ArticlesRituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial
Introduction
Childhood nephrotic syndrome is a disorder affecting the kidneys in which a large amount of protein passes through the glomerular filter, resulting in hypoproteinaemia and generalised oedema. Idiopathic nephrotic syndrome occurs in two or more of every 100 000 children1 and is the most common chronic glomerular disease in paediatric nephrology practice. Minimal change nephrotic syndrome is the most common form of the disorder, for which steroid therapy is effective for most patients.2 Those who respond well rarely progress to chronic renal failure, but up to half develop frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS; table 1).2 Moreover, 10–20% of patients with idiopathic nephrotic syndrome have steroid-resistant nephrotic syndrome (table 1).2
Standard treatments for FRNS, SDNS, and steroid-resistant nephrotic syndrome are immunosuppressive agents: cyclophosphamide, chlorambucil, ciclosporin, tacrolimus, and levamisole are used for paediatric FRNS or SDNS, and ciclosporin for paediatric steroid-resistant nephrotic syndrome.3, 4, 5 Most children are effectively treated with these drugs; however, some have frequent relapses. In two studies,6, 7 10–20% of children taking ciclosporin had frequent relapses, and in another study,8 about 30% of the patients with steroid-resistant nephrotic syndrome after ciclosporin had steroid-sensitive, frequent relapses after complete remission. In addition to being ineffective in some patients, ciclosporin can cause side-effects—the most common of which is chronic nephrotoxicity9, 10—suggesting that it should be discontinued within 24 months. However, discontinuation of ciclosporin almost always results in frequent relapses requiring long-term steroid treatment,11 which also poses a long-term risk to children. Therefore, a new treatment that does not involve steroids or immunosuppressive agents is urgently needed.
In the past 10 years, rituximab has had some success in complicated FRNS and SDNS,12, 13 and several research groups have done single-arm or short-term studies of this drug.14, 15, 16 The 2012 Kidney Disease: Improving Global Outcomes clinical practice guidelines17 introduced rituximab as a treatment option for childhood-onset, complicated FRNS and SDNS. However, the efficacy and safety of rituximab for complicated FRNS and SDNS are yet to be established.17 We aimed to assess the efficacy and safety of rituximab in patients with high disease activity.
Section snippets
Study design and participants
In a multicentre, double-blind, randomised, placebo-controlled trial, we enrolled patients at nine centres in Japan. Full eligibility criteria are listed in the appendix. Briefly, we screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1–18 years (appendix). Patients with complicated FRNS or SDNS (table 1) who met all other criteria were eligible for inclusion after remission of the relapse they were
Results
Between Nov 13, 2008, and May 19, 2010, 52 patients were randomly assigned to rituximab or placebo. Follow-up ended on Nov 10, 2011. The preplanned interim analysis showed that rituximab was superior to placebo, after which the independent data and safety monitoring committee advised us to discontinue randomisation as specified in the protocol. Therefore, randomisation ended earlier than planned, on May 21, 2010.
52 patients underwent randomisation (figure 2). 48 patients received the assigned
Discussion
We have shown that the relapse-free period increases with rituximab in patients with childhood-onset, complicated FRNS and SDNS. Adverse events were generally mild and the frequency of serious adverse events did not differ significantly between groups. As far as we are aware, we are the first to show that rituximab is safe and effective for at least 1 year of treatment in a multicentre, double-blind, randomised, placebo-controlled trial (panel).
Patients with complicated FRNS or SDNS usually
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