The records of children, who attended the Pediatric Nephrology clinic at a tertiary pediatric referral hospital, in Southern India between June 2004 and June 2011 were analyzed retrospectively. Children aged 1-18 years receiving levamisole for at least six months for treatment of SDNS or FRNS were included. Infantile NS, congenital NS and NS secondary to systemic illnesses were excluded. SDNS was defined when there were two consecutive relapses while on alternate day steroids or within 14 days of their discontinuation. FRNS was defined by two or more relapses in six months or more than three relapses in any twelve months. Relapses were treated according to Indian Pediatric Nephrology Group guidelines [4]. Levamisole was started in SDNS/FRNS children daily at a dose of 2 mg/kg/day at the end of two weeks of daily steroids on inducing remission. Prednisolone was given at a dose of 1.5 mg/kg every other day for 4 weeks and then gradually tapered to a maintenance dose of 0.5 mg/kg every other day at 6 months and 0.25 mg/kg every other day at end of 1 year.

All children were monitored every three months for response and side effects; urinalysis, total and differential blood cell counts, and liver enzymes were done. At the end of one year, serum albumin, serum cholesterol and urine albumin were checked, and if under remission, prednisolone was discontinued. Levamisole was stopped at the end of two years and these children were followed up for at least one year following cessation of therapy.

Levamisole was considered effective, if the children were able to maintain remission when steroids were tapered and stopped. It was considered ineffective if child developed two or more relapses while on every other day steroids or when steroids could not be withdrawn. Levamisole was stopped when it was considered ineffective. Children in post-immunosuppressive therapy (cyclophosphamide), presenting with SDNS/FRNS were included and their response to levamisole was analyzed. Statistical analyses were done using Repeated measures ANOVA, F-test, and Chi-Squared test. P <0.05 was taken as significant.

A total of 97 children (53 boys) completed 6 months of levamisole therapy; 62 (64%) of these were FRNS. None of the children had renal failure, hypertension or gross hematuria. The baseline characteristics at the start of levamisole therapy are shown in Table I.

TABLE I	Baseline Characteristics of The Study Population

The duration of levamisole therapy ranged from 6 to 24 months with a mean (SD) duration of 18.7 (6.4) months. Levamisole was effective in 77.3% children, was stopped in 15 (15.5%) children as it was ineffective, and 7 (7.2%) children were lost to follow-up. Frequent relapsers showed a better efficacy to levamisole in comparison to steroid-dependent NS (80.6% vs. 71.4%; P=0.001).

Prednisolone was tapered to 0.5 mg/kg/day at the end of 6 months with a mean (SD) duration of 5 (1.1) months. Sixty-five children completed one year of therapy and prednisolone was stopped with a mean (SD) duration of 11.84 (1.3) months. Mean (SD) serum albumin at the start of therapy was 2.32 (0.5) g/dL and at completion of therapy was 4.12 (0.3) g/dL.

At the end of 24 months, 40 children completed therapy and these children were kept under surveillance for at least a year. A total of 34 children were followed-up for 1 year post-therapy and the cumulative steroid dose and relapse rates are shown in Table II. The steroid dose and relapse rates were significantly less after levamisole therapy. Relapse free period was observed in 25 (73.5%) children during therapy and in 22 (64.7%) children during the one year period of post-levamisole therapy.

TABLE II	Cumulative Steroids and Relapse Rates in Children With FRNS/SDNS 

Before the administration of levamisole, 7 SDNS children had received cyclophosphamide. Renal biopsy was performed in all these children. Four children had minimal change disease and 3 had diffuse mesangial proliferation by histopathology. Levamisole therapy was effective in 5 children.

In this retrospective study of 97 children with SDNS or FRNS, levamisole was found to be effective in majority (77.3%), with a better efficacy in children with FRNS as compared to those with SDNS.

In our study, levamisole was administered in daily dosing schedule based on personal experience; most guidelines suggest alternate day therapy in nephrotic syndrome. Fu, et al. [5], 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. We did not have any comparison group as this study was a retrospective analysis.

Madani, et al. [6] evaluated the efficacy of levamisole among 304 children and demonstrated that it was effective in children with both SDNS and FRNS. In their study, the relapse rates reduced by about one-half after levamisole therapy. Alsaran, et al. [7] documented response in 90.6% children with FRNS/SDNS. Sumegi, et al. [8] followed 34 children for a duration of 5–36 months and documented a reduction in relapse rate after levamisole therapy. Our results are in concordance with the above studies. In children with effective therapy, we were able to taper and stop steroids in majority of patients. Bagga, et al. [9] also showed that levamisole was effective in children with SDNS. In a meta-analysis of randomized controlled trials [10], Durkan, et al. showed that prolonged course of levamisole reduces the incidence of relapses.

Various studies have reported side effects while on alternate day levamisole schedule, though these were not life-threatening and were reversible on discontinuing levamisole [6,7,9,11]. We did not observe any side effects, even in those who completed 2 years of daily levamisole therapy.

To conclude, daily levamisole along with initial low dose steroid therapy can be effective in children with FRNS/SDNS with a better efficacy in children with FRNS. It significantly reduces the cumulative dose of steroid intake and relapse rates. Levamisole can be used as an effective steroid-sparing agent in children with frequently-relapsing and steroid dependent nephrotic syndrome.

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