Use of Rituximab in Childhood Idiopathic Nephrotic Syndrome

Abstract

Rituximab is an established therapy in children with idiopathic nephrotic syndrome to sustain short- to medium-term disease remission and avoid steroid toxicities. Recent trials focus on its use as a first-line agent among those with milder disease severity. Rituximab is used in multidrug refractory nephrotic syndrome and post-transplant disease recurrence, although the evidence is much less substantial. Available data suggest that the treatment response to rituximab depends on various patient factors, dosing regimen, and the concomitant use of maintenance immunosuppression. After repeated treatments, patients are found to have an improving response overall with a longer relapse-free period. The drug effect, however, is not permanent, and 80% of patients eventually relapse and many will require an additional course of rituximab. This underpins the importance of understanding the long-term safety profile on repeated treatments. Although rituximab appears to be generally safe, there are concerns about long-term hypogammaglobulinemia, especially in young children. Reliable immunophenotyping and biomarkers are yet to be discovered to predict treatment success, risk of both rare and severe side effects, e.g. , persistent hypogammaglobulinemia, and guiding of redosing strategy. In this review, we highlight recent advances in the use of rituximab for childhood nephrotic syndrome and how the therapeutic landscape is evolving.

Trial registration: ClinicalTrials.gov NCT03560011 NCT03899103.

Figure 1

Potential immune mechanism of action of rituximab in childhood idiopathic nephrotic syndrome. Rituximab treatment can restore the immune homeostasis of pediatric patients with idiopathic nephrotic syndrome by directly (solid lines) or indirectly (dashed lines) affecting different B- and T-cell subsets. Rituximab directly depletes CD20-expressing transitional, mature, and memory B-cell subsets. In some days, also short-lived plasmablasts/plasma cells, which do not express CD20 antigen, are indirectly depleted due to their limited lifespan. B-cell depletion could affect the production of the described nephrotic syndrome–associated podocyte-damaging autoantibodies such as anti-CD40, anti-UCHL1, and antinephrin IgG^– or cytokines such as IL-4, produced by B cells activated locally in the glomerulus. In addition, B-cell depletion can indirectly modulate the cross talk between B cells and specific T-cell subsets by affecting antigen presentation (MHC class II—TCR complex) and costimulation, resulting in a reduction of effector T cells such as Th2, Th17, T follicular helper (Tfh) cells, and invariant natural killer T (iNKT) cells and in a rise of regulatory T (Treg) cells.^– Created with BioRender.com.

Figure 2

Clinical and immunological factors that determine the treatment outcomes after rituximab therapy in children with frequently relapsing, steroid-dependent nephrotic syndrome. MMF, mycophenolate mofetil.