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Indian Pediatr 2017;54:831-834 |
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Levamisole in
Frequently-relapsing and Steroid-dependent Nephrotic Syndrome
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Evangeline Mary Kiruba Samuel, Sriram Krishnamurthy,
Singanamalla Bhanudeep and Sravani Muske
From the Department of Pediatrics, Jawaharlal
Institute of Postgraduate Medical Education and Research (JIPMER),
Pondicherry, India.
Correspondence to: Dr Sriram Krishnamurthy,
Additional Professor, Department of Pediatrics, JIPMER,
Pondicherry 605 006, India.
Email: [email protected]
Received: August 23, 2016;
Initial Review: February 22, 2017;
Accepted: June 14, 2017.
Published online: July 11, 2017.
PII:S097475591600077
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Objectives: To evaluate
the efficacy of levamisole in children with frequently relapsing
nephrotic syndrome (FRNS) and steroid dependent nephrotic syndrome
(SDNS) when administered on an alternate day (‘initial therapy’ in all
cases) or daily basis (‘rescue therapy’ in whom alternate day therapy
failed). Methods: The records of 95 children (age 1-18y)
with FRNS (62) and SDNS (33), who were treated at the Pediatric
nephrology clinic, and received levamisole therapy (maximum 2 y
duration, between 2010-2013) with a follow-up period of minimum 1 y,
were included. Results: Alternate day levamisole therapy
was efficacious in 73.7% (n=70). The overall
efficacy of levamisole therapy was 88.4% (n=84). Levamisole
therapy decreased the mean (SD) number of relapses from 4.22 (0.46)/y to
1.35 (0.36)/y (P<0.01); and cumulative median (IQR) prednisolone
dosage from 4200 (3200–4300) mg/m2 to 1100 (IQR 500–2900) mg/m2 (P<0.001).
On a one-year follow up of the cases in whom levamisole therapy was
efficacious during therapy (median 24 mo) (n=84), a frequently
relapsing or steroid dependent course continued to persist in 48.8%
(41), necessitating oral cyclophosphamide (n= 22) or
mycophenolate mofetil (n=19). Conclusions: Daily
levamisole therapy was useful in 56% of children who demonstrated
failure while on alternate day levamisole therapy, and could be a useful
therapeutic option in FRNS and SDNS.
Keywords: Corticosteroids, Immunomodulators,
Proteinuria, Outcome, Treatment.
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Of all the children with nephrotic syndrome who experience relapses,
approximately 50% will develop frequently-relapsing nephrotic syndrome
(FRNS) or steroid-dependent nephrotic syndrome (SDNS), placing them at
risk for steroid toxicity [1]. Levamisole is a common immunosuppressive
drug used as a first line steroid sparing agent in the management of
FRNS and SDNS [2-5]. There are only few published studies regarding
usage of levamisole in FRNS and SDNS from India [2,5]. Most studies and
guidelines refer to alternate day levamisole therapy [1,3,5,6]. There is
limited information regarding the usage of daily levamisole [2,7]. We
conducted this study with the primary objective of evaluating the
efficacy of levamisole in SDNS and FRNS children. The secondary
objectives were to compare the efficacy of levamisole between SDNS and
FRNS children and evaluate its efficacy when
administered on daily or alternate day schedules .
Methods
This retrospective record-based study was conducted
in May and June 2016 after obtaining approval from the Institute Ethics
Committee. We retrieved data from the case records of patients who were
initiated on levamisole therapy between 2010-2013, with the last
follow-up being completed in March 2016. The records of children aged
1-18 years with FRNS and SDNS who attended the Pediatric nephrology
clinic and received levamisole therapy with a follow-up period of 1 year
were included. Infantile nephrotic syndrome, congenital nephrotic
syndrome and secondary nephrotic syndrome (such as lupus nephritis and
IgA nephropathy) were excluded. Waiver of consent was obtained as
anonymity of subjects was maintained.
Definitions for FRNS, SDNS, remission and relapse
were as per the Indian Pediatric Nephrology Group guidelines [1]. Other
definitions used in the study were adapted from the same reference [1]:
success of levamisole therapy: less than 2 relapses over a 6-month
period while on alternate or daily levamisole; and failure of levamisole
therapy: two or more relapses over a 6-month period while on alternate
or daily levamisole.
In children with FRNS and SDNS, following treatment
of a relapse, prednisolone was gradually tapered to maintain the patient
in remission on alternate day doses of 0.5-0.7 mg/kg, which was
administered for 9-18 months. If the steroid threshold to maintain
remission was more than 0.5-0.7 mg/kg prednisolone on alternate days,
after induction of remission with prednisolone (2 mg/kg/day), levamisole
was administered at a dose of 2-2.5 mg/kg on alternate days for 24
months [1,8]. Co-treatment with prednisolone at a dose of 1.5 mg/kg on
alternate days was given for 4 weeks; its dose was gradually tapered at
the rate of 0.25 mg/kg every 4 weeks. If there was failure of alternate
day levamisole therapy, daily doses of levamisole 2-2.5 mg/kg were
administered along with alternate day prednisolone [6]. Total leukocyte
count was performed 6-monthly while on levamisole therapy. If there was
failure of daily levamisole therapy, oral cyclophos-phamide or
mycophenolate mofetil were used.
The cumulative doses of prednisolone and the number
of relapses during therapy (and the year preceding the commencement of
levamisole therapy) were recorded in a structured proforma. In children
in whom levamisole therapy (alternate or daily) was a success, after
completion of the 2-year course, the drug was discontinued. The number
of relapses over the succeeding year was documented.
Statistical analysis: Data were compared using
student t or Mann Whitney U test. Proportions were compared using
Chi-square test or Fisher exact test. Data were analyzed using SPSS
version 20.
Results
A total of 95 children were included (Table
I). In both SDNS and FRNS children taken together, levamisole
(alternate day or daily therapy) was effective in 84 (88.4%) children.
Children with FRNS showed a better response to levamisole as compared to
SDNS (82% vs 58%, P=0.01). Daily levamisole therapy was
successful in 14/25 (56%) children who failed on alternate day
levamisole. No adverse effects such as leukopenia, hepatotoxicity, rash
or flu-like illnesses were recorded. The mean (SD) threshold of
prednisolone for starting levamisole in FRNS was 0.92 (0.14) mg/kg while
the corresponding threshold for SDNS was 0.88 (0.17) mg/kg (P=0.22).
TABLE I Clinical Characteristics of Children with Nephrotic Syndrome Treated with Levamisole (N=95)
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FRNS, n=62 |
SDNS, n=33 |
P value |
Age at enrolment |
8 (61,2.5) |
9.5 (5.5,14) |
0.30 |
Age at onset |
2.5 (1.9,4) |
2 (1.8,4) |
0.39 |
Age at initiation of levamisole |
5 (3,8) |
6 (3,8) |
0.65 |
Males [n (%)] |
37 (59.7) |
18 (54.6) |
<0.001 |
Duration of Levamisole therapy (mo) |
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In children in whom it was efficacious (mo) |
24 (12.5,24) |
24 (7.8,24) |
0.16 |
In children in whom it was not efficacious (mo) |
7 (5.25,8) |
6 (6,9) |
0.01 |
Efficacy of alternate day levamisole therapy (%) |
82 |
58 |
0.01 |
Overall efficacy of levamisole (daily and alternate therapy) (%) |
93.5 |
79 |
0.03 |
Value in median (IQR) unless specified otherwise; FRNS:
Frequently relapsing nephtotic syndrome; SDNS: Steroid dependent
nephrotic syndrome. |
The relapse rates as well as the cumulative dose of
steroids decreased significantly during levamisole therapy (P<0.01)
(Table II). Overall, there was an increase in relapse rate
to a mean of 2.57relapses/year after completion of therapy. In 41/84
(48.8%) of children in whom levamisole therapy was efficacious, the
effect of levamisole was not sustained after stopping the drug, and a
frequently-relapsing or steroid-dependent course continued to persist
necessitating alternative immunosuppressants viz. oral
cyclophosphamide (n= 22), and mycophenolate mofetil (n=19).
TABLE II Relapse Rates and Cumulative Dosage of Prednisolone Before, During and After Levamisole Therapy
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1 year before therapy |
During therapy |
1 year after discontinuation |
FRNS (n=62) |
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No. of relapses per year, mean (SD) |
4.21 (0.45) |
1.11 (1.18) |
2.55 (1.1)* |
Cumulative dose of prednisolone, median (IQR) (mg/m2) |
4200 (3125, 5200) |
1000 (400, 1400) |
2500 (1250, 3900)* |
SDNS (n=33) |
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No. of relapses per year, mean (SD) |
4.24 (0.56) |
1.79 (1.58) |
4.22 (0.46)# |
Cumulative dose of prednisolone, median (IQR) (mg/m2) |
4200 (3500, 5600) |
1300 (600, 4250) |
3200 (2350, 4500)# |
Overall (n=95) |
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No. of relapses per year, mean (SD) |
4.22 (0.46) |
1.35 (0.36) |
2.57 (1.06)$ |
Cumulative dose of prednisolone, median (IQR) (mg/m2) |
4200 (3200, 4300) |
1100 (500, 2900) |
2800 (1375, 4200)$ |
P value <0.01 between the groups (within FRNS, SDNS and the
overall subjects); FRNS- Frequently relapsing Nephrotic
Syndrome; SDNS-Steroid Dependent Nephrotic Syndrome; *n=51
children (in whom the drug was efficacious); #n=19
children (in whom the drug was efficacious); $n=70
children (in whom the drug was efficacious). |
Discussion
Beneficial effects of levamisole in terms of
reduction in relapse rates and significantly reduced cumulative dosage
of steroids have been documented in published literature [6-14]. A
meta-analysis has also documented the efficacy of levamisole [4]. We too
found that alternate day levamisole along with initial low dose steroid
therapy can be effective in children with FRNS/SDNS (with a better
efficacy in FRNS). However, the observation that almost half of the
children continue to have a frequently relapsing or steroid dependent
course after discontinuation of the drug, implies lack of a remnant
effect of the drug. Our study also demonstrated that daily levamisole is
a feasible and efficacious option in 56% of children who failed
alternate day therapy. This is an important observation because current
guidelines [1] recommend only alternate day levamisole and advise usage
of other alternate immunosuppressants such as oral cyclophosphamide or
mycophenolate mofetil in case of alternate-day levamisole failure.
The rationale for usage of daily levamisole is based
on the fact that the half-life of levamisole is 5.2 hours [7,11].
Ekambaram, et al. [2] reported that daily levamisole was
effective in 77.3% of 95 children. Fu, et al. [7] in a
comparative study between daily and alternate day levamisole usage in
children with FRNS and SDNS, reported that daily levamisole usage can be
considered when response to alternate day usage is unsatisfactory. La
Manna, et al. [11] studied the effect of levamisole on 13 FRNS
and/or SDNS children. These children were treated with 2.5 mg/kg
levamisole twice a week (Cycle A) for 2-16 months (mean 5.8 months).
Following failure of the regime, 8 children were given the same dose of
levamisole on a daily basis. A clinical improvement was observed in 6
children; 4 with cycle A and 2 with cycle B. The authors noted minimal
side effects (e.g., transient neutropenia) in both drug regimes.
We did not observe any side-effects attributable to levamisole, similar
to the observations of Ekambaram, et al. [2]
The study adds valuable information regarding the
efficacy of alternate day or daily levamisole therapy. The retrospective
nature of the study, however, makes it more susceptible to ‘selection
bias’. Randomized controlled trials evaluating daily levamisole in
comparison to other therapeutic options in children who fail alternate
day therapy with levamisole are needed to further validate these
results. Nevertheless, based on the observations of our study, it may be
prudent to recommend a trial of daily levamisole in children who
demonstrate alternate day levamisole therapy failure before switching
over to more potentially toxic therapeutic options.
Contributors: EMKS collected the
data, was involved in protocol preparations and drafted the manuscript.
SK managed the patients, conceptualized the study, reviewed the
literature and critically reviewed the manuscript. SB and SM were
involved in the management of the patients, performed the statistical
analysis, and assisted in drafting the manuscript. All authors
contributed to writing the paper and approved the final version of the
manuscript.
Funding: None; Competing interest:
None stated.
What This Study Adds?
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Daily levamisole therapy is a
useful therapeutic option in nephrotic syndrome with failure of
alternate day levamisole therapy.
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About half of children who complete levamisole therapy
continue to have a frequently-relapsing or steroid-dependent
course after discontinuation of the drug.
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