Steroid treatment for the first episode of childhood nephrotic syndrome: comparison of the 8 and 12 weeks regimen using an individual patient data meta-analysis

Abstract

Steroids are the cornerstone of the treatment of childhood nephrotic syndrome. The optimal duration for the first episode remains a matter of debate. The aim of this study is to determine whether the 8 weeks International Study of Kidney Disease in Children (ISKDC) regimen is equally effective as the 12 weeks steroid regimen from the German society of pediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie [APN]). An individual patient data (IPD) meta-analysis of randomized controlled trials reporting on prednisolone treatment for a first episode of childhood nephrotic syndrome was conducted. European trials aimed at investigating the ISKDC and/or APN steroid regimen were selected. The lead investigators of the selected trials were requested to provide the IPD of the specific treatment groups. Four trials included European cohorts using dosing schedules according to the regimens studied. IPD of two trials were available. A significant difference was found in time to first relapse after cessation of steroid treatment between the 8 and 12 weeks treatment group with a median time to relapse of 29 and 63 days, respectively. Moreover, relapse rate ratios during total follow-up were 51% higher for the 8 weeks regimen. Finally, younger children have a significantly lower time to first relapse and frequently relapsing nephrotic syndrome.Conclusions: The results of this IPD meta-analysis suggest that the 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen. Moreover, this study highlights the importance of using uniform definitions to enable accurate comparison and interpretation of trial results.Trial registration: Registration number: CRD42020199244, date of registration 16-08-2020What is Known:• Steroids are the cornerstone of the treatment of childhood nephrotic syndrome, however the optimal duration for the first episode remains a matter of debate.• Currently, the 8 weeks ISKDC protocol and 12 weeks APN protocol are among the most frequently used protocols in Europe.What is New:• The 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen for the treatment of a first episode of nephrotic syndrome.• Younger children have a significantly shorter time to first relapse and time to frequent relapsing nephrotic syndrome.

Protocol for an open-label, single-arm, multicentre clinical study to evaluate the efficacy and safety of rituximab in the first episode of paediatric idiopathic nephrotic syndrome

“…Following the first episode, 70%–90% of children with SSNS relapse 1 year after disease onset 12. Data from a meta-analysis6 demonstrated that the median time to relapse was 63 days after cessation of 12 weeks of corticosteroids. Relapse-free rates at 3, 6, 12 and 24 months after the end of continuous therapy were 71%, 44%, 29% and 23%, respectively 6.…”

“…Data from a meta-analysis6 demonstrated that the median time to relapse was 63 days after cessation of 12 weeks of corticosteroids. Relapse-free rates at 3, 6, 12 and 24 months after the end of continuous therapy were 71%, 44%, 29% and 23%, respectively 6. The overall 1-year relapse rate of first-onset INS in our unpublished data from China was similar to the results of the previous meta-analysis 6.…”

“…According to previous literature, the 1-year relapse-free survival rate is approximately 30% in children with the first episode of SSNS after standardised prednisone/prednisolone treatment. 6 Based on this previous study, 6 we estimated that a sample size of 44, with the assumption of a 10% dropout rate, would provide 80% power to detect a 20% increase in the relapse-free rate between the traditional method and RTX treatment at a two-sided alpha level of 0.05.…”

“…Approximately, 85% of patients experience complete remission of proteinuria within 4–6 weeks following guideline-recommended corticosteroids and have steroid-sensitive nephrotic syndrome (SSNS). However, the 1-year relapse-free survival rate is only approximately 30%,6 and the risk for all relapses is 66.2%–87.4% 7. Half of these children will experience frequentlyrelapsing nephrotic syndrome (FRNS) or become steroid-dependent nephrotic syndrome (SDNS),8 and they may experience serious side effects from further steroid treatment or other immunosuppressive drugs.…”

Clinical practice guidelines for nephrotic syndrome: consensus is emerging

“…Likewise, therapy for 2 months versus 3 months or longer was not associated with increased risk of relapse (RR 0.91; 95% CI 0.78-1.06; 637 participants; 5 studies; I 2 = 47%) or frequent relapses (RR 0.99; 95% CI 0.82-1.19; 585 participants, 4 studies; I 2 = 0%). Individual patient data analyses of two European studies suggest that initial therapy for 12 weeks was better than 8 weeks in terms of delaying the time to first relapse (63 vs. 29 days; log rank P = 0.04) and fewer relapses on short-term followup (1.2 vs. 0.8 relapses per year; relative relapse rate 0.66; 95% CI 0.49-0.90) [13]. Post hoc analyses of the Indian [9] and British [11] placebo-controlled RCTs indicated that prolonged therapy in young children might reduce the risk of first relapse, but not frequent relapses [9].…”