Corticosteroid therapy for steroid-sensitive nephrotic syndrome in children: dose or duration?

Idiopathic nephrotic syndrome, although a rare disease, is the most common primary glomerular disease among children. It causes substantial morbidity because it typically runs a relapsing course punctuated with prolonged periods of corticosteroids and other immunosuppressive medication. It affects about 2 children per 100,000 aged ,16 years in Europe and North America, with higher rates reported among children from the Indian subcontinent. Approximately 80% of children achieve complete remission with 4 weeks of corticosteroid therapy after their first presentation and are considered to have steroid-sensitive nephrotic syndrome (SSNS), but a similar proportion relapse $1 times. Among children who relapse, about 50% will relapse frequently (defined by the International Study of Kidney Disease in Children [ISKDC] as $2 relapses within 6 months of initial response, or $4 relapses in any 12-month period) or will have a steroid-dependent disease (defined by Arbetsgemeinschaft für Pädiatrische Nephrologie [APN] as $2 consecutive relapses either during corticosteroid therapy or within 2 weeks of ceasing it). Despite relapses, most children continue to be steroid responsive, maintain normal kidney function, and ultimately, will be cured as they age into adolescence and early adult life. Over 40 years ago, the ISKDC proposed a regimen for the initial episode of SSNS, which comprised 60 mg/m per day of prednisolone for 4 weeks followed by 40 mg/m administered on 3 of 7 days for a further 4 weeks. Subsequently, a randomized trial coordinated by the APN demonstrated that alternate-day prednisolone was more effective in maintaining remission than prednisolone given on consecutive days. Most pediatric nephrologists adopted a regimen of daily prednisolone for 4 weeks followed by 4 weeks of alternate-day prednisolone as their standard regimen for the treatment of the first episode of SSNS. Because of the high relapse rate with this regimen, several trials have evaluated whether extending the duration of prednisolone therapy would result in fewer children relapsing and developing frequently relapsing nephrotic syndrome (FRNS). In a systematic review, data from six randomized controlled trials (RCTs) show that compared with 8 weeks of initial therapy, increasing the duration of prednisolone to $3 months reduced the risk of relapse over the following 12–24 months by 30% (relative risk [RR], 0.70; 95% confidence intervals [CI], 0.58–0.84) and the number of childrenwith FRNS by 37% (RR, 0.63; 95% CI, 0.46–0.84). A meta-analysis of four RCTs demonstrates that compared with 3 months, 6 months of prednisolone reduced the risk of relapse by 12–24 months by 43% (RR, 0.57; 95% CI, 0.45–0.71) and the number of children with FRNS by 45% (RR, 0.55; 95% CI, 0.39–0.80). However, increased duration of prednisolone also resulted in an increased total dose of prednisolone, so it remained unclear whether the benefit resulted from the increased duration or the total dose of prednisolone. Regression analysis suggested that an increased duration, rather than dose, was the most influential variable; however, because it was a nonrandomized comparison, the potential existed for confounding by design. In this issue of JASN, Teeninga et al. report the results of a placebo-controlled, parallel group trial in which 150 children aged between 9 months and 17 years with their first episode of idiopathic nephrotic syndrome were randomized at diagnosis to receive 12 weeks of prednisolone followed by 12 weeks of placebo (74 children) or 24 weeks of prednisolone (76 children), with the dosage regimens designed to provide the same total dose of prednisolone in both groups. The primary outcome was the number of children who developed FRNS, with the secondary outcomes being the number with relapse and the adverse events seen. Twenty-four children (12 children from each treatment group) were excluded from the analysis because of primary steroid resistance (11 children) or withdrawal of consent for the study (13 children). There was no significant difference in the number of children who developed FRNS between treatment groups, whether FRNSwas defined according to strict ISKDC criteria (45% versus 50%) or using clinical extended criteria (50% versus 59%). Similarly, there was no significant difference in the number of children with any relapse (77% versus 80%). Adverse effects (hypertension, ophthalmologic complications, moon face, striae, viral and bacterial infections), growth rates, bone mineral densities, and behavioral scores did not differ Published online ahead of print. Publication date available at www.jasn.org.