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

Abstract

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

Methods: 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.

Results: 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 median 4.9-year (Q1-3 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 HR 0.90, 95%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).

Conclusions: 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.

Keywords: calcineurin inhibitors; focal segmental glomerulosclerosis; minimal change disease; nephrotic syndrome; rituximab.