Balancing Benefits and Risks of Rituximab in Pediatric Idiopathic Nephrotic Syndrome: The Critical Role of Age

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Rituximab is an effective therapeutic option for pediatric idiopathic nephrotic syndrome (NS), significantly reducing relapse rates and steroid exposure in children with frequently relapsing NS and/or steroid-dependent NS (SDNS). However, treatment response and safety profiles vary by age, and important concerns remain regarding long-term safety, particularly in younger children (Figure 1).

Figure 1.

Rituximab is an effective steroid-sparing therapy for pediatric frequently relapsing or steroid-dependent nephrotic syndrome, significantly reducing relapse rates and prolonging remission. Its benefits include durable disease control and improved growth outcomes, with repeated dosing further extending relapse-free intervals. However, safety concerns remain, particularly hypogammaglobulinemia and infection risk, which are more pronounced in younger children. Age is a key factor influencing both efficacy and safety, with older children generally achieving longer remission and fewer adverse events. Careful patient selection, monitoring, and consideration of long-term uncertainties are essential in clinical decision-making.

The principal benefit of rituximab lies in its ability to prevent relapse. In a randomized controlled trial of complicated frequently relapsing NS and/or SDNS, Iijima et al.¹ demonstrated that the median relapse-free survival was significantly longer in the rituximab group than in the placebo group (267, 95% confidence interval [CI]: [223–374] days vs. 101 [70–155] days; hazard ratio: 0.27 [0.14–0.53]; P < 0.0001). A subsequent Japanese randomized placebo-controlled trial confirmed that rituximab significantly reduced relapses during the first year, with sustained effects observed even after B-cell recovery.² Notably, the 3-year cumulative relapse-free survival was 38% in the rituximab group compared with 9% in the placebo group, suggesting durable remission in a subset of patients.

A further major advantage is its steroid-sparing effect. In a randomized controlled trial comparing rituximab with tacrolimus in pediatric SDNS, rituximab markedly reduced cumulative prednisolone exposure over 12 months (25.8 mg/kg vs. 86.3 mg/kg), accompanied by clinically meaningful improvements in growth velocity and body mass index.³ Patients receiving rituximab showed greater improvement in height Z-score at 12 months (0.42 vs. 0.07; P = 0.02), with sustained remission achieved in 90% compared with 60% in the tacrolimus group. In addition, rituximab was associated with fewer adverse events and improved quality of life.

Repeated rituximab administration appears to prolong remission. In an international multicenter study of 346 children, successive doses were associated with progressively longer relapse-free intervals, extending from a median of 10 months after the first dose to 12 to 16 months after subsequent doses.⁴ Renal function remained normal in 96% of patients, and most were able to reduce concomitant immunosuppressive therapy. Importantly, repeated dosing was generally well-tolerated, without evidence of cumulative toxicity.

Hypogammaglobulinemia represents the most common clinically significant adverse effect. A systematic review and meta-analysis reported an incidence of 11.4% (95% CI: 6.4–19.5) among children treated with rituximab for NS, corresponding to a 1.81-fold increased risk compared with controls.⁵ Among 517 reported episodes, 18% were associated with infection, including 4 fatal cases. The median onset was approximately 12 months after treatment, although earlier and later presentations occur. Identified risk factors include younger age at initiation, repeated dosing, and lower baseline immunoglobulin levels.

Infusion-related reactions are common but typically mild to moderate, presenting with symptoms such as nausea, rash, fever, and chills.² These are usually manageable with antihistamines, antipyretics, and reduced infusion rates. Severe reactions, including bronchospasm and hypotension, are rare. Premedication with antihistamines and acetaminophen is routinely recommended.

Despite concerns related to B-cell depletion, infection rates in clinical trials have been reported to be comparable to or lower than those observed with placebo; however, serious and opportunistic infections have been documented in postmarketing settings.⁶

Long-term safety remains a critical area of uncertainty. The Kidney Disease: Improving Global Outcomes 2025 guidelines explicitly state that “there is substantial uncertainty regarding the long-term safety profile of rituximab, particularly in children younger than 7 years and in those receiving repeated doses.”⁶ This reflects limited long-term data, especially regarding immune system development, vaccine responsiveness, and malignancy risk. Careful patient selection and thorough informed consent are therefore essential.

Age is a key determinant of both efficacy and safety. Colucci et al.⁷ reported that children aged ≥ 9.8 years had a significantly lower relapse risk than younger patients (hazard ratio: 0.44; 95% CI: 0.26–0.74). Older children exhibited slower recovery of memory B cells, which correlated with prolonged remission. Age at treatment and baseline memory B-cell levels were the strongest predictors of both relapse and B-cell reconstitution, underscoring the role of immunological maturity.

Conversely, younger age at treatment initiation is associated with increased risk. Children who develop clinically significant hypogammaglobulinemia are younger at first rituximab exposure (median: 8.0 vs. 10.0 years; P = 0.01).⁴ In addition, younger patients demonstrate more rapid reconstitution of B-cell subsets, including memory B cells, which is linked to earlier relapse.⁷

In a recent multinational retrospective cohort study, Chan et al.⁸ analyzed data from 16 pediatric nephrology centers across 10 countries. Each additional month of concomitant immunosuppression following rituximab was associated with a 7% reduction in relapse risk (adjusted hazard ratio: 0.93; 95% CI: 0.89–0.96; P < 0.001). Increasing age showed a trend toward reduced relapse risk (adjusted hazard ratio: 0.76/yr; 95% CI: 0.57–1.03; P = 0.07). The most common adverse events were hypogammaglobulinemia, neutropenia, and infection. Lower baseline IgG levels were associated with subsequent hypogammaglobulinemia. In a secondary analysis comparing younger (aged < 6 years) and older children, younger patients exhibited a trend toward earlier relapse and higher complication rates, although differences were not statistically significant. The authors concluded that rituximab should generally be reserved for patients in whom conventional therapies have failed. Although effective in younger children, its use is associated with shorter remission duration and increased risk of adverse events, creating a therapeutic dilemma.

The Kidney Disease: Improving Global Outcomes 2025 guidelines recommend rituximab as one of several steroid-sparing options for frequently relapsing NS and/or SDNS, alongside calcineurin inhibitors, cyclophosphamide, levamisole, and mycophenolate mofetil.⁶ For SDNS, rituximab is considered a preferred option because of its efficacy and favorable short-term safety profile. Treatment decisions should be individualized, taking into account disease severity, previous treatment response, patient and family preferences, and age-related factors.

Regarding retreatment, Kidney Disease: Improving Global Outcomes recommends limiting repeated dosing to patients who cannot be adequately controlled with calcineurin inhibitors or mycophenolate mofetil. Combination therapy with mycophenolate mofetil may prolong remission and reduce the need for repeated rituximab exposure.^6,9 Although some centers use B-cell–guided strategies for retreatment, optimal protocols remain to be established.

In clinical practice, rituximab use requires a comprehensive, individualized assessment, including age, disease severity, previous therapies, steroid toxicity, patient and family preferences, and risk of adverse effects. In children aged < 7 years, the uncertainty surrounding long-term safety should be explicitly discussed, and alternative therapies carefully considered. Ongoing monitoring for hypogammaglobulinemia and infection is essential, with some experts recommending immunoglobulin assessment every 3 to 6 months following treatment.

Disclosure

The author declared no competing interests.

Declaration of Generative AI and AI-assisted Technologies in the Manuscript Preparation Process

During the preparation of this work, the author used Gemini/free ver. to make Figure 1. After using this tool, the author reviewed and takes full responsibility for the content of the published figure.