Open Journal of Nephrology, 2013, 3, 189-193
Published Online December 2013 (http://www.scirp.org/journal/ojneph)
http://dx.doi.org/10.4236/ojneph.2013.34033
Open Access OJNeph
Does Low-Dose Intravenous Methylprednisolone
Pulse Therapy Pr oduce Unacceptable Adverse
Effects in Children?*
Daishi Hirano1,2, Shuichiro Fujinaga1, Amane Endo1, Tsuneki Watanabe1, Hi ro y u ki Ida2
1Division of Nephrology, Saitama Children’s Medical Center, Saitama, Japan
2Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan
Received September 22, 2013; revised October 20, 2013; accepted November 15, 2013
Copyright © 2013 Daishi Hirano et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Background: Intravenous methylprednisolone pulse therapy has been used since the late 1960s for acute transplant
rejection or severe renal involvement in systemic lupus erythematosus and primary glomerulonephritis. However, re-
ports of serious adverse effects such as life-threatening cardiac arrhythmias and sudden death raise questions about its
safety. Objective: To investigate the incidence of significant adverse effects associated with low-dose methylpredniso-
lone pulse therapy (LDMPT) in pediatric patients. Methods: We retrospectively analyzed adverse effects during and
after LDMPT in 68 patients (median age: 11.4 years; 43% male) with various glomerular diseases who were admitted to
Saitama Children’s Medical Center between April 2007 and December 2010. LDMPT consisted of pulse methylpred-
nisolone (15 - 20 mg/kg; maximum 600 mg/d) for 3 consecutive days weekly for 2 - 3 weeks. Results: Although ad-
verse effects occurred in 54 of 68 patients (79%), most were mild and transient. Transient glycosuria was noted in 46
patients (68%), hypertension in 6 (9%), elevated intraocular pressure in 6 (9%), hypokalemia in 5 (7%), and liver dam-
age in 2 (3%). No late-onset adverse effects such as osteoporotic fractures, steroid diabetes mellitus, or short stature
were observed. Conclusion: LDMPT appears to be relatively safe and well tolerated in children with various glomeru-
lar diseases.
Keywords: Methylprednisolone Pulse Therapy; Adverse Effects; Side Effects; Steroid; Children
1. Introduction
Conventional high-dose intravenous methylprednisolone
pulse therapy (HDMPT) first came into clinical use over
40 years ago to treat acute renal graft rejection. Although
MPT has since become an essential tool for clinicians
treating various kidney diseases, little is known about its
mechanism of effect and magnitude of associated adverse
effects [1-5]. The most serious problems associated with
HDMPT in adults are cardiovascular reactions, including
death [6,7], but in children, the adverse effects are re-
ported by some researchers to be quite different [8]. The
most common adverse effects in children are psychiatric
reactions (e.g., mood alteration, hyperactivity, psychosis,
disorientation, and sleep disturbances), which are seen in
about 10% of children receiving HDMPT [8]. According
to recent reports, these adverse effects are associated
with higher doses of methylprednisolone (mPSL) and
higher rates of intravenous administration [5,9]. In fact,
Klein-Gitelman et al. reported that remarkable improve-
ment was observed in some children with a decreased
dose or an increased time interval between administra-
tions [8]. However, adverse effects of decreased doses of
mPSL have not been clearly delineated. Based on these
reports, we now treat a variety of kidney diseases using
“low-dose” MPT (LDMPT), which extends the infusion
time (>2 h) and reduces the dosage, in order to reduce
adverse effects. The objective of this study was to deter-
mine the frequency and severity of adverse effects asso-
ciated with LDMPT in pediatric patients.
2. Patients and Materials
2.1. Patients
In this retrospective case series study, we collected and
*The authors have no conflicts of interest to declare.

D. HIRANO ET AL.
190
analyzed data on 196 courses of LDMPT given to 68
children (29 boys, 39 girls) at the Saitama Children’s
Medical Center in Saitama, Japan from April 2007
through December 2010. Informed consent was obtained
from the patients’ parents. Prior to LDMPT, all patients
were given a complete physical examination in order to
screen and exclude those with known infections, uncon-
trolled hypertension, congestive heart failure, or uncon-
trolled diabetes mellitus. The physical examination in-
cluded measurement and evaluation of systolic blood
pressure, diastolic blood pressure, and baseline chemistry
parameters. Only data from patients with normal values
for these parameters were included in the analysis.
2.2. Low-Dose Methylprednisolone Pulse
Therapy
LDMPT was defined as mPSL administered at a dose of
15 - 20 mg/kg/d (maximum: 600 mg/d) in 50 - 100 ml of
5% dextrose solution given intravenously over 2 h for 3
consecutive days weekly for 2 - 3 weeks. In comparison,
the “high dose” for HDMPT is 30 mg/kg/d (maximum 1
g/d). All LDMPT administrations took place in a hospital
setting under physician supervision, with monitoring of
vital signs every 30 min or more frequently if an abnor-
mality was found or the patient experienced any symp-
toms.
2.3. Adverse Effects
Adverse effects were defined as any new symptom or
sign (e.g., skin rash, headache, dizziness, dysgeusia,
chest pain, palpitations, dyspnea, nausea, osteonecrosis
of the femoral head, psychiatric reaction, steroid diabetes
mellitus, and short stature) that appeared during or after
each LDMPT course Adverse effects were categorized as
either early or late onset. Early-onset adverse effects
were defined as those appearing during LDMPT or with-
in 4 weeks after initiation of LDMPT, and late-onset ad-
verse effects were defined as those appearing ≥4 weeks
after initiation of LDMPT. For late-onset adverse effects
such as osteonecrosis of the femoral head or short stature,
we analyzed data from 34 children with IgA nephropathy
(IgAN) who had been followed for ≥1 year. We identi-
fied other adverse sequelae from diagnostic procedures
such as laboratory tests or from records of vital signs
(blood pressure and heart rate changes) outside the nor-
mal range. We retrieved data from medical records rele-
vant to the number, frequency, and total dosage of
LDMPT administrations. We also collected information
pertaining to diagnosis, age, sex, laboratory data at the
time of reaction, other medications received, and history
of other adverse drug events.
2.4. Statistical Analysis
Continuous variables were expressed as median and
range; categorical variables were expressed as number
and percentage values. Statistical analysis was performed
using SAS software, version 9.3 (SAS Institute, Cary,
NC). Statistical significance was defined as p < 0.05.
3. Results
3.1. Patient Characteristics
Table 1 summarizes the characteristics of patients trea-
ted with LDMPT. The patients were 29 boys (43%) and
39 girls (57%), with a median age was 11.4 years (range:
1.4 - 18.1 years), who together had received 196 LDMPT
treatments. Underlying disease was IgAN in 35 patients
(51%), Henoch-Schönlein purpura nephritis in 20 (29%),
membranoproliferative glomerulonephritis in 6 (9%),
nephrotic syndrome in 5 (7%), and other in 2 (4%). Six-
ty-six children received <3 LDMPT treatments and 2
received ≥4 LDMPT treatments. Median mPSL dose was
15.0 mg/kg/d (range: 7.9 - 24.1 mg/kg/d); since the ma-
ximum mPSL dosage that could be given was 600 mg/d,
the dose could be <15 mg/kg, but could be slightly >20
mg/kg because standard size ampules (100 mg or 250 mg)
were used.
3.2. Early-Onset Adverse Effects
Early-onset adverse effects occurred in 54 of 68 children
(79%), but most were mild, transient, and required no
medical treatment (Table 2). Transient glycosuria, the
most common symptom, was seen in 46 children (68%).
It occurred within the first 3 doses of LDMPT, but usu-
ally disappeared soon after LDMPT course ended. Mild
hypertension was noted in 6 children (9%), but all re-
quired antihypertensive medication to control blood
pressure. These children continued LDMPT with the
antihypertensive agents without further significant ad-
Table 1. Baseline characteristics of patients receiving low-
dose methylprednisolone pulse ther apy (LDMP T).
Total number of patients 68
Sex (male/female) 29/39
Median age, years (range) 11.4 (1.4 - 18.1)
Number of LDMPT courses
Total number of LDMPT courses 196
1 - 3 times/patient 181/66
>3 times/patient 15/2
Disease, n (%)
IgA nephropathy 35 (51)
Henoch-Schönlein purpura nephritis 20 (29)
Membranoproliferative glomerulonephritis 6 (9)
Nephrotic syndrome 5 (7)
Other 2 (4)
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D. HIRANO ET AL. 191
Table 2. Adverse effects during and after low-dose methyl-
prednisolone pulse therapy.
Adverse effect n (%)
Transient glycosuria 46 (68)
Hypertension 6 (9)
Elevated intraocular pressure 6 (9)
Hypokalemia 5 (7)
Elevated liver transaminase levels 2 (3)
Severe adverse effect
Bacterial infection 0 (0)
Cardiac arrhythmia 0 (0)
Bradycardia 0 (0)
Thrombosis 0 (0)
Peptic ulcer 0 (0)
Acute pancreatitis 0 (0)
Neuropsychiatric disorder 0 (0)
verse effects. Other adverse effects associated with
LDMPT included elevated intraocular pressure, hypo-
kalemia, and liver damage, which were detected in 6
(9%), 5 (7%), and 2 (3%) patients, respectively. None of
the children needed treatment for severe adverse effects
such as cardiac arrhythmia, bradycardia, bacterial infec-
tion, thrombosis, peptic ulcer, acute pancreatitis, or neu-
ropsychiatric disorder.
3.3. Late-Onset Adverse Effects
To assess late-onset adverse effects, we analyzed data
from the 34 children with IgAN who had been given
bone density tests while being followed for ≥1 year. Me-
dian height of these patients at last observation was
−0.09 standard deviation score (SDS) for normal-for-age
height (range: −1.57 to +2.28 SDS), and none of these
patients had abnormally short stature (−2.0 SDS). There
were no statistical differences between the median SDS
before LDMPT and that for the last observation. We
found no documented case of osteonecrosis.
4. Discussion
This study investigated the frequency and severity of
adverse effects associated with LDMPT in pediatric pa-
tients. Although MPT has become an important thera-
peutic modality for clinicians treating autoimmune dis-
eases, there is as yet insufficient evidence for its mecha-
nism of action and magnitude of benefits and adverse ef-
fects [10]. Moreover, its adverse effects are reported to
differ between adults and children.
In a previous prospective study of the frequency and
severity of adverse reactions associated with HDMPT in
children with rheumatic disease, Klein-Gitelman et al.
found that 46% (22/213) had adverse reactions, although
none required hospitalization [8]. Baethge et al. also re-
ported that HDMPT had an acceptably low incidence of
significant adverse effects in adults [11]. In contrast,
Garrett et al. found adverse effects in 56% of a group of
adult patients with rheumatic disease who received
HDMPT, of whom 24% needed medical intervention
[12]. Undoubtedly MPT can lead to severe life-threat-
ening complications such as cardiac arrhythmias, sudden
death, circulatory collapse, and cardiac arrest [6,7]. How-
ever, most of the reported cases have involved adults
with underlying cardiac disease, usually following rapid
administration of large doses of mPSL (>500 mg admin-
istered over <10 min) [6]. In human studies, pulse dosing
of intravenous mPSL alters the stimulation threshold of
myocardial cells. It also alters serum potassium and uri-
nary excretion of both potassium and sodium. These
changes might conceivably alter electrolyte shifts across
the myocardial cell membrane [13,14]. In our study, pa-
tients were free of underlying cardiac disease prior to the
onset of renal disease or intractable hypertension. Also,
our patients were given mPSL over 2 h, with frequent
monitoring of vital signs, and no episodes of serious car-
diovascular adverse effects occurred. However, some did
experience hypertension that responded rapidly to appro-
priate intervention.
The most common adverse effect among our pediatric
patients was renal glycosuria. Glucocorticoids impair glu-
cose metabolism mainly by inducing insulin resistance
and increasing hepatic gluconeogenesis. Insulin resis-
tance appears to occur at both receptor and post-receptor
sites, and variations between glucocorticoids with regard
to insulin binding do exist. Glucocorticoids can also in-
duce hyperglycemia through the stimulation of α-cells,
leading to hyperglucagonemia and increased glycogenoly-
sis [15,16]. These hyperglycemic effects are responsible
for the so-called steroid diabetes observed in 25% (6) of
subjects treated with long-term oral corticosteroid thera-
py [17,18]. Unlike oral treatment, however, there is insuf-
ficient quantitative data on the hyperglycemic effects of
intravenous MPT. What we do know is that in a study by
Baethge et al. 19% (16/84) of adults with rheumatic dis-
ease had hyperglycemic effects associated with HDMPT,
with only 1 insulin-dependent patient requiring hypogly-
cemic therapeutic adjustment [11]. Feldman-Billard et
al.’s analysis of serial fasting blood glucose measure-
ments in 198 nondiabetic and 28 diabetic patients with
eye disease treated by MPT revealed that the diabetic
patients tended to show a cumulative hyperglycemic ef-
fect of iterative MPT, whereas nondiabetic patients were
able to spontaneously regulate MPT-induced hypergly-
cemia [19]. These findings indicate that close glycemic
monitoring is not needed during MPT with nondiabetic
patients.
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D. HIRANO ET AL.
192
In a cohort of 539 patients with systemic lupus ery-
thematosus, Zonana-Nacach et al. found no association
between intravenous steroid therapy and osteoporotic
fractures, but did find an association with high dose oral
steroids, reporting a strong association between cumula-
tive prednisolone dose and adverse effects [20]. In our
study, we fortunately did not experience late-onset ad-
verse effects such as osteoporotic fractures, steroid dia-
betes mellitus, and short stature. This might be because
we administered a lower dose of oral mPSL (1 mg/kg/d,
maximum 30 mg/d) on alternate days after LDMPT.
The minimum effective dose of mPSL is unclear.
While one study has suggested that doses as low as 320
mg administered intravenously or intramuscularly are as
effective as 1 g of intravenous mPSL [21], another study
has shown that reducing the intravenous mPSL dose
from 1 g to 500 mg results in a substantial loss of effi-
cacy [22]. Our findings suggest that LDMPT could be a
potentially effective and safe alternative for pediatric pa-
tients with various glomerular diseases. However, more
studies are needed to further characterize the optimal
dosages and mechanisms of action of MPT.
5. Limitations
The present study was a retrospective analysis of treat-
ment performed at a single center, so there may be some
selection bias in the cohort. The single center cohort de-
sign also limits the external validity of our findings. In
addition, we could not determine the true frequency of
minor adverse effects such as metallic taste and facial
flushing because of the manner in which this retrospec-
tive study was performed. However, we are confident
that we did not miss any serious treatment complications.
6. Conclusion
This case series indicated that LDMPT might have an
acceptably low risk of significant adverse effects and
therefore can be an effective treatment modality for pe-
diatric patients with various glomerular diseases.
7. Tables
Table 1 summarizes the characteristics of patients treated
with LDMPT.
Adverse effects were categorized as either early or late
onset. And Table 2 summarizes the adverse effects dur-
ing and after low-dose methylprednisolone pulse therapy.
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