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Original Article

Use of Levamisole in Children with Nephrotic Syndrome:

A Retrospective Study to Examine its Adverse Effects in
Children with Nephrotic Syndrome
Lt Col Suprita Kalra1,2, Maj Gen Madhuri Kanitkar VSM2, Kara Tiewsoh3
1
Department of Pediatrics, Command Hospital, 2Dean and Deputy Commandant, AFMC, Pune, Maharashtra, 3Department of Pediatrics, PGIMER, Chandigarh, India

Abstract
Introduction: Levamisole, a synthetic imidazothiazole derivative has been used as a steroid sparing agent in children with Frequently Relapsing
Nephrotic Syndrome (FRNS) and Steroid Dependent Idiopathic Nephrotic Syndrome (SDNS). Levamisole has been essentially considered
a safe drug with minimal toxicity. We conducted this study to re-examine the safety of Levamisole in children with nephrotic syndrome and
to describe the clinical profile of these children. Materials and Methods: Records of children with idiopathic nephrotic syndrome between
June 2014 and December 2016 were reviewed. We identified frequently relapsing or steroid dependent children between 1-18 years of age
who had received Levamisole for at least six months or in whom Levamisole was started but had to be withdrawn due to some adverse events
in the first 6 months. Results: 21 children were started on Levamisole in the study period. 13 (61.90%) were FRNS and remaining had a
steroid dependent course. Levamisole had to be withdrawn in one child at 1 month 13 days after initiation when the child developed severe
headache. Levamisole also had to be discontinued in a 9 years old girl at 13 months after initiation of therapy due to polyarticular arthralgia
involving both the small and large joints. Conclusions: The use of Levamisole warrants caution in children with Nephrotic Syndrome and its
efficacy needs to be balanced against its potential side effects.

Keywords: Levamisole, Nephrotic Syndrome, Steroid dependence

Introduction of Levamisole and to describe the clinical profile of these

Levamisole, a synthetic imidazothiazole derivative, has been
used as a steroid‑sparing agent in children with Frequently
Relapsing Nephrotic Syndrome (FRNS) and Steroid Dependent
Idiopathic Nephrotic Syndrome (SDNS). Studies have shown
that it reduces the frequency of relapses and cumulative
corticosteroid dose in children with FRNS and SDNS, thereby
minimizing steroid toxicity in such children.[1‑3]
Levamisole has been essentially considered a safe drug
with minimal toxicity as compared to other steroid‑sparing
agents including alkylating agents and calcineurin inhibitors.
The adverse effects of Levamisole are reported rarely and
have been found to be completely reversible after stopping
levamisole.[4]
We conducted this study to re‑examine the safety of
levamisole in children with Nephrotic Syndrome in the light
of some of our patients facing adverse effects with the use
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children.
Materials and Methods
We conducted a retrospective study on all children with
nephrotic syndrome attending the Pediatric Nephrology Out
Patient Department (OPD) who had received Levamisole as
a steroid‑sparing agent for at least 6 months. The study was
approved by the institutional ethics committee.
We reviewed the records of children with Idiopathic Nephrotic
Syndrome on follow‑up at Pediatric Nephrology OPD at our
Address for correspondence: Lt Col Suprita Kalra,
Department of Pediatrics, Command Hospital, AFMC, Pune,
Maharashtra, India.
E‑mail: kalrasuprita@gmail.com
This is an open access article distributed under the terms of the Creative Commons
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How to cite this article: Kalra S, Kanitkar M, Tiewsoh K. Use of levamisole

DOI: in children with nephrotic syndrome: A retrospective study to examine
10.4103/jmms.jmms_41_17 its adverse effects in children with nephrotic syndrome. J Mar Med Soc
2017;19:87-90.

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Kalra, et al.: Adverse effects of Levamisole in children with nephrotic syndrome
center between June 2014 and December 2016. We included
all children with FRNS or SDNS between 1 and 18 years of
age who had received Levamisole for at least 6 months or in
whom Levamisole was started but had to be withdrawn due
to some adverse events in the first 6  months. The children
who were noncompliant were excluded. The records of these
children were then analyzed retrospectively to determine the
adverse effects associated with the use of Levamisole. SDNS
was defined as two consecutive relapses while on alternate‑day
steroids or within 14 days of their discontinuation. FRNS was
defined as two or more relapses in 6 months or more than three
relapses in any 12  months. Levamisole had been started in
children with FRNS or SDNS with features of steroid toxicity
as evidenced by short stature (defined by height <3  SD for age),
cushingoid habitus, presence of cataract or raised intraocular
pressure, or impaired glucose tolerance or if they had one or
more relapses at a steroid dose of >0.5 mg/kg/day. All children
received Levamisole at a dose of 2 mg/kg every alternate day.
All children were monitored every month for response to
therapy and examined for side effects. The number of relapses
in the previous 6 months before initiation of Levamisole was
recorded and compared to the number of relapses in the first
6 months on Levamisole as all children were followed up for
a minimum of 6 months after starting levamisole. Complete
blood counts including total and differential blood cell counts,
liver function tests, serum urea, and creatinine were done every
3 months. Steroids were tapered by 0.5 mg/kg every 2 weeks
if the child continued to be in remission. Two or more relapses
or when the dose of alternate‑day steroid was >0.5 mg/kg/day
in 6 months after starting levamisole was taken as failure of
Levamisole. The results were analyzed using Microsoft Excel.
Results
Twenty‑one children were started on Levamisole in the study
period. Thirteen (61.90%) were FRNS and remaining had a
SDNS. The baseline characteristics at the start of levamisole
therapy are shown in Table  1. The duration of levamisole
therapy ranged from 1  month, 13  days to 26  months with
a   median duration 18 months. Two children were excluded
due to noncompliance, i.e., they stopped therapy after being
on Levamisole for <6 months. These children had 37 relapses
in the 6  months prior to initiation of Levamisole therapy
(mean number of relapses: 1.76/child). Six children had one
relapse in the 6  months prior to initiation of Levamisole
therapy but were given Levamisole due to steroid threshold
being of  >0.5  mg/kg/day. Fourteen relapses  (mean number
of relapses: 0.67/child) were seen in the same children in the
first 6 months of Levamisole therapy (P < 0.05). Three of the
21 children had two relapses in the 6  months’ period after
they were started on Levamisole and were still on alternate
day steroids  >0.5  mg/kg/day and were placed on alternate
steroid‑sparing agents.
Levamisole had to be withdrawn in one child at 1 month, 13 days
after initiation when the child developed severe headache
which was bifrontal, throbbing in nature, and lasted >4 h on 2
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Table 1: Baseline characteristics of the children on
levamisole therapy
Baseline characteristics n
Age in months* 42 months
Males, n (%) 11 (52.38)
FRNS, n (%) 10 (47.61)
Age at onset of nephrotic syndrome in months* 23 (34-19)
Number of relapses in 6 months prior to levamisole 1.76 (0.55)
therapy**
Duration of levamisole therapy in months* 18 (24-12.75)
Age at initiation of levamisole therapy in months 42 (48-34)
Number of relapses in 6 months after starting 0.67 (0.73)
levamisole therapy**
Children on previous therapy with 3
cyclophosphamide (n)
Children on previous therapy with mycophenolate 2
mofetil
*Values in median (IQR), **Values in mean (SD). SD: Standard
deviation, IQR: Interquartile range, FRNS: Frequently relapsing nephrotic
syndrome
consecutive days with only partial relief with oral paracetamol.
The patient, a 5‑year‑old male, was in relapse at that time with
urine protein of 4 + on dipstick examination. His blood pressure
was 90/66 mmHg (<90th centile for age and gender), there was
no papilledema or other signs of raised intracranial pressure on
fundus examination. There was no focal neurological deficit
on examination. Magnetic resonance (MR) imaging brain and
MR venogram were done which were normal. The child had no
history of migraine and no history of similar headache in any
relapse prior to starting Levamisole. The child was managed
as per standard guidelines for relapse and later continued on
long‑term alternate‑day steroids. He had no recurrence of
headache on follow‑up in the subsequent 12 months.
Levamisole also had to be discontinued in a 9‑year‑old girl at
13 months after initiation therapy due to polyarticular arthralgia
involving both the small and large joints. She had significant
pain in both the ankle joints, right knee joint, and small joints
of both the hands, interfering with her activities of daily living.
A  history of morning stiffness was also present. There was
no history of fever or symptoms of upper respiratory tract
infection preceding the onset of joint pain. On examination,
the child had no effusion or restriction of movement in any
joint. Investigations showed raised C‑reactive protein and
erythrocyte sedimentation rate. She was started on naproxen
for the joint pains, but reported only minor relief. The arthralgia
resolved 14  days after cessation of levamisole therapy and
she had no recurrence in subsequent 12 months of follow‑up.
The details of clinical features and investigations of the
children who faced adverse effects after starting levamisole
are mentioned in Table 2.
Discussion
Various immunosuppressive agents have been used in
the management of children with FRNS and SDNS to
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Kalra, et al.: Adverse effects of Levamisole in children with nephrotic syndrome

manifestation in the form of headache relatively early after

Table 2: Profile of children who faced adverse effects
the initiation of therapy (at 1 month, 13 days) while the
after starting levamisole
other child developed arthralgia at 13 months after she was
Patient 1 Patient 2 put on Levamisole therapy. The duration of therapy to onset
Age in completed years 5 9 of adverse effects has not been shown to be consistent and
Gender Male Female children may have the same any time during treatment with
Predominant symptom Headache Arthralgia Levamisole. Several cases of severe agranulocytosis have
necessitating withdrawal
been described in cocaine users inadvertently using cocaine
of levamisole
Investigations
contaminated with Levamisole. Cutaneous manifestations
Total leukocyte count in 11,600/cumm 12,000/cumm
consisting of large, painful hemorrhagic bullae and/or
cumm with neutrophils neutrophils 65% neutrophils 67% necrosis, most commonly involving the face, hyponatremia,
CRP Negative Positive seizures, and various other serious side effects, have been
(>6 mg/dL) described in this subset of patients. Gas chromatography
ESR 5 mm fall in 1st h 20 mm fall in 1st h or mass spectrometry has been used to test patients’ urine
Total bilirubin (mg/dL)/ 0.6/26/16 0.5/24/20 for the presence of Levamisole to confirm levamisole as the
AST/ALT (IU/mL)
causative agent.[6,11] This was, however, not required in our
Urea/creatinine (mg/dL) 24/0.4 17/0.3
children as exposure was definite, but to pinpoint Levamisole
Investigations specific to MRI brain and C3: Normal
presenting symptoms MR venography:
as the cause of adverse effect required exclusion of other
ANA by
Normal IF: Negative possible etiologies.
RA factor: The incidence of adverse events was not reported to be higher
Negative
with daily dosing of Levamisole as compared to the standard
CRP: C‑reactive protein, ESR: Erythrocyte sedimentation rate, AST:
Aspartate aminotransferase, ALT: Alanine aminotransferase, MRI: practice of giving it on alternate days.[3]
Magnetic resonance imaging, ANA: Antinuclear antibody, RF: Rheumatic
factor, IF: immuneflorescence
The strength of our study was that it focused on the adverse
events associated with Levamisole, The obvious limitation of
our study was that it was a retrospective analysis of data in a
minimize the toxicity of corticosteroids. Levamisole is a
single center.
well‑known anthelmintic agent with immunomodulatory
action. It also acts as an immune enhancer by increasing The adverse effects of Levamisole brought out in children with
macrophage chemotaxis and T‑cell function. It has been nephrotic syndrome in our study were found to be reversible
used in childhood idiopathic nephrotic syndrome since with drug withdrawal. However, their relatively high incidence
1980.[1] The effectiveness of levamisole in reducing the and the potential risk of serious side effects should be kept in
frequency of relapses in children with FRNS and SDNS mind while prescribing Levamisole which was traditionally
is well documented,[2,3] and it was seen in our study also. considered safe as compared to other immunosuppressive
It was withdrawn from use as an anthelmintic agent due agents in children with nephrotic syndrome.
to the risk of agranulocytosis and is not available in the This study also emphasizes the need for a large multicentric
US and Canada.[4,5] Apart from agranulocytosis, the other analysis of data related to the adverse events of all drugs used
prominent side effects include retiform purpura and seizures. as steroid‑sparing agents in children with nephrotic syndrome
The cutaneous lesions may represent a true vasculitis with to help weigh the benefits against the possible side effects.
positive staining for IgM, IgA, IgG, and C3, and vascular
staining for fibrin or a pseudovasculitis with negative
staining on immunofluorescence. The nervous system
Conclusions
manifestations have been attributed to accentuated nicotinic Although the number of relapses in children with FRNS and
acetylcholinergic release. Arthralgias and arthritis, especially SDNS is significantly reduced with the use of Levamisole, we
of the large joints, have also been commonly described.[6] In need to be cautious against its potential side effects.
children with nephrotic syndrome, studies have described Financial support and sponsorship
the incidence of side effects to vary from almost none[7,8] to Nil.
nearly 15%, but the adverse effects have been reported to
resolve completely after stopping therapy.[9] Rarely, serious Conflicts of interest
side effects such as disseminated autoimmune disease with There are no conflicts of interest.
high titers of IgM anticardiolipin and p‑Antineutrophil
cytoplasmic antibody   antibodies have been described.[10] References
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