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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 55
| Issue : 1 | Page : 43-52 |
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Efficacy and safety of levamisole in childhood nephrotic syndrome: A meta-analysis
Girish Chandra Bhatt1, Bhupeshwari Patel1, Rashmi Ranjan Das2, Shikha Malik1, Martin Bitzan3, Nihar Ranjan Mishra4
1 Department of Pediatrics, Division of Pediatric Nephrology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
2 Department of Pediatrics, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
3 McGill University Health Centre, Montreal, Canada; Department of Pediatrics, Kidney Centre of Excellence, Al Jalila Children's Hospital, Dubai, United Arab Emirates
4 Department of Pediatrics, All India Institute of Medical Sciences, Kalyani, West Bengal, India
| Date of Submission | 23-Aug-2021 |
| Date of Decision | 07-Feb-2023 |
| Date of Acceptance | 08-Feb-2023 |
| Date of Web Publication | 20-Mar-2023 |
Correspondence Address:
Girish Chandra Bhatt
Department of Pediatrics, Room No. 1023, Academic Block, Hospital Complex, Saket Nagar, All India Institute of Medical Sciences, Bhopal - 462 020, Madhya Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijp.ijp_673_21
Present evidence regarding the efficacy and safety of levamisole in childhood nephrotic syndrome (NS), particularly the steroid-sensitive NS (SSNS), is limited. We searched relevant databases such as PubMed/MEDLINE, Embase, Google Scholar, and Cochrane CENTRAL till June 30, 2020. We included 12 studies for evidence synthesis (5 were clinical trials that included 326 children). The proportion of children without relapses at 6–12 months was higher in the levamisole group as compared to steroids (relative risk [RR]: 5.9 [95% Confidence interval (CI): 0.13–264.8], I2 = 85%). Levamisole as compared to the control increased the proportion of children without relapses at 6–12 months (RR: 3.55 [95% CI: 2.19–5.75], I2 = 0%). The GRADE evidence was of “very-low certainty” except for the comparison of levamisole with control, the latter being of “moderate certainty.” To conclude, levamisole given to children with SSNS is beneficial in preventing relapses and achieving remission as compared to placebo or low-dose steroids. Good-quality trials are needed to provide a robust evidence in this regard. PROSPERO Registration number: CRD42018086247.
Keywords: Evidence-based medicine, levamisole, nephrotic syndrome, systematic review
How to cite this article:
Bhatt GC, Patel B, Das RR, Malik S, Bitzan M, Mishra NR. Efficacy and safety of levamisole in childhood nephrotic syndrome: A meta-analysis. Indian J Pharmacol 2023;55:43-52 |
How to cite this URL:
Bhatt GC, Patel B, Das RR, Malik S, Bitzan M, Mishra NR. Efficacy and safety of levamisole in childhood nephrotic syndrome: A meta-analysis. Indian J Pharmacol [serial online] 2023 [cited 2023 May 31];55:43-52. Available from: https://www.ijp-online.com/text.asp?2023/55/1/43/372166 |
| » Introduction | |  |
Childhood nephrotic syndrome (NS) is a common disease, usually treated with oral steroids.[1],[2] Complete remission of proteinuria is observed in approximately 80% of children, and this type is also known as steroid-sensitive NS (SSNS). The remaining 20% fail to respond to initial steroid therapy. In the SSNS group, approximately 40%–50% of patients either develop frequent relapse NS (FRNS) or become steroid-dependent NS (SDNS).[1],[3] These children may need repeat (or continuous) treatment with corticosteroids, making them vulnerable to glucocorticoid-associated adverse events. Several steroid-sparing agents such as cyclophosphamide, mycophenolate mofetil (MMF), levamisole, calcineurin inhibitors, or rituximab have been tried to prevent relapses and decrease steroid toxicity in these groups of children.[1],[4],[5],[6] Among these drugs, levamisole is considered to be cost-effective and relatively safe, compared with other glucocorticoid-sparing agents. Previous randomized controlled trials (RCTs),[7],[8],[9] and retrospective studies,[10],[11],[12] have shown that levamisole may be beneficial in children having FRNS or SDNS. However, the present evidence for the use of levamisole in childhood NS is limited. Moreover, a recent multicentric RCT has shown that long-term use of levamisole in FRNS or SDNS prolongs the time to first relapse and prevents relapses of proteinuria during 1-year period.[13] We tried to synthesize the current evidence for the use of levamisole in childhood SSNS.
| » Objectives | | |
The objectives of this study were to compare the efficacy and safety of levamisole versus other drugs/immunomodulators used in the treatment of children with SSNS.
| » Methods | | |
Types of studies
We included controlled clinical trials (randomized and quasi-randomized) for evidence synthesis.
Study populations
Children from 1 to 18 years of age and having SSNS were included. Those with steroid-resistant NS, impaired renal function, steroid toxicity, intake of immunosuppressive agents other than levamisole, and serious infections (peritonitis, pneumonia, and cellulitis) were excluded.
Types of intervention
The intervention consisted of giving levamisole after achieving remission through daily steroid (prednisolone) therapy.
Types of comparison/control
The studies comparing levamisole with placebo or standard alternate-day prednisolone therapy or another immunosuppressive therapy were considered.
Outcomes
Primary
- Proportions of children being relapse free at 6, 12, and 24 months
- Time (months) taken to first relapse.
Secondary
- Mean number of relapses per year
- Side effects
- Difference in the cumulative steroid dose between the two groups.
Outcome definitions
- Remission: Absence or trace proteinuria daily for 3 consecutive days.
- Relapse: Proteinuria ≥3+ daily for 3 consecutive days.
Database search
We searched relevant databases such as PubMed/MEDLINE, Embase, Google Scholar, Cochrane CENTRAL, and Clinical Trials Registry (Clinicaltrials.gov, and CTRI) till June 30, 2020. We used the following keywords: ((((((levamisole) OR non-corticosteroid immunosuppressive agents) OR steroid sparing agents)) AND ((((nephrotic syndrome) OR (steroid sensitive nephrotic syndrome) OR (frequently relapsing nephrotic syndrome) OR (steroid dependent nephrotic syndrome)) AND ((((children) OR infants) OR childhood) OR Pediatrics)). No language restrictions were applied. Two authors (GCB and NRM) evaluated the search strategy for identification of relevant studies.
Extraction of data
Two review authors (GC and BP) extracted the data with the help of a predesigned pro forma. Data extraction was done by two authors. The data which were extracted included name of the authors, year of publication, study setting, population type, dose of levamisole, and its duration. We also looked for the sources of funding for the study. We resolved any disagreement by discussion with another author (RRD).
Assessment of study quality or risk of bias
Study quality or risk of bias in the included studies was independently assessed by two review authors (RRD and GCB) by using the Cochrane Collaboration tool.[14] We resolved any disagreement by discussion with another author (NRM).
Data synthesis
For continuous data (time to remission and cumulative steroid dosage), the mean difference with 95% confidence interval (CI) was calculated. For dichotomous data (number of relapses and side events), relative risk (RR) with 95% CI was calculated. P <0.05 was taken as statistically significant. I2 statistics was used to assess study heterogeneity. If heterogeneity was high (I2 > 50%) or statistically significant, we tried to find out the cause. Review Manager (version 5.3) was the statistical software used.[15]
Publication bias
This was assessed by methods (construction of inverted funnel plot) described previously.[16] In case of publication bias, trim and fill method was used to estimate for missing or unreported studies and recalculate effect estimate.[17]
Certainty of evidence
This was assessed by construction of a table through the GRADEprofiler software (v. 3.2).[18],[19] The certainty of evidence can be either high or moderate or low or very low.
| » Results | | |
A total of 202 articles were obtained by applying the above-mentioned search strategy. After screening, 182 articles got excluded, and after full-text review, another 8 articles got excluded (ongoing study = 1, review articles or non-RCTs = 6, and evaluated interleukin levels after giving levamisole = 1), and finally, 12 articles were included in the evidence synthesis [Figure 1]. Six studies compared alternate-day levamisole with placebo or no treatment,[7],[8],[9],[13],[20],[21],[22] one compared alternate-day prednisolone (<0.5 mg/kg for 1 year) with alternate-day levamisole,[23] one compared levamisole with MMF,[24] one compared cyclophosphamide with levamisole,[25] and the other compared levamisole with cyclophosphamide and controls.[21] One study compared daily with alternate-day levamisole,[26] and the other compared daily levamisole with MMF.[27] Only one study had “low risk” of bias in all the domains, and the others had “unclear risk” of bias in one or more domains except for blinding (high risk of bias) [Figure 2]. The studies were conducted in the following countries: India (n = 4),[8],[21],[24],[27] Sri Lanka (n = 2),[20],[26] Saudi Arabia (n = 1),[23] Bangladesh (n = 1),[9] and Egypt (n = 1).[25] Three studies were multicentric in the USA, The Netherlands, and the UK.[7],[13],[22] The details of these studies are provided in [Table 1]. | Figure 1: PRISMA flow diagram. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Click here to view |
Primary outcomes
Proportion of children being relapse free at 6, 12, and 24 months
Proportion of children without relapses at 6–12 months:
- Levamisole versus steroids: Data from two studies were pooled.[9],[23] Levamisole group had a greater number of patients with sustained remission/without relapse (RR: 5.9 [95% CI, 0.13–264.8], I2 = 85%) [Figure 3]
- Levamisole versus placebo or no treatment: Data from three studies were pooled.[7],[13],[21] Levamisole group had a greater number of patients with sustained remission/no relapses (RR: 3.55 [95% CI, 2.19–5.75], I2 = 0%) [Figure 3]
- Levamisole versus steroids/placebo or no treatment: Data from three studies were pooled.[7],[13],[21] Levamisole group had a greater number of patients with sustained remission/no relapses (RR: 3.25 [95% CI, 1.86–5.67], I2 = 31%) [Figure 3]. One study stratified the groups based on steroid dependence/frequent relapsers;[13] however, the difference was not statistically significant (RR: 0.56 [95% CI, 0.21–1.47])
- Levamisole versus cyclophosphamide: Two studies reported this outcome.[21],[25] No significant difference in the proportion of patients in sustained remission was found (RR: 1.11 [95% CI, 0.58–2.14]) even 6 months after stopping medications. The authors used IV cyclophosphamide pulse therapy
- Levamisole versus MMF: Two studies reported this outcome.[24],[27] One study compared alternate-day levamisole with daily MMF (750 mg to 1000 mg/m2), but no significant intergroup difference was found (RR: 1.32 [95% CI, 0.68–2.57]).[24] Another study comparing daily levamisole with MMF[27] also found no intergroup difference in the number of relapses (RR: 0.78 [95% CI, 0.20–3.11]) over 1-year study follow-up.
 | Figure 3: Proportions of SDND/FRNS children without relapses at 6–12 months (levamisole vs. steroids/placebo or no treatment). SDNS = Steroid-dependent nephrotic syndrome, FRNS = Frequent relapse nephrotic syndrome
Click here to view |
Proportion of children without relapses at 24 months:
- Levamisole versus steroids or placebo or no treatment: No study reported the proportion of patients without relapses at 24 months. In one study, the proportion of children without relapse at 30-month follow-up was not significantly different (RR: 2.07 [95% CI, 0.84–5.08]).[8] In this study, levamisole was given for a period of 12 months
- Levamisole versus cyclophosphamide: One study found no significant difference (RR: 3 [95% CI, 0.34–26.45]).[26]
Time to first relapse
One study (n = 103) reported this outcome.[13] The Kaplan–Meier analysis showed no difference in relapse-free survival over the initial 100 days. However, after 100 days, the relapse-free survival was favoring levamisole (P = 0.015).
Secondary outcomes
Proportion of the children with frequent relapse nephrotic syndrome
None of the studies reported this outcome. One study reported failure of the therapy in 9.4% versus 50% in children who received levamisole and low-dose prednisolone, respectively.[23]
Cumulative steroid dose (mg)
One study reported a mean (standard deviation) cumulative prednisolone dose of 255 (157) mg versus 327 (96) mg (P < 0.0001) in children who received levamisole and low-dose steroids, respectively.[24] In another study, less number of patients required steroid in the levamisole group (RR: 0.77 [95% CI, 0.61–0.97]).
Side effects or adverse events
Gastrointestinal symptoms
Mild symptoms were reported in two studies.[7],[23] However, no significant statistical difference was achieved between the patients receiving levamisole as compared to placebo or low-dose steroids (RR: 2.57 [95% CI, 0.28–24.01]) [Figure 4]. Studies comparing levamisole with MMF have shown comparable episodes of acute gastroenteritis [Supplementary Figure 1]. | Figure 4: Adverse events in SDNS/FRNS children receiving levamisole versus steroids/placebo or no treatment, SDNS = Steroid-dependent nephrotic syndrome, FRNS = Frequent relapse nephrotic syndrome
Click here to view |
Leukopenia
This outcome was reported by all the studies comparing levamisole versus steroid/placebo or no treatment.[7],[8],[9],[13],[20],[21] In five studies, leukopenia was not seen. One study found no significant intergroup difference (RR: 5.00 [95% CI, 0.61–41.28]) [Figure 4].[13] Pooled data from two studies found no significant difference (RR: 0.25 [95% CI, 0.04–1.48]).[21],[25] Two studies compared levamisole with MMF, and the proportion of the patients developing leukopenia was comparable in two groups (RR: 0.64 [95% CI, 0.08–5.04], I2 = 0%) [Supplementary Figure 1].
Infections
One study compared levamisole versus cyclophosphamide, and found no significant difference (RR: 1.17; 95% CI: 0.74–1.85) [Figure 5].[25] | Figure 5: Adverse events in SDNS children receiving levamisole versus cyclophosphamide. SDNS = Steroid-dependent nephrotic syndrome
Click here to view |
Reduced estimated glomerular filtration rate and antineutrophil cytoplasmic antibody- positive arthritis
One study found no significant intergroup difference (one patient in each group developed these adverse events) [Figure 4].[13]
Alopecia
One study compared levamisole versus cyclophosphamide,[25] and found no significant intergroup difference (RR: 0.14 [95% CI, 0.10–2.60]) [Figure 5].
Hepatotoxicity
One study compared levamisole versus cyclophosphamide,[25] and found no significant intergroup difference (RR: 0.33 [95% CI, 0.01–7.72]) [Figure 5].
Daily versus alternate-day Levamisole
A crossover study (n = 64) reported the impact of daily dose of levamisole compared to standard alternate-day dose over 12 months.[26] The mean number of relapse episodes was 2.8 in patients on alternate-day levamisole, and 1.3 in those on daily levamisole. The major drawback of the study was the crossover nature, and the outcomes studied were drug efficacy only (the adverse effects were not reported).
Publication bias
As the number of studies was <10 for the primary outcome, we could not construct an inverted funnel plot to assess publication bias.
Sensitivity analysis
We did a sensitivity analysis by analyzing studies with a high and low risk of bias for blinding, but there was no significant difference in the results [Supplementary Figure 2] and [Supplementary Figure 3].
Certainty of evidence
It was of “very low certainty” (except of “moderate certainty” for comparison of levamisole with placebo or no treatment) [Table 2]. This was due to significant study limitations and significant heterogeneity among the studies. | Table 2: Levamisole compared to placebo or standard care for nephrotic syndrome
Click here to view |
| » Discussion | | |
Summary of findings
A total of 12 studies were included in the evidence synthesis. Our result indicated that levamisole given to children with SSNS led to a higher rate of sustained remission/without relapse. The certainty of evidence generated for primary outcome was of “very low” to “moderate” certainty.
The present systematic review shows that levamisole probably decreases the relapses in children with SDNS/FRNS course. Two studies compared levamisole with low-dose steroid,[9],[23] while another three compared levamisole with placebo or no treatment.[7],[13],[20] In the study by the British Association of Pediatric Nephrology (BAPN),[7] the efficacy of levamisole became apparent after 40 days compared to another multicenter study,[13] where the beneficial effect was observed in 100 days. The possible reasons could be a longer steroid treatment in the later study as compared to that by BAPN. Moreover, children in the BAPN study also received cyclophosphamide before starting levamisole, which has been suggested to be more efficacious in children who had previously received an alkylating agent.[28] The authors in the multicenter study[13] also showed an inferior response of SDNS patients (mostly from Europe) as compared to FRNS patients (mostly from India) in the subgroup analysis. A possible genetic and immunological switch because of steroid dependency and preceding long-term steroid therapy were hypothesized by the authors.[13],[29]
Levamisole stimulates T-helper cells (Th1 and Th2) by increasing expressions of interleukin-8 activity and thereof has immunomodulatory activity,[30] and it is considered safe and less expensive among available steroid-sparing agents for preventing relapses in SSNS.[31] Limited studies comparing levamisole with other immunosuppressive agents such as cyclophosphamide or MMF have shown comparable efficacy profile.[21],[24],[25],[27] In one study comparing alternate-day levamisole with MMF, levamisole was found to be comparable with MMF, though the dose of MMF used was lower (750–1000 mg/m2). The same study in post hoc analysis reported longer remission with MMF compared to levamisole.
Retrospective studies and a single crossover study[26] have shown a beneficial role of higher dose of levamisole (daily) as compared to alternate-day dosage in FRNS/SDNS. The rational for using daily levamisole in these studies was shorter half-life of levamisole (5.2 h).[32] In another study, the authors concluded that daily levamisole can be considered when alternate-day therapy is unsatisfactory, without increase in any adverse events.[32] However, more evidence is needed in this regard.
The adverse effects of levamisole are mostly transient and mild, and usually disappear after discontinuation of the drug. The pooled analysis found no significant difference in the rate of adverse events as compared to long-term steroid therapy or control.
Limitations
The included studies were heterogeneous (patient selection, duration of drug therapy, outcome definitions, and drug dosage). Moreover, the number of studies comparing levamisole with cyclophosphamide or MMF is limiting.
| » Conclusion and Future Areas for Research | | |
Levamisole increases the proportion of children with remission compared to steroids (very low certainty evidence) and placebo or no treatment (moderate certainty evidence) in children. Future, multicenter studies looking at the efficacy of levamisole with other second-line agents and addressing the above-mentioned limitation are required.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| » References | | |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]
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