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CASE SERIES
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Levamisole in steroid-dependent nephrotic syndrome in children: A case series


1 Flushing Hospital Medical Center, New York, USA
2 Nephrology Division, GMC, Secunderabad, Telangana, India
3 Department of Medicine GMC Baramulla, J and K Health Services, GMC, Srinagar, Kashmir, India
4 Pathology Division, GMC, Srinagar, Kashmir, India

Date of Submission27-Apr-2020
Date of Decision22-Jun-2020
Date of Acceptance24-Jul-2020

Correspondence Address:
Muzamil Latief,
MS 1 OP Block, Gandhi Hospital, Secunderabad - 500 003, Telangana
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_211_20

  Abstract 


Nephrotic syndrome (NS) is a common clinical entity encountered in children and adults. Steriod Dependent Nephrotic Syndrome(SDNS) is one of the most common pediatric glomerular diseases. However, a significant chunk of cases follows a relapsing and remitting course. Various modalities such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil (MMF), levamisole, and rituximab have been tried in patients with steroid-dependent or frequently relapsing NS (FRNS). We describe our experience of using levamisole in nine patients with steroid-dependent NS. We used the regimen of levamisole dosing at 2.5 mg/kg on alternate days, along with alternate dosing of steroids at the lowest possible doses to achieve remission. During follow-up, two of the patients were switched over to a calcineurin inhibitor (tacrolimus). All the remaining seven patients responded to levamisole and attained remission. At 18 months follow-up, four patients were on a minimal dose of steroids (prednisolone 0.25 mg/kg alternate day) with levamisole 2.5 mg/kg, whereas three patients were on prednisolone 0.5 mg/kg/alternate day with levamisole 2.5 mg/kg alternate day. Among the patients with steroid-sensitive NS, 30%–60% are frequently relapsing or steroid-dependent forms of NS. Corticosteroids have well recognized and potentially serious adverse effects. A lot of steroid-sparing agents such as MMF, rituximab, alkylating agents like cyclophosphamide, and calcineurin inhibitors have been used in clinical medicine, to mitigate the above mentioned adverse effects of prolonged use of corticosteroids, with varying success. But these medications have significant side effects and toxicity profiles of their own. Our case series reiterates the role of levamisole in FRNS and SDNS patients without much risk of adverse events in patients and hence being a relatively less expensive treatment option.

Keywords: Levamisole, nephrotic syndrome, steroid



How to cite this URL:
Shafi O, Latief M, Hassan Z, Abbas F, Farooq S. Levamisole in steroid-dependent nephrotic syndrome in children: A case series. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Nov 30]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=319168




  Introduction Top


Nephrotic syndrome (NS) is a common clinical entity encountered in children and adults. It is characterized by proteinuria (3.5 g/day in adults and 40 mg/m2/hour in children), hypoalbuminemia (<2.5 g/dl), generalized edema, and normal glomerular function.[1] A fraction of children with NS achieves spontaneous remission, whereas most require immunosuppression in the form of steroids to achieve remission. Most of the children with idiopathic NS (iNS) respond to steroids initially. Steroid sensitive NS (SDNS) is one of the most common pediatric glomerular diseases. However, a significant chunk of cases follows a relapsing and remitting course, with approximately 50% of all cases relapsing once or even more frequently.[2],[3] Overtime frequent courses of steroid therapy carry the risk of significant toxicity. To overcome this various modalities such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil (MMF), levamisole, and rituximab have been tried in patients with steroid-dependent or frequently relapsing NS (FRNS).

Levamisole, as a drug, was first used as an anthelmintic drug.[4] It has been used since the early 1980s in the treatment of SSNS.[5] It stimulates the immune system and has been shown to have a steroid-sparing potential in children with SSNS. It is minimally toxic and less expensive therapy among the currently available options in SSNS.[6] Many randomized controlled trials have shown the effectiveness of levamisole in reducing the frequency of relapses in steroid-dependent NS, with minimal adverse effects.[4]

[TAG:2]Case Series [/TAG:2]

We describe our experience of using levamisole in nine patients with steroid-dependent NS. All the nine patients had biopsy-proven minimal change disease. The baseline parameters are mentioned in [Table 1]. The mean age of our patients was 6.88 ± 0.14 years. They were started on levamisole as the initial steroid-sparing agent. We used the regimen of levamisole dosing at 2.5 mg/kg on alternate days, along with alternate dosing of steroids at the lowest possible doses to achieve remission. During follow-up, two of the patients were switched over to a Calcineurin inhibitor (tacrolimus). Both of them were male patients. The first one developed severe leukopenia, which recovered after discontinuing levamisole, and the other patient did not respond to levamisole. All the remaining seven patients responded to levamisole and attained remission. At 18 months follow-up, four patients were on a minimal dose of steroids (prednisolone 0.25 mg/kg alternate day) with levamisole 2.5 mg/kg, whereas three patients were on on prednisolone 0.5 mg/kg/alternate day with Levamisole 2.5 mg/kg alternate day. The mean ± standard deviation of relapse episodes per year was 4.57 ± 0.53 before levamisole and 1.14 ± 0.69 after levamisole use. However, we could not stop the steroids altogether in the patients, and they continue to remain in remission on minimal steroid dose. As there was a recognizable drop in relapse rate with the introduction of levamisole, we, therefore, found it a reasonable option considering its low cost, wide availability, and minimal adverse effects.
Table 1: Baseline parameters of the patients

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  Discussion Top


NS is a common clinical condition in pediatric population, and treatment with steroids is still the first choice because of satisfactory response in iNS. Majority of patients (90%) of NS show remission within 4 weeks of treatment with steroids.[4] NS is classified as steroid-sensitive NS (SSNS) if they respond to steroids, as defined by the International Study of Kidney Disease in Children.[7] The overall outcome of children suffering from NS is good. The disease generally disappears at the onset of puberty, although up to 85% develop at least one relapse within the next 5 years.[8]

Among the patients with SSNS, 30%–60% are frequently relapsing or steroid-dependent forms of NS.[2],[3] FRNSis defined as more than four relapses in 1 year or more than two relapses following the first 6 months after the initial presentation. Patients with at least two relapses during treatment with alternate-day steroids or within 14 days after stopping steroid treatment are classified as steroid-dependent (SDNS).[3],[9] Treatment of relapses is usually based on steroids with a shorter duration (prednisone 60 mg/m2 until remission, 4 weeks 40 mg/m2 every other day).[7] FRNS and SDNS usually respond to treatment with glucocorticoids, and long-term prognosis regarding renal function is good.[10] However, these patients require frequent courses of steroids. Corticosteroids have well recognized and potentially serious adverse effects. The long list of adverse effects with steroid treatment includes cushingoid changes, skin atrophy, striae, peptic ulcer, adrenal suppression, increased blood pressure, hyperglycemia, behavioral changes, infection, and abnormal bone metabolism.[11],[12],[13] A lot of steroid-sparing agents such as MMF, rituximab, alkylating agents like cyclophosphamide, and calcineurin inhibitors have been used in clinical medicine, to mitigate the above mentioned adverse effects of prolonged use of corticosteroids, with varying success. But these medications have significant side effects and toxicity profiles of their own.[7],[14]

Levamisole has been shown to have a steroid-sparing effect in children with SSNS in multiple studies.[15],[16],[17],[18],[19],[20],[21],[22],[23] It is the least toxic and least expensive drug for preventing relapses and is used as the initial preferred steroid-sparing medication in many resource-poor countries. The KDIGO guidelines recommend a dose of 2–2.5 mg/kg given on alternate days (maximum dose of 150 mg).[7] In a multicenter clinical trial of children managed with standard steroid therapy, the inclusion of levamisole for 1 year increased the remission rate at 12 months (26% vs. 6%).[23] However, as is seen with Levimasole, most patients relapsed after cessation of treatment. Neutropenia, which was reversible, was the most common adverse effect noted in this study, occurring in approximately 2% of treated patients. In our study, we noted leucopenia in one patient, which improved after cessation of levimasole. Another open-label trial of children with FRNS or SDNS, levamisole (2.5 mg/kg on alternate days), and MMF (750–1000 mg/m2) had comparable rates of sustained remission, reduction of steroid use, and frequency of relapses in two groups.[24] A prospective study revealed, levamisole at 2.5 mg/kg daily was effective and safe. The mean number of relapses per patient was 2.8 ± 0.8 in patients on an alternate-day regimen of levamisole and 1.3 ± 0.9 on a daily regimen of levamisole.[25] In our study also we saw an encouraging response to levamisole alternate-day regimen in most patients. Levamisole-induced changes in the immune-mediated response may cause a reduction of relapses in predominantly immune-mediated diseases that have been suggested as the mechanism.[4]

The adverse effects of levamisole are mostly mild and transient, disappearing after its discontinuation. Common adverse effects include gastrointestinal symptoms (nausea, abdominal cramps), and pyrexia.[26],[27] Very few serious adverse events have been observed in studies on iNS. Few cases of gastrointestinal disturbances or leukopenia have been reported in the RCTs.[19],[15] The majority of retrospective studies reported either no side effects of levamisole or only minor reversible effects such as rash, fever, abdominal pain, elevated liver enzymes, neutropenia, or thrombocytopenia, which all disappeared after cessation of levamisole.[20],[28],[29],[30] The reported incidence of leukopenia varies from 0% to 20%, which is spontaneously reversible after discontinuation of the treatment.[23] The side effects, except for one patient with reversible leucopenia, were not observed in our case series. Regular monitoring of complete blood count should be performed because the most serious adverse effect of levamisole is reversible neutropenia. Levamisole can lead to a variety of dermatologic adverse effects such as leg ulcers, purpura of the ears, cutaneous necrosis lichenoid eruption and fixed drug eruptions.[31] Like other adverse events, symptoms resolved when levamisole treatment was stopped. In addition, leukoencephalopathy, skin necrosis, hyponatremia, acute coronary syndrome, pulmonary hypertension, granulomatosis with polyangiitis, and pyoderma gangrenosum have been reported.[32] Overall the adverse effects with levamisole are not long lasting and, in most cases, disappear on cessation of the drug.


  Conclusion Top


Our case series reiterates the role of levamisole in FRNS and SDNS patients without much risk of adverse events in patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Kyrieleis HA, Lowik MM, Pronk I, Cruysberg HR, Kremer JA, Oyen WJ, et al. Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin J Am Soc Nephrol 2009;4:1593-600.  Back to cited text no. 11
    
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Pravitsitthikul N, Willis NS, Hodson EM, Craig JC. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev 2013;(10):CD002290. Published 2013 Oct 29. doi:10.1002/14651858.CD002290.pub4.  Back to cited text no. 15
    
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Mongeau JG, Robitaille PO, Roy F. Clinical efficacy of levamisole in the treatment of primary nephrosis in children. Pediatr Nephrol 1988;2:398-401.  Back to cited text no. 16
    
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Barletta GM, Smoyer WE, Bunchman TE, Flynn JT, Kershaw DB. Use of mycophenolate mofetil in steroid-dependent and -resistant nephrotic syndrome. Pediatr Nephrol 2003;18:833-7.  Back to cited text no. 18
    
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Boyer O, Moulder JK, Grandin L, Somers MJ. Short- and long-term efficacy of levamisole as adjunctive therapy in childhood nephrotic syndrome. Pediatr Nephrol 2008;23:575-80.  Back to cited text no. 20
    
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Elmas AT, Tabel Y, Elmas ON. Short-and long-term efficacy of levamisole in children with steroid-sensitive nephrotic syndrome. Int Urol Nephrol 2013;45:1047-55.  Back to cited text no. 22
    
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Gruppen MP, Bouts AH, Jansen-van der Weide MC, Merkus MP, Zurowska A, Maternik M, et al. A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome. Kidney Int 2018;93:510-8.  Back to cited text no. 23
    
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Kuzma-Mroczkowska E, Skrzypczyk P, Pańczyk-Tomaszewska M. Levamisole therapy in children with frequently relapsing and steroid-dependent nephrotic syndrome: A single-center experience. Cent Eur J Immunol 2016;41:243-7.  Back to cited text no. 29
    
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