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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 19  |  Issue : 2  |  Page : 87-90

Use of levamisole in children with nephrotic syndrome: A retrospective study to examine its adverse effects in children with nephrotic syndrome


1 Department of Pediatrics, Command Hospital; Dean and Deputy Commandant, AFMC, Pune, Maharashtra, India
2 Dean and Deputy Commandant, AFMC, Pune, Maharashtra, India
3 Department of Pediatrics, PGIMER, Chandigarh, India

Date of Web Publication13-Feb-2018

Correspondence Address:
Dr. Suprita Kalra
Department of Pediatrics, Command Hospital, AFMC, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmms.jmms_41_17

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  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1-18 years of age who had received Levamisole for at least six months or in whom Levamisole was started but had to be withdrawn due to some adverse events in the first 6 months.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 Levamisole had to be withdrawn in one child at 1 month 13 days after initiation when the child developed severe headache.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


How to cite this article:
Kalra S, Kanitkar M, Tiewsoh K. Use of levamisole in children with nephrotic syndrome: A retrospective study to examine its adverse effects in children with nephrotic syndrome. J Mar Med Soc 2017;19:87-90

How to cite this URL:
Kalra S, Kanitkar M, Tiewsoh K. Use of levamisole in children with nephrotic syndrome: A retrospective study to examine its adverse effects in children with nephrotic syndrome. J Mar Med Soc [serial online] 2017 [cited 2018 Apr 19];19:87-90. Available from: http://www.marinemedicalsociety.in/text.asp?2017/19/2/87/225274




  Introduction Top


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],[2],[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 of Levamisole and to describe the clinical profile of these children.


  Materials and Methods Top


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 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 Top


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.
Table 1: Baseline characteristics of the children on levamisole therapy

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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 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].
Table 2: Profile of children who faced adverse effects after starting levamisole

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  Discussion Top


Various immunosuppressive agents have been used in the management of children with FRNS and SDNS to minimize the toxicity of corticosteroids. Levamisole is a well-known anthelmintic agent with immunomodulatory action. It also acts as an immune enhancer by increasing macrophage chemotaxis and T-cell function. It has been used in childhood idiopathic nephrotic syndrome since 1980.[1] The effectiveness of levamisole in reducing the frequency of relapses in children with FRNS and SDNS is well documented,[2],[3] and it was seen in our study also. It was withdrawn from use as an anthelmintic agent due to the risk of agranulocytosis and is not available in the US and Canada.[4],[5] Apart from agranulocytosis, the other prominent side effects include retiform purpura and seizures. The cutaneous lesions may represent a true vasculitis with positive staining for IgM, IgA, IgG, and C3, and vascular staining for fibrin or a pseudovasculitis with negative staining on immunofluorescence. The nervous system manifestations have been attributed to accentuated nicotinic acetylcholinergic release. Arthralgias and arthritis, especially of the large joints, have also been commonly described.[6] In children with nephrotic syndrome, studies have described the incidence of side effects to vary from almost none [7],[8] to nearly 15%, but the adverse effects have been reported to resolve completely after stopping therapy.[9] Rarely, serious side effects such as disseminated autoimmune disease with high titers of IgM anticardiolipin and p-Antineutrophil cytoplasmic antibody antibodies have been described.[10] In our study also, we found the incidence of adverse effects to be 9.52% (2/21), and as described in previous studies, the adverse effects resolved completely on withdrawal of levamisole. In our series, one child had neurological manifestation in the form of headache relatively early after the initiation of therapy (at 1 month, 13 days) while the other child developed arthralgia at 13 months after she was put on Levamisole therapy. The duration of therapy to onset of adverse effects has not been shown to be consistent and children may have the same any time during treatment with Levamisole. Several cases of severe agranulocytosis have been described in cocaine users inadvertently using cocaine contaminated with Levamisole. Cutaneous manifestations consisting of large, painful hemorrhagic bullae and/or necrosis, most commonly involving the face, hyponatremia, seizures, and various other serious side effects, have been described in this subset of patients. Gas chromatography or mass spectrometry has been used to test patients' urine for the presence of Levamisole to confirm levamisole as the causative agent.[6],[11] This was, however, not required in our children as exposure was definite, but to pinpoint Levamisole as the cause of adverse effect required exclusion of other possible etiologies.

The incidence of adverse events was not reported to be higher with daily dosing of Levamisole as compared to the standard practice of giving it on alternate days.[3]

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 single center.

The adverse effects of Levamisole brought out in children with nephrotic syndrome in our study were found to be reversible with drug withdrawal. However, their relatively high incidence and the potential risk of serious side effects should be kept in mind while prescribing Levamisole which was traditionally considered safe as compared to other immunosuppressive agents in children with nephrotic syndrome.

This study also emphasizes the need for a large multicentric analysis of data related to the adverse events of all drugs used as steroid-sparing agents in children with nephrotic syndrome to help weigh the benefits against the possible side effects.


  Conclusions Top


Although the number of relapses in children with FRNS and SDNS is significantly reduced with the use of Levamisole, we need to be cautious against its potential side effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tanphaichitr P, Tanphaichitr D, Sureeratanan J, Chatasingh S. Treatment of nephrotic syndrome with levamisole. J Pediatr 1980;96:490-3.  Back to cited text no. 1
    
2.
Bagga A, Sharma A, Srivastava RN. Levamisole therapy in corticosteroid-dependent nephrotic syndrome. Pediatr Nephrol 1997;11:415-7.  Back to cited text no. 2
    
3.
Ekambaram S, Mahalingam V, Nageswaran P, Udani A, Geminiganesan S, Priyadarshini S, et al. Efficacy of levamisole in children with frequently relapsing and steroid-dependent nephrotic syndrome. Indian Pediatr 2014;51:371-3.  Back to cited text no. 3
    
4.
Centers for Disease Control and Prevention (CDC). Agranulocytosis associated with cocaine use - four states, March 2008-November 2009. MMWR Morb Mortal Wkly Rep 2009;58:1381-5.  Back to cited text no. 4
[PUBMED]    
5.
Knowles L, Buxton JA, Skuridina N, Achebe I, Legatt D, Fan S, et al. Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia. Harm Reduct J 2009;6:30.  Back to cited text no. 5
[PUBMED]    
6.
Lee KC, Culpepper K, Kessler M. Levamisole-induced thrombosis: Literature review and pertinent laboratory findings. J Am Acad Dermatol 2011;65:e128-9.  Back to cited text no. 6
[PUBMED]    
7.
Al-Saran K, Mirza K, Al-Ghanam G, Abdelkarim M. Experience with levamisole in frequently relapsing, steroid-dependent nephrotic syndrome. Pediatr Nephrol 2006;21:201-5.  Back to cited text no. 7
[PUBMED]    
8.
Basu B, Babu BG, Mahapatra TK. Long-term efficacy and safety of common steroid-sparing agents in idiopathic nephrotic children. Clin Exp Nephrol 2017;21:143-51.  Back to cited text no. 8
    
9.
Sümegi V, Haszon I, Iványi B, Bereczki C, Papp F, Túri S, et al. Long-term effects of levamisole treatment in childhood nephrotic syndrome. Pediatr Nephrol 2004;19:1354-60.  Back to cited text no. 9
    
10.
Barbano G, Ginevri F, Ghiggeri GM, Gusmano R. Disseminated autoimmune disease during levamisole treatment of nephrotic syndrome. Pediatr Nephrol 1999;13:602-3.  Back to cited text no. 10
    
11.
McGrath MM, Isakova T, Rennke HG, Mottola AM, Laliberte KA, Niles JL, et al. Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease. Clin J Am Soc Nephrol 2011;6:2799-805.  Back to cited text no. 11
    



 
 
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