Treatment of Frequently Relapsing Nephrotic Syndrome

Abstract

Source: Gellerman J, Weber L, Pape L, et alfor the Gesellschaft für Pädiatrische Nephrologie. Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome [published online ahead of print June 27, 2013]. J Am Soc Nephrol; doi: 10.1681/ASN.2012121200Investigators from Germany conducted a multicenter, randomized, open-label, crossover trial comparing the efficacy and safety of mycophenolate mofetil (MMF) to cyclosporin A (CsA) in pediatric patients with frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). FR-SSNS was defined as >4 relapses in 12 months. Patients with FR-SSNS who were 3 to 18 years old and had minimal change glomerulopathy on biopsy, an estimated glomerular filtration rate (eGFR) of ≥90 ml/min per 1.73 m2, and were in remission after a recent relapse were eligible for inclusion. Participants were randomized to receive either MMF for 12 months followed by CsA for 12 months (Group A) or CsA for 12 months followed by MMF for 12 months (Group B).Demographic and clinical characteristics were collected at baseline. During the study period of 2 years, participants had monthly physical examinations, assessment of side effects, screening for proteinuria, and therapeutic drug monitoring. Other blood tests (eg, lipid profile) were performed every 3 months and blood pressure (BP) monitoring was performed at 12 and 24 months. The primary study outcome was the number of relapses per patient per year during the treatment period. Secondary endpoints included pharmacokinetic profiles, cumulative dose of corticosteroids, side effects, and changes in eGFR, BP, and lipid profile.A total of 60 patients (80% boys) were enrolled and randomized to the 2 treatment groups. There were no significant differences between groups in participant age, eGFR, duration of disease, or relapses before study entry. Most participants (75%) had received previous courses of immunosuppressive therapy in addition to corticosteroids.Significantly more patients relapsed while on MMF than on CsA during the first year of the trial (1.10 relapses per patient per year vs 0.24, P = .03) but not during the second year. The time without relapse was significantly longer with CsA compared to MMF during the first year (P < .05), but not during the second year. The eGFR decreased from 12 months to 24 months in Group A (corresponding with CsA treatment), and increased from 12 months to 24 months in Group B (corresponding with MMF treatment). There were no statistically significant follow-up differences between groups with regards to blood pressure, lipid levels, or adverse events.The authors conclude that MMF was inferior to CsA in preventing relapses in children with FR-SSNS but may be a less nephrotoxic treatment.Dr Sethna has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Idiopathic nephrotic syndrome, namely minimal change nephrotic syndrome, diffuse mesangial proliferation, and focal segmental glomerulosclerosis, account for 90% of all cases of nephrotic syndrome with an incidence in the United States of 2 to 7 per 100,000.1 The first line therapy is corticosteroids. Approximately 80% of cases are steroid-responsive at presentation, indicating a favorable prognosis for kidney function.1 Children who become steroid-dependent (SDNS) or frequently relapse are more difficult to treat.Although the pathogenesis of SDNS and FR-SSNS are not fully understood, an underlying immunological defect is suspected and serves as the rationale for use of second-line immunosuppressant treatment. Such second-line agents are also utilized to avoid serious side effects of prolonged steroid exposure. The preferred class and sequence of immunomodulatory drugs for the treatment of SDNS and FR-SNSS have varied with time and region. Alkylating agents such as cyclophosphamide, chlorambucil, levamisole, and the calcineurin inhibitor CsA have been used for over 20 years.2 Severe side effects, however, have led to consideration of several new classes of drugs that target various stages of T- and B-cell action. Tacrolimus, a calcineurin inhibitor that inhibits interleukin-2-driven T-cell activation, has shown promising results in various single-centered studies. 3 Tacrolimus has a milder side effect profile than CsA; however, nephrotoxicity remains a limitation.MMF, a T- and B-cell proliferation inhibitor, has been recently introduced for the treatment of SSNS. Although the current study demonstrated inferiority of MMF compared to CsA in preventing relapses, it is efficacious in inducing remission of nephrotic syndrome with the advantage of no risk of nephrotoxicity. More recently, the monoclonal antibody rituximab, an anti-B-cell treatment, has been used as a “rescue medication” for especially difficult patients. Past studies have shown promising results although long-term side effects and remission sustainability are uncertain.4 Treatment of SDNS and FR-SSNS in children can often prove to be challenging. There is continued need for large-scale randomized controlled trials that provide strong evidence to guide therapy.