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PACULit Literature Updates August 2025: Pediatrics

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PACULit Daily Literature Update

Early relapse during B lymphocyte depletion of children with frequently relapse steroid dependent nephrotic syndrome after rituximab treatment

Tu J, Wan L, Li H, Chen C. Early relapse during B lymphocyte depletion of children with frequently relapse steroid dependent nephrotic syndrome after rituximab treatment. BMC Nephrol. 2025;26(1):412. doi:10.1186/s12882-025-04246-5.

Introduction

Steroid-dependent nephrotic syndrome (SDNS) in children poses considerable clinical challenges due to its frequent relapses and reliance on steroids, which carry substantial adverse effects. Rituximab, an anti-CD20 monoclonal antibody that depletes B lymphocytes, has become a key steroid-sparing agent in managing frequently relapsing or steroid-dependent nephrotic syndrome (FRSDNS), offering substantial reduction in relapse rates and steroid exposure.

Despite this therapeutic advance, some children experience early disease relapse even during complete peripheral B-cell depletion, highlighting a potential role for alternative immune pathways, such as T-cell mediated mechanisms, in disease recurrence and challenging traditional treatment paradigms. The present study aimed to characterize clinical features predictive of early relapse during B-cell depletion post-rituximab to guide improved management strategies.

Study Overview

Study Type: Retrospective cohort study comparing two pediatric FRSDNS groups differentiated by relapse status during B-cell depletion

Population: 21 children with frequently relapsing or steroid-dependent nephrotic syndrome; 6 early relapse cases and 15 controls without relapse

Intervention: Rituximab administration with B lymphocyte depletion monitoring

Outcomes: Clinical relapse and steroid dosing patterns during the 1-year post-treatment follow-up

The study focused on baseline immunologic and therapeutic parameters including CD4+ T cell levels and glucocorticoid dosing as potential predictors of relapse during the period of B-cell depletion induced by rituximab.

Key Findings

  • All patients (100%) in the early relapse group had elevated CD4+ T cell levels at baseline versus 47% in the control group (P = 0.046), indicating a statistically significant immune profile difference.
  • The relapse group received significantly lower baseline glucocorticoid dosing (83.3%) compared to controls (26.7%) (P = 0.046), suggesting under-treatment may predispose to early relapse.
  • During the year following rituximab administration, relapse group experienced a median of 1.5 relapses (interquartile range 1 to 2.5), while controls had zero relapses (IQR 0 to 0), a highly significant difference (Z = -3.708, P = 0.000).
  • The study concluded lower glucocorticoid dosing and elevated CD4+ T cell counts at baseline predicted early relapse, with such patients demonstrating poorer rituximab treatment efficacy.

Evidence Synthesis

This study’s findings align with and extend the current understanding of rituximab’s immunologic effects in pediatric steroid-dependent nephrotic syndrome. Critically, relapse during B-cell depletion challenges the classical theory that B cells are the sole drivers, highlighting T-cell mediated disease mechanisms and potential glucocorticoid dosing influence.

Clinical Practice Guidelines

  • Shen et al., 2025: Clinical guidelines underscore rituximab as standard care for pediatric SDNS with recommended dosing and monitoring protocols. However, they acknowledge relapse despite B-cell depletion, reflecting unmet therapeutic challenges. (PMID: 40802032)

Supporting Primary Research

  • Sato et al., 2018: Identified relapse occurrences during peripheral blood B-cell depletion after rituximab, emphasizing a non-B-cell dependent pathogenesis in nephrotic syndrome relapse. (PMID: 28434126)
  • Kanamori et al., 2023: Reported elevated CD4+ and CD8+ T-lymphocytes as predictive markers of relapse post-rituximab in refractory childhood nephrotic syndrome, providing direct corroboration of the source study’s key immunological findings. (PMID: 37095341)

Reviews & Broader Context

  • Chan et al., 2023: Comprehensive review highlighting high relapse rates after rituximab treatment and the urgent need for biomarkers beyond B-cell enumeration to enhance risk stratification and therapeutic individualization. (PMID: 36456193)
Reference Key Finding Clinical Relevance
Shen et al., 2025 (PMID: 40802032) Rituximab established as standard; relapse noted despite B-cell depletion Highlights need for predictors beyond B cells; standardizes care
Sato et al., 2018 (PMID: 28434126) Relapse during B-cell depletion suggests alternate pathophysiology Supports T-cell role; challenges sole B-cell targeting
Kanamori et al., 2023 (PMID: 37095341) Elevated T-cell counts predict relapse post-rituximab in children Direct biomarker candidate; aligns with source study
Chan et al., 2023 (PMID: 36456193) High relapse rates; need for multi-modal biomarker strategies Guides future research and clinical management refinement

Clinical Implications

  • Baseline immunophenotyping including CD4+ T cell assessment may identify children at higher relapse risk despite rituximab B-cell depletion.
  • Optimization of baseline glucocorticoid dosing in conjunction with RTX might reduce early relapse incidence and improve treatment efficacy.
  • Integrating T-cell markers into monitoring protocols could inform personalized therapeutic strategies and guide adjunct immunosuppression.

Strengths & Limitations

Strengths Limitations
Detailed immunologic profiling with baseline CD4+ T lymphocyte quantification Retrospective design limits causality and potential for selection bias
Clear definition of relapse group and comparison cohort Small sample size (N=21) restricts generalizability
Combination of clinical and laboratory data provides integrative insights Unmeasured confounding factors including variations in glucocorticoid tapering protocols

Future Directions

Prospective studies validating CD4+ T cell and glucocorticoid dosing interactions as relapse predictors are essential. Mechanistic research to elucidate T-cell mediated pathways in nephrotic syndrome relapse despite complete B-cell depletion will support development of targeted therapies. Interventional trials integrating T-cell biomarkers into therapeutic algorithms are warranted to optimize individualized patient care.

Conclusion

Early relapse during B lymphocyte depletion after rituximab treatment in pediatric FRSDNS is associated with elevated baseline CD4+ T lymphocyte levels and lower glucocorticoid dosing, indicating a complex immunopathogenesis beyond B-cell targeting.

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References

  1. Shen Q, Xia ZK, Liu JL, Shao LL, Chen QX, Wang HS, et al. Clinical practice guidelines for rituximab treatment in children with steroid-sensitive nephrotic syndrome. World J Pediatr. 2025 Aug 13. doi:10.1007/s12519-025-00957-9. PMID: 40802032.
  2. Sato M, Kamei K, Ogura M, Ishikura K, Ito S. Relapse of nephrotic syndrome during post-rituximab peripheral blood B-lymphocyte depletion. Clin Exp Nephrol. 2018;22(1):110-116. doi:10.1007/s10157-017-1415-8. PMID: 28434126.
  3. Kanamori T, Kamei K, Sato M, Nishi K, Okutsu M, Ishiwa S, et al. CD4+ and CD8+ T-lymphocyte number as predictive marker of relapse after rituximab treatment in childhood-onset refractory nephrotic syndrome. Clin Exp Nephrol. 2023;27(7):622-630. doi:10.1007/s10157-023-02343-z. PMID: 37095341.
  4. Chan EY-H, Yap DY-H, Colucci M, Ma AL-T, Parekh RS, Tullus K. Use of Rituximab in Childhood Idiopathic Nephrotic Syndrome. Clin J Am Soc Nephrol. 2023;18(4):533-548. doi:10.2215/CJN.08570722. PMID: 36456193.
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