety and efficacy at lower and less
IV epoetin alfa thrice weekly.
frequent doses compared to epoetin.

TABLE 8: A general comparison of some commonly used 1st and 2nd Generation
Erythropoiesis Stimulating Agents, based on previous clinical trails
HD: Haemodialysis, SC: Subcutaneous, IV: Intravenous, Hb: Haemoglobin, EPO: Erythropoietin, rHuEPO: Recombinant Human
Erythropoietin, ESRD: End-stage Renal Disease, rcEPO: Recombinant Human Erythropoietin, t1/2 : drug half-life, ESA: Erythropoiesis
Stimulating Agent

Limitations
As no review or study is perfect, this literature review has an important set of limitation: papers
were excluded if they were published in a language other than English, study types that met our
exclusion criteria like commentaries or animal-based studies were excluded, our focus was
mainly limited to studies based on adult CKD patients, and we mainly covered 1st and 2nd
generation ESAs in our review. Additionally, the majority of studies in anemic CKD patients
included in this review pertain to HD dependent ESRD patients. While significant efforts were
made to review a broad range of publications from different years, it is still pertinent to
mention the selection bias that may be present in this review with regards to the articles chosen
for review and their relevance. Future research work that corrects these limitations may very
well lead to different outcomes or impressions on the reader.

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 Conclusions
The studies discussed in this literature review are suggestive of greater efficacy and benefits via
the SC route of EPO administration over the IV route in most cases of chronic kidney disease,
keeping in view the factors mentioned earlier - drug costs, efficacy, convenience, dosage
frequency, stage of CKD, type of ESA used, and drug safety and tolerability. More work,
however, is definitely needed in elucidating the individual effects of each of these factors
among the two routes of administration, using multi-center randomized trials with much larger
sample sizes, especially on the use of ESAs according to the stage of CKD and holistic
comparisons of long acting against short acting ESAs, whilst measuring secondary outcomes
like patient satisfaction and convenience of use. This may very well help formulate more
practical guidelines, help improve the efficiency of ESA use, ensure cost saving, improve quality
of care for patients and provide clinicians with better insight during decision making.

Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors
declare the following: Payment/services info: All authors have declared that no financial
support was received from any organization for the submitted work. Financial relationships:
All authors have declared that they have no financial relationships at present or within the
previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or
activities that could appear to have influenced the submitted work.

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2020 Shahab et al. Cureus 12(9): e10358. DOI 10.7759/cureus.10358 19 of 19