Persistent Hypogammaglobulinemia is associated with Longer Remission Without Increased Infection Risk in Pediatric Nephrotic Syndrome After Rituximab Therapy

Abstract Background Rituximab-induced hypogammaglobulinemia (HGG) is common in pediatric nephrotic syndrome(NS), yet its heterogeneity—particularly the distinction between transient and persistent forms and the clinical relevance of combined IgG/IgM deficiency—remains poorly understood. This study aimed to characterize HGG subtypes, identify predictors of HGG, and evaluate their associations with relapse-free survival and infection risk. Methods This retrospective study included pediatric patients with steroid-dependent (SD) or frequently relapsing (FR) nephrotic syndrome treated with rituximab at Beijing Children’s Hospital from January 2015 to December 2023. Hypogammaglobulinemia (HGG) was defined as post-rituximab IgG/IgM below the lower limit of the age-specific reference ranges and classified as transient (THGG; resolving within 12 months) or persistent (PHGG;>12 months). Relapse-free survival was defined as no relapse wihtin 2 years post-rituximab. Multivariable logistic regression identified risk factors for THGG/PHGG, and Kaplan-Meier analysis compared relapse-free survival among non-HGG, THGG, and PHGG groups. Results Among 102 pediatric patients with FRNS/SDNS treated with rituximab (RTX), hypogammaglobulinemia (HGG) occurred in 74 (72.5%), comprising transient HGG (THGG; n = 33, 32.4%) and persistent HGG (PHGG; n = 41, 40.2%). Baseline serum IgG levels were significantly higher in the non-HGG group compared with both the THGG (P = 0.001) and PHGG (P = 0.006) groups. Similarly, baseline IgM levels in the non-HGG group were significantly higher than those in the THGG (P = 0.002) and PHGG (P < 0.001) groups, with the THGG group also demonstrating significantly higher IgM than the PHGG group (P = 0.005). Combined IgG/IgM deficiency was significantly more prevalent in the PHGG group [15/41 (36.6%)] than in the THGG group [2/33 (6.1%); P = 0.002].Multivariate logistic regression identified lower baseline IgG (OR = 0.026, 95% CI: 0.004–0.152, P < 0.001) and lower baseline IgM (OR = 0.690, 95% CI: 0.491–0.971, P = 0.033) as independent risk factors for THGG, alongside a greater number of RTX cycles (OR = 1.912, 95% CI: 1.073–3.407, P = 0.028). For PHGG, only the total number of RTX cycles was an independent predictor (OR = 1.616, 95% CI: 1.153–2.267, P = 0.005). Clinically, the relapse rate was inversely associated with HGG duration (non-HGG 50.0% vs. THGG 33.3% vs. PHGG 17.1%; P = 0.015), with Kaplan-Meier analysis confirming significantly superior relapse-free survival in the PHGG group versus the non-HGG group (P = 0.002). Importantly, no significant differences were observed among the three groups in the incidence of frequent infections (P = 0.640) or severe infections requiring hospitalization (P = 0.930). Conclusion Persistent hypogammaglobulinemia (low IgG and/or IgM) after rituximab is associated with a favorable phenotype with extended remission and no excess infection risk, highlighting its role as a clinically actionable biomarker for individualized follow-up in pediatric nephrotic syndrome.