Rituximab-induced persistent hypogammaglobulinemia in children with nephrotic syndrome: common or rare?

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In recent years, B-cell targeted therapies (BCTT), especially rituximab (RTX), have become an integral part of management in difficult-to-treat pediatric nephrotic syndrome (NS). They serve as a third-line therapeutic option for both steroid-dependent/frequently relapsing (SD/FR) NS as well as steroid-resistant (SR) NS patients ([1], [2]). With its wide adoption as a treatment option for childhood NS, practitioners have described a growing list of adverse effects. In this editorial, we aim to highlight the risk of transient hypogammaglobulinemia (HGG) and persistent hypogammaglobulinemia (PHGG) post-BCTT in children with NS. NS is the most frequent pediatric glomerular disease, with an incidence of between 1.1 and 16.9 per 100 000 children/year [1]. Ninety percent of cases respond to steroid therapy. Most children experience disease relapses and almost 50% develop frequent relapses or become steroid-dependent. For those children who do not respond to steroids or become dependent/frequent relapsers, second-line therapeutic options such as cyclophosphamide, mycophenolate mofetil, and calcineurin inhibitors are utilized. It has been nearly 20 years since the initial Japanese report demonstrated efficacy of RTX—used then for treatment of post-transplant lymphoproliferative disorder—in treating recurrent NS in the same patient [3]. This report was subsequently followed by prospective studies and approvals from governing bodies, establishing RTX as a therapeutic option for pediatric NS. Consequently, a significant subset of SD/frequently relapsing nephrotic syndrome (FRNS) patients were able to discontinue steroid therapy and/or required less immunosuppressive therapy to maintain remission [4]. RTX is an anti-CD20 chimeric monoclonal antibody that depletes B cells. Since CD20 is found on pre-B cells and B cells but not on antibody-producing plasma cells, it was initially thought that RTX would not significantly affect overall immunoglobulin (Ig) levels. Indeed, in early studies of RTX in autoimmune diseases (AID), HGG was not identified as a major side effect [5]. Subsequently, much larger numbers of AID patients have been treated, with longer follow-up duration, often receiving multiple RTX doses. Post-RTX HGG varies from transient and asymptomatic to persistent with severe clinical consequences [6]. Post-RTX HGG has been reported in 8%–58% of pediatric NS patients [7]. However, PHGG post-RTX in pediatric NS is less frequently encountered and is considered more prevalent in certain adult BCTT populations [8]. It is hypothesized that RTX-related PHGG relates to the prolonged/profound depletion of B cells, subsequently limiting the availability of plasma cell precursors and thereby reducing the normal replacement of mature plasma cells [6]. Hirano et al. reported that 70% of children with NS who developed PHGG post-RTX did not recover immunoglobulin (Ig) levels after an average follow-up of 2.8 years [9]. This suggests significant implications for BCTT use and the need for subsequent Ig replacement therapy (IgRT). Post-BCTT HGG issues are multi-faceted, including variations in Ig monitoring, timing, definitions of HGG and PHGG, clinical impact, and IgRT indications. Despite literature advancing considerably, many questions remain. For example, Choi et al. found only 8% developed HGG, but Igs were only monitored in 31% of patients [10]. Studies may not always clearly differentiate between HGG and PHGG. Inoki et al. highlighted this distinction, reporting that 58.4% developed HGG, while only 22.3% developed PHGG [11]. PHGG was defined as hypogammaglobulinemia persisting for >1 year or until the next RTX administration, while HGG showed recovery in <1-year post-RTX. Table 1 illustrates the variability in PHGG prevalence, which may partly relate to the differing definitions. RTX regimens and dosages also varied considerably. Some studies did not specify the number of doses per course [9]. The cumulative RTX dose may affect PHGG risk, although this was not seen in all studies, most of which were retrospective. Follow-up length and study design also contributed to the variability in reported HGG prevalence. Survey studies have limitations and biases. Another possible confounder is that RTX therapy for NS has evolved significantly (chronological effect) recently, becoming more accessible and widely adopted in guidelines, even with off-label dosing and regimens [12]. Summary of studies examining the prevalence of HGG and PHGG in children with NS treated with Rituximab. AOS, ambispective observational study; CNI, calcineurin inhibitor; FR, frequent relapsing; MC-R, multi-center randomized; MMF, mycophenolate mofetil; OS, observational study; R, retrospective; RCT, randomized control trial; S, survey. Summary of studies examining the prevalence of HGG and PHGG in children with NS treated with Rituximab. AOS, ambispective observational study; CNI, calcineurin inhibitor; FR, frequent relapsing; MC-R, multi-center randomized; MMF, mycophenolate mofetil; OS, observational study; R, retrospective; RCT, randomized control trial; S, survey. Published studies vary widely in reporting concomitant immunosuppressive medication usage, dosage, and whether antibiotic (Pneumocystis jirovecii) prophylaxis was prescribed to children post-BCTT. The clinical impact of HGG/PHGG is not always described, and this needs further data. Inoki et al. reported no difference in infections between PHGG and normogammaglobulinemia groups. Both Inoki et al. and Hirano et al. noted neutropenia as a confounding factor for infections in post-BCTT HGG [9], [13]. Dmytro Ivanov et al. noted 4/29 children with NS required IgRT [14], but IgRT use is not always commented on, and indications vary in the published studies. Although there are IgRT guidelines in autoimmune rheumatic disease, we consider that there is a pressing need for guidelines specific to NS [15]. In children with NS, the complexity differs from other BCTT indications, as Ig levels reflect both BCTT impact on B-cell homeostasis affecting Ig production, and urinary protein loss affecting Ig catabolism. Indeed, Ig levels in NS often increase after BCTT commencement, unlike many other AID [11]. The introduction of novel BCTT, which may produce more profound B-cell depletion, only affirms the need for specific guidelines. Furthermore, to compound matters, a recent clinical trial evaluating immunomodulatory effects of intravenous Ig (IVIg) in combination with RTX [16] reported its results at the 2025 IPNA Congress; addition of monthly IVIg following a single RTX dose did not significantly improve relapse-free survival in children with FRNS/steroid-dependent nephrotic syndrome (SDNS) and did not prevent infection-related adverse events [17]. In our institution, we studied 104 children who received BCTT for autoimmune disease or malignancy. Of these, 40 children (mean age 9.2 ± 3.9 years) received BCTT for NS [30 SDNS, 10 steroid-resistant nephrotic syndrome (SRNS)]. All children in our cohort received RTX therapy while in remission. We did not give routine prophylactic antibiotics post-RTX therapy. Children in our NS BCTT cohort were followed for an average of 31.6 ± 20.0 months, receiving a mean cumulative RTX dose of 1140 ± 545 mg. Baseline Ig results were available in 34/40 (85.0%), and baseline IgG was low in 15/34 (44.1%) patients. While transient HGG was common post-BCTT, this was not our experience with PHGG. Indeed, only 3/40 (7.5%) patient developed PHGG during the study period, whereas no patients required IgRT for recurrent infection. There were no NS patients who developed agranulocytosis related to BCTT. There was no difference in PHGG prevalence between SD/FR and SRNS, two SD/FR, and one SRNS patient. In our institution, RTX therapy is guided by B-cell depletion; all children received a single dose of 375 mg/m2. A second dose after 2 weeks was given only if the CD19+ cells were not depleted (i.e. did not drop below 1%). Repeat dosi

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