Steroid-sparing drugs in children and young adults with nephrotic syndrome: a target trial emulation

Children and young adults with nephrotic syndrome are commonly treated with steroid-sparing immunosuppressive medications. Rituximab is increasingly used in frequently relapsing disease, but the real-world comparative effectiveness of rituximab and calcineurin inhibitors is unclear.

Using target trial methods, we emulated a pragmatic randomized controlled trial using observational data from two prospective nephrotic syndrome cohorts. We included children and adults (aged 1-40 years) with steroid-sensitive nephrotic syndrome that first initiated rituximab or calcineurin inhibitor treatment during follow-up. Randomization was emulated using overlap weighting of propensity scores for treatment assignment. The primary outcome was time-to-relapse, analyzed by weighted Cox proportional hazards models. Secondary outcomes were relapse counts, subsequent immunosuppressive treatment, kidney function, hypertension and all-cause mortality.

Of 372 eligible participants, 104 initiated rituximab and 268 initiated calcineurin inhibitors. Baseline characteristics were balanced after propensity score weighting. Mean age at medication initiation was 13.2 years, 61% were male and 69% had received prior steroid-sparing medications. Throughout a median 4.9-year (quartile 1-3, 2.0-7.2) follow-up, relapses occurred in 58 participants (56%) treated with rituximab and 209 (78%) treated with calcineurin inhibitors. There was no significant difference in time-to-relapse after rituximab vs calcineurin inhibitor treatment [weighted hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.59-1.38]. There were also no significant differences in relapse rates or kidney function decline. Participants treated with rituximab were at lower risk of developing hypertension (weighted HR 0.24, 95% CI 0.08-0.79).

Using real-world data, there was no difference in relapse rates after rituximab vs calcineurin inhibitors among children and young adults with steroid-sensitive nephrotic syndrome. Steroid-sparing immunosuppression selection should be a shared decision, considering medication-specific side effects, costs, access, duration and adherence.