Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome

Abstract

Prolonged prednisolone treatment for the initial episode of childhood nephrotic syndrome may reduce relapse rate, but whether this results from the increased duration of treatment or a higher cumulative dose remains unclear. We conducted a randomized, double-blind, placebo-controlled trial in 69 hospitals in The Netherlands. We randomly assigned 150 children (9 months to 17 years) presenting with nephrotic syndrome to either 3 months of prednisolone followed by 3 months of placebo (n=74) or 6 months of prednisolone (n=76), and median follow-up was 47 months. Both groups received equal cumulative doses of prednisolone (approximately 3360 mg/m(2)). Among the 126 children who started trial medication, relapses occurred in 48 (77%) of 62 patients who received 3 months of prednisolone and 51 (80%) of 64 patients who received 6 months of prednisolone. Frequent relapses, according to international criteria, occurred with similar frequency between groups as well (45% versus 50%). In addition, there were no statistically significant differences between groups with respect to the eventual initiation of prednisolone maintenance and/or other immunosuppressive therapy (50% versus 59%), steroid dependence, or adverse effects. In conclusion, in this trial, extending initial prednisolone treatment from 3 to 6 months without increasing cumulative dose did not benefit clinical outcome in children with nephrotic syndrome. Previous findings indicating that prolonged treatment regimens reduce relapses most likely resulted from increased cumulative dose rather than the treatment duration.

Figure 1.

Patients were analysed in a modified intention to treat analysis. All patients that started trial medication were analysed according to their allocated treatment. SRNS, steroid-resistant NS.

Figure 2.

Treatment regimens were built up of comparable cumulative doses of prednisolone. The dotted line represents the median number of days to remission (10 days in both groups), the gray area represents the IQR. Doses are in mg/m². AD, alternate days; D, daily.

Figure 3.

Initial prednisolone treatments of 3 and 6 months resulted in similar therapeutic outcome. Kaplan–Meier curves represent cumulative incidences of (A) strict FNRS based on more than or equal to two relapses within 6 months after initial treatment or four relapses within any 12 months, (B) clinical FRNS according to either the definition of strict FRNS or a clinical indication for additional treatment (e.g., prednisolone maintenance therapy, cyclophosphamide, etc.), and (C) cumulative incidence of a first relapse.

Figure 4.

Meta-analyses of studies comparing 3 months of prednisolone to 6 months of prednisolone do not reveal a benefit of prolonged treatment duration. (A) All four available studies (B) Two fully published studies. In both analyses, numbers of FRNS of the current study correspond with numbers of strict FRNS. Analyses were performed with Review Manager (RevMan) version 5.1 for Windows (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2011).