Initial Treatment of Idiopathic Nephrotic Syndrome in Children
Authors: Peter F. Hoyer, Johannes Brodehl
Journal: Journal of the American Society of Nephrology (2006)

Previous studies of the Arbeitsgemeinschaft fu[Combining Diaeresis]r Pa[Combining Diaeresis]diatrische Nephrologie in children with steroid-sensitive nephrotic syndrome have shown that the length of initial prednisone therapy has an impact on the subsequent relapse rate. The aim of this randomized, prospective, multicenter study was to reduce the number of relapses further by increasing the initial immunosuppression: Patients with an initial attack of nephrotic syndrome were randomly allocated to treatment with 6 wk of 60 mg/m2 per d prednisone followed by 6 wk of 40 mg/m2 per 48 h (Pred group) or to the same prednisone treatment plus 8 wk of cyclosporine (Pred+CsA group). The primary end point was first relapse; follow-up was truncated at 2 yr. In the Pred+CsA group (n = 49 patients), the first relapse occurred later compared with the Pred group (n = 55 patients) (median 22.8 versus 12.5 mo). After 6 mo, 10.4% of patients in the Pred+CsA group experienced a first relapse versus 31.5% in the Pred group (P = 0.01); after 1 yr, 36.5 versus 51% (P = 0.15); and after 2 yr, 51 versus 50%. The mean relapse rate per patient was 0.12 versus 0.57 after 6 mo (P = 0.01), 0.63 versus 1.03 after 1 yr (P = 0.02), and 1.03 versus 2.06 after 2 yr (not significant). The significant benefit for adding CsA was lost after 9 to 12 mo. GFR remained unchanged. The subsequent treatment rate with cyclophosphamide was lower in the CsA group (five versus 12 patients) after 2 yr. With the use of logistic regression statistics, children who were younger than 7 yr show a significantly better sustained remission rate with initial CsA treatment for the 2-yr observation time (P = 0.03). It remains questionable, however, whether the intensified initial treatment with CsA could be recommended generally. Previous studies of the Arbeitsgemeinschaft fu[Combining Diaeresis]r Pa[Combining Diaeresis]diatrische Nephrologie (APN) have shown that the risk for relapses in patients with steroid-sensitive nephrotic syndrome (NS) depends on the intensity of initial treatment with glucocorticosteroids (1,2). Before that, published data (3,4) claimed that the risk for relapses in steroid-sensitive NS was positively correlated with the degree of adrenal suppression by steroid therapy. This was not confirmed by previous prospective, randomized trials of the APN. On the contrary, a short-term glucocorticosteroid treatment course for initial treatment of patients with NS resulted in more relapses compared with standard treatment (1). In the recent studies of the APN, the initial treatment was extended to 6 wk of daily treatment with prednisone (60 mg/m2 body surface area) followed by 6 wk of alternate-day treatment (40 mg/m2 per 48 h) (2). This resulted in a significant increase in the cumulative rate of patients with sustained remission after 2 yr (49% with new standard initial treatment versus 19% with standard initial treatment; P < 0.01). These prospective, randomized trials of the APN led to the hypothesis that the initial amount of immunosuppressive treatment has an impact on the further relapse rate of patients with steroid-sensitive NS (5). On the basis of this hypothesis, it was reasonable to design a study with the aim to reduce the number of subsequent relapses by further increasing the initial immunosuppression. Because of the increase in glucocorticosteroid-associated side effects with the new standard treatment, it seemed to be unacceptable to increase total initial immunosuppression by further increasing the prednisone dose. In many studies, cyclosporine A (CsA) has been reported to be very effective in preventing relapses in steroid-dependent NS (6–10). Levamisole was used by the British APN in a randomized trial with some short-term success but no long-term effect on relapse rates (11–14). For that reason, CsA was chosen to be tested as an additional immunosuppressive agent for the initial treatment of idiopathic NS in children. The aims of this study were to test the hypothesis that the amount of initial immunosuppression has an impact on subsequent relapses and to prove its efficacy in reducing the number of relapses, mean relapse rates per patient, and cumulative prednisone doses that are necessary for treatment of relapses and to assess the tolerability and the safety of the total immunosuppressive load as well as the specific CsA-associated side effects.