Rituximab in Childhood Steroid-dependent Nephrotic Syndrome: A Single-center Experience

Rituximab in Childhood Steroid-dependent Nephrotic Syndrome: A Single-center Experience | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Rituximab in Childhood Steroid-dependent Nephrotic Syndrome: A Single-center Experience Shrouq Badr, Mahmoud Mohi El-Din El-Kersh, Samar Atef Elshafey, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6736011/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Sep, 2025 Read the published version in Egyptian Pediatric Association Gazette → Version 1 posted 14 You are reading this latest preprint version Abstract Background: Most children with idiopathic nephrotic syndrome are steroid-sensitive. However, the majority of them relapse. Unfortunately, 50–70% of relapsers will develop frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome (SDNS). This study focused on the effect and safety of rituximab in childhood SDNS. Methods: This retrospective study included SDNS children who received rituximab from 1/1/2021 to 30/6/2023. Data were collected about age at onset of nephrotic syndrome, age at first rituximab dose, and details of infusions. Time till CD19+B cell repletion and time till relapse post-rituximab, as well as total dose of steroids given per year and duration of remission, one year before and one year after rituximab, were analyzed. Results: Thirty SDNS patients received rituximab treatment at a median age of 9.75 years for the first dose. During a median follow-up period of 19 months, only 16.7% developed complications, mostly allergic reactions, and 47.6% of patients relapsed. No significant correlation was observed between the time till CD19+ B-cell reconstitution and the time till relapse. A significant positive correlation was found between the time till relapse post-rituximab and the duration of nephrotic syndrome before rituximab. However, no similar correlation was found with the age at the first rituximab dose or renal biopsy findings. The total steroid dose (per year) was significantly lower, and the duration of remission was significantly longer in the year after rituximab compared to the year before. Conclusion: Rituximab significantly prolongs the duration of remission and decreases the total steroid doses needed. There is a positive correlation between the time till relapse post-rituximab and the duration of nephrotic syndrome before rituximab. There is no significant difference in relapse incidence with or without routine prophylactic rituximab retreatment after B-cell repletion. Children Nephrotic Rituximab Steroid-dependent Steroid-sparing B-cell depletion Figures Figure 1 Figure 2 Figure 3 BACKGROUND Idiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in childhood. Fortunately, the majority of INS children (between 80–90%) have steroid-sensitive nephrotic syndrome (SSNS). However, 60–80% of patients with SSNS experience relapse, and 50–70% of them will develop frequently relapsing nephrotic syndrome (FRNS) or SDNS [ 1 ]. To minimize the side effects of long-term high-dose steroid therapy in children with FRNS/SDNS, other immunosuppressants are prescribed [ 2 ]. These usually include levamisole, cyclophosphamide, calcineurin inhibitors (CNIs), and mycophenolate mofetil (MMF). However, the lack of efficacy and/or serious side effects of these common steroid-sparing agents highlights the need for alternative options, presumably with a more favorable profile, such as rituximab. Rituximab is a chimeric anti-CD20 monoclonal antibody with documented efficacy in several kidney disorders. It mediates its effects through multiple mechanisms, including B-cell depletion, direct and indirect actions on T-cells, and direct action on podocytes [ 3 ]. Unfortunately, there is currently no consensus on the optimal rituximab dose per treatment (375–1500 mg/m2), the number of infusions per course (1–4), the redosing policy, post-rituximab immunosuppression, or long-term safety [ 4 ]. To address these concerns and considering the known ethnic variations in childhood INS [ 5 ], we studied the clinical profile of rituximab in a cohort of children with SDNS. METHODS This is a retrospective study on children with confirmed SDNS [ 1 ], who received rituximab from 1/1/2021 to 30/6/2023. Children with NS receiving rituximab for other indications (secondary NS or steroid-resistant NS) were excluded. A written informed consent was obtained from the parents or caregivers of the studied children. The study was conducted after approval by the Ethics Committee. All infants receive BCG and HBV vaccines as part of the national immunization program. HBV, HCV, HIV, tuberculosis, and other infections were excluded before prescribing rituximab. A course of 1 to 4 weekly rituximab intravenous infusions at a dose of 375mg/m 2 /infusion was administered until B-cell depletion: B-cells (+ CD19) of < 1% of total lymphocytes at 7 days post-infusion [ 2 ]. Patients received pre-medication consisting of intravenous chlorpheniramine, dexamethasone, and paracetamol 30 minutes before rituximab and were closely monitored for side effects during and after rituximab infusions [ 1 ]. All patients received prophylaxis against Pneumocystis jiroveci with co-trimoxazole, and maintenance immunosuppression with MMF (1200 mg/m 2 ) for at least 6 months post-rituximab. We neither prescribed routine rituximab maintenance after the repletion of CD19 + B-cells nor regularly scheduled 3–6 monthly doses to prolong B-cell depletion. Instead, the decision to prescribe another course of rituximab as maintenance before the occurrence of relapse is based on the history of relapse severity, signs of steroid and other immunosuppressant toxicity, the risk of rituximab complications, and available resources. Similarly, tapering steroids and other immunosuppressants was individualized according to the patients' clinical profiles. Data were collected from patients’ files, including age at onset of nephrotic syndrome, renal histopathology reports, age at first rituximab dose, total dose of steroids given per year before rituximab administration, and duration of remission over one year before rituximab. White blood cell counts, urine protein-to-creatinine ratio, and CD19+/CD20 + B-cells were checked monthly for at least six months after each rituximab course. The time till B-cell repletion and the time till relapse were recorded. The total dose of steroids given per year after rituximab administration and the duration of remission over one year after rituximab were recorded. Statistical analysis Data were analyzed using the IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp). Categorical variables are presented as numbers (percentages), and continuous variables as medians (IQR). The significance of the obtained results was judged at the 5% level. RESULTS As shown in Table 1 , we studied 30 children who had SDNS for a median duration of 5.54 years and were started on rituximab treatment at a median age of 9.75 years. Out of 28 biopsied patients, seventeen (60.7%) had a minimal change pattern. Five patients (16.7%) experienced side effects after rituximab treatment, mostly mild allergic reactions. Only one patient had moderate neutropenia (neutrophil count 0.9×10 9 /L) that persisted until the end of the follow-up period but was not associated with any febrile illness requiring treatment (Table 2 ). During the study period, the 30 patients received a total of 61 rituximab treatment courses (22 patients received 31 retreatment courses). Of the 31 rituximab retreatment courses, 12 courses (38.7%) were prescribed after the occurrence of relapses, while 19 courses were prescribed as relapse prophylaxis after B-cell repletion. Complete depletion of CD19 + B-cells was observed after a single rituximab infusion in all but one (required 2 infusions) course. B-cell repletion occurred at a median of 6 months post-rituximab (IQR 5–7 months). Table 1 Study group characteristics No. % Gender Male 15 50 Female 15 50 Age at onset of nephrotic syndrome (years) Min. – Max. 1.33–10.08 Median (IQR) 3.13 (2.0–5.0) Renal biopsy finding (n = 28) No LM changes 17 60.7 Mesangial proliferation 8 28.6 Focal and segmental glomerulosclerosis 2 7.1 IgM nephropathy 1 3.6 Duration of nephrotic syndrome before rituximab (years) Min. – Max. 1.17–13.08 Median (IQR) 5.54 (3.0–8.0) Age at first rituximab dose (years) Min. – Max. 3.50–13.75 Median (IQR) 9.75 (7.0–12.0) Regarding the efficacy of rituximab during the follow-up period (mean 19.8 ± 8.16 months), the total dose of steroids given per year was significantly lower (Fig. 1a), and the duration of remission was significantly longer (Fig. 1b) in the year after rituximab compared to the year before. In addition, 8 patients (26.7%) could eventually stop all immunosuppressive medications, including steroids, by the end of the follow-up period. However, 14 patients (46.7%) relapsed at a median of 13 months after the first rituximab course (Table 2 ). There was no significant correlation between time till B-cell repletion and time till relapse (Fig. 2a), and two patients relapsed even before B-cell repletion. Those who relapsed and those who did not had similar times till B-cell repletion on the Kaplan-Meier curve (Fig. 2b). Only the duration of nephrotic syndrome before rituximab positively correlated with the time till relapses. However, neither biopsy findings nor age at first rituximab dose showed a similar correlation with the duration until relapses (Table 3 ). Notably, after excluding rituximab retreatment courses administered for actual relapses (12 courses) and the 7 courses in which B-cell repletion did not occur by the end of the study, the remaining 42 courses were evaluated regarding relapse incidence. After 19 courses, rituximab was prescribed as prophylaxis after B-cell repletion (none of these patients experienced relapses). In the remaining 23 courses, where no rituximab was given after B-cell repletion, only 3 patients (13%) relapsed (Fig. 3). This difference was statistically insignificant (p = 0.239), raising questions about the practice of prophylactic rituximab after B-cell repletion. Table 2 Rituximab infusion details No. % Complications 5 16.7 Mild allergic reaction 3 10 Severe allergic reaction 1 3.3 Moderate neutropenia (neutrophil count 0.9×109/L) 1 3.3 Duration of follow-up after starting rituximab treatment (months) Min. – Max. 7–36 Median (IQR) 19 (13-27.75) Time till CD19 and CD20 repletion after all courses (months)* Min. – Max. 2–12 Median (IQR) 6 (5–7) Time till relapse after first rituximab course (months) (n = 14) Min. – Max. 6– 26 Median (IQR) 13 (8–18) *Seven patients did not experience B-cell repletion after their latest rituximab treatment course until the end of the study. Table 3 Correlations of different patient parameters and time till first relapse after starting rituximab treatment Duration till relapse (years) (n = 14) Duration of nephrotic syndrome before rituximab rs = 0.538 P = 0.047* Age at first rituximab dose rs = 0.334 P = 0.243 Renal biopsy findings H = 0.054 P = 0.815 *: Statistically significant at p ≤ 0.05 rs: Spearman coefficient H: H for Kruskal-Wallis test DISCUSSION The clinical course and outcome of childhood FRNS/SDNS are quite heterogeneous, depending on several patient factors. Undoubtedly, these factors would also modify the response to rituximab [ 3 ]. One of the patient variables we studied was the duration of SDNS before rituximab (median 5.54 years), which positively correlated with the time till relapse. One could argue that a longer duration of NS reflects an older age at the first rituximab dose. Although earlier studies did not support this observation [ 4 ], several studies [ 5 – 7 ] reported a higher efficacy of rituximab with older age [ 8 , 9 ]. They explained this through faster repletion of B-cells at younger ages, which increases relapse potential. However, we failed to identify a similar correlation between patients' chronological age at the first rituximab dose and time till relapse, undermining the validity of this explanation. However, a longer duration of NS would imply a more severe disease, with the use of multiple immunosuppressants before rituximab. Such severe disease was often associated with a less favorable response [ 7 , 10 , 11 ]. A possible final argument in this regard would be the historically reported nature of childhood SSNS, where children are less likely to relapse as they grow older from onset [ 12 , 13 ]. In our study, 93.3% of patients underwent a kidney biopsy. In agreement with several studies [ 9 , 14 – 16 ], we have not identified the histopathology as a significant predictor of time till relapse post-rituximab. In terms of dosing, we adopted a rituximab regimen of 1–4 weekly doses (375 mg/m²/dose) per course until B-cell depletion. This was achieved after a single infusion on all but one occasion. Complete B-cell depletion occurred after a single rituximab infusion in 85.7% of Colucci et al [ 17 ] and 10% of Sellier-Leclerc et al [ 18 ] patients. The rituximab regimen prescribed in childhood NS was four weekly infusions of 375 mg/m² each [ 13 ]. Later, rituximab protocols described in the RCTs and retrospective studies of childhood FRNS/SDNS varied in both number of infusions (single, 2, 4, and 7) and dose (between 100–1500 mg/m²/infusion) [ 13 ]. Although earlier studies reported a longer time till relapse with higher doses (1125–1500 mg/m²) [ 4 ], a more recent study showed that only very-low doses (100 mg/m² ) were linked to earlier relapses, while the 750 mg/m² dose was not associated with a better response than 375 mg/m² [ 5 ]. A lower rituximab dose is currently promoted to minimize costs and side effects [ 3 , 13 , 19 , 20 ]. A significant proportion of rituximab-treated SSNS children were reported to relapse within a year [ 7 , 21 , 22 ], and this occurred in 46.7% of our patients (median time till relapse after starting rituximab treatment was 13 months). All children in RITURNS RCT [ 22 ] relapsed within 6–24 months, whereas 82.8% of Chan et al [ 9 ] patients relapsed, and the median time till relapse was 10.0 months after the first rituximab treatment, extending to 16 months after the fourth. The optimal strategy for combating post-rituximab relapses, such as redoing rituximab and post-rituximab immunosuppression, remains controversial, and one should carefully balance relapse control against safety concerns [ 15 ]. Post-rituximab relapses have historically been associated with B-cell recovery [ 5 , 6 , 11 , 21 ]. However, in our study, the median time till B-cell repletion was only 6 months compared to a median time till relapse of 13 months, with no significant correlation between time till B-cell repletion and time till relapse. Moreover, two of our patients relapsed even before B-cell repletion. A similar discrepancy in the temporal relationship between relapse and B-cell repletion has frequently been reported [ 15 , 17 , 23 ]. Sato et al [ 23 ] noted patients who repeatedly relapsed during B-cell depletion, despite multiple rituximab courses and concomitant immunosuppression. These observations [ 15 , 23 ], along with ours, indicate that routine B-cell monitoring, although sometimes helpful, is not a reliable marker to guide rituximab retreatment once repletion occurs. Conversely, some studies supported the routine prescription of rituximab at regular intervals of 3–6 months, regardless of B-cell counts, to induce persistent B-cell depletion [ 24 ]. However, this approach subjects patients to an excessive number of rituximab infusions, with the highest potential for developing anti-rituximab antibodies and persistent hypogammaglobulinemia [ 3 ]. None of our patients received such a regimen of rituximab redosing. In this study, we neither gave maintenance rituximab routinely after B-cell repletion nor as a routine schedule to extend B-cell depletion. Instead, we individualized rituximab retreatment based on the history of relapse severity, signs of steroids and other steroid-sparing agents’ toxicity, risk of rituximab complications, and available resources. Accordingly, 22/30 of our patients (73.3%) received 31 rituximab retreatment courses (up to 3 courses), 12 of these courses were administered after actual relapses (38.7%), while the remaining were prophylactic after B-cell repletion. In Guigonis et al.'s [ 25 ] prospective study, more than half of the patients received rituximab retreatment, mostly as maintenance after B-cell repletion without relapse. In contrast, relapses were the main (87%) indication for redoing rituximab in the Chan et al [ 9 ] multicenter study. In their 2022 SSNS guidelines, the International Pediatric Nephrology Association (IPNA) [ 13 ] introduced the concept of complicated relapse, which is a relapse requiring hospitalization due to one or more of: severe edema, symptomatic hypovolemia or AKI, thrombosis, or severe infections. In addition to frequency and treatment responsiveness, IPNA advised applying this new aspect of relapse classification to guide SSNS management decisions [ 13 ]. We believe our approach in planning rituximab-redosing was very close to this concept. Alternatively, post-rituximab immunosuppression helps to maintain remission without prolonging B-cell depletion from recurrent infusions [ 15 ]. Chan et al [ 7 ] compared 6 rituximab regimens: 375, 750, or 1125–1500 mg/m 2 per course, with or without maintenance immunosuppression (steroids, MMF, and/or CNI for > 6 months). Only the group that received the lowest rituximab dose (375 mg/m 2 ) without maintenance immunosuppression had earlier relapses. Unfortunately, the ideal post-rituximab immunosuppressant has not been established yet [ 6 , 15 ]. Although CNI was reported to be superior to MMF for this purpose [ 26 ], 26 (86.6%) of our patients had already received CNI pre-rituximab, and 15 of them (57.7%) suffered from CNI side effects. Therefore, we opted for MMF post-rituximab maintenance. Although its efficacy was not confirmed in some studies [ 6 , 15 ], prospective RCTs validated the use of MMF after rituximab in children with complicated FRNS/SDNS [ 22 , 27 ]. The ideal therapy of FRNS/SDNS would sustain long remission with minimal steroid toxicity. As for rituximab in our patients with SDNS, these targets were successfully fulfilled. Aligning with other studies [ 14 , 28 , 29 ], our patients maintained longer relapse-free intervals in the post-rituximab year and were exposed to a significantly lower dose of steroids per year. Eight (26.7%) patients could eventually stop all immunosuppressants, including steroids. While all Delbet et al [ 30 ] patients stopped immunosuppression 2 months post-rituximab, this occurred in only 46.67% of the Ruggenenti et al [ 14 ] cohort. Those differences might be due to physician preferences, parents' choices, and the clinical characteristics of the cohort. In agreement with other studies [ 4 , 10 , 11 , 14 , 15 ], allergic reactions were the most frequent rituximab side effects. Over a mean follow-up period of 19.8 ± 8.16 months, none of our patients witnessed severe infections such as the fulminant enterovirus myocarditis and atypical Pneumocystis jiroveci pneumonia previously reported in 7- and 3-year-old patients, respectively [ 31 , 32 ]. Only one patient (3.3%) developed moderate neutropenia (neutrophil count 0.9×10 9 /L). Despite persisting till the end of follow-up, this patient did not develop any infections. The reported incidence of post-rituximab neutropenia ranged from 1.2 to 20% [ 23 , 33 ]. In contrast to our study, Kamei et al [ 34 ] observed agranulocytosis (neutrophil count of < 500/mm 3 ) in 9.6%, more in younger children (6.4 vs 12.5 years), who often suffered febrile illness, requiring antibiotics and granulocyte colony-stimulating factor [ 34 ]. Despite currently lacking a consensus, we applied Pneumocystis jiroveci prophylaxis with co-trimoxazole in all our patients. However, one cannot attribute our low rate of post-rituximab side effects only to Pneumocystis prophylaxis. Indeed, we should highlight that our patients first received rituximab at a remarkably older age (median 9.75 years) than the patients who developed the abovementioned complications [ 31 , 32 , 34 ], aligning with the concerns for rituximab safety in younger children [ 3 ]. This study is limited by the relatively small number of patients, its retrospective nature, and the non-uniform pre-rituximab immunosuppression among our patients. Additionally, we cannot fully and confidently correlate all favorable responses obtained to rituximab, as all patients received post-rituximab MMF immunosuppression. Another limitation of this study is that we did not monitor immunoglobulin levels to address the long-term side effects of persistent hypogammaglobulinemia reported in other studies [ 35 , 36 ]. CONCLUSIONS Rituximab is a promising, relatively safe alternative that can significantly prolong the duration of remission and reduce the cumulative dose, and thus side effects, of steroids and other cytotoxic medications in children with SDNS. Abbreviations CNIs Calcineurin Inhibitors FRNS Frequently relapsing nephrotic syndrome INS Idiopathic nephrotic syndrome MMF Mycophenolate Mofetil SDNS Steroid-dependent nephrotic syndrome SSNS Steroid-sensitive Nephrotic syndrome Declarations Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Research Ethics Committee of the Faculty of Medicine. IRB No.: 00012098-FWA No.: 00018699 (Date: 9/4/2023, Serial No: 0107661) Consent to Participate: Informed consent for participation was obtained from all children’s parents. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author Contribution S.B. Material preparation, followed-up the patients, collected and analyzed the data. M.M.E. designed the study, interpreted the data and revised the final manuscript. S.A.E. was a major contributor in writing and editing the manuscript. N.A. suggested the manuscript’s idea, designed the study, shared in data collection and interpretation and wrote the first draft. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. 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Eur J Pediatr 172(4):513–8. https://doi.org/10.1007/s00431-012-1913-3 Iijima K, Sako M, Oba M, Tanaka S, Hamada R, Sakai T, Ohwada Y, Ninchoji T, Yamamura T, Machida H, et al. (2022) Mycophenolate mofetil after rituximab for childhood-onset complicated frequently-relapsing or steroid-dependent nephrotic syndrome. J Am Soc Nephrol 33(2):401–19. https://doi.org/10.1681/asn.2021050643 Zhu Y, Chen J, Zhang Y, Wang X, Wang J (2024) Immunosuppressive agents for frequently relapsing/steroid-dependent nephrotic syndrome in children: a systematic review and network meta-analysis. Front Immunol 15:1310032. https://doi.org/10.3389/fimmu.2024.1310032 Wang L, Zhu J, Xia M, Hua R, Deng F (2022) Comparison of rituximab, cyclophosphamide, and tacrolimus as first steroid-sparing agents for complicated relapsing/steroid-dependent nephrotic syndrome in children: an evaluation of the health-related quality of life. Arch Med Sci 18(1):275–8. https://doi.org/10.5114/aoms/145587 Delbet JD, Leclerc G, Ulinski T (2019) Idiopathic nephrotic syndrome and rituximab: may we predict circulating B lymphocytes recovery? Pediatr Nephrol 34(3):529–32. https://doi.org/10.1007/s00467-018-4139-4 Sellier-Leclerc AL, Belli E, Guérin V, Dorfmüller P, Deschênes G (2013) Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome. Pediatr Nephrol 28(9):1875–9. https://doi.org/10.1007/s00467-013-2485-9 Sato M, Ito S, Ogura M, Kamei K, Miyairi I, Miyata I, Higuchi M, Matsuoka K (2013) Atypical Pneumocystis jiroveci pneumonia with multiple nodular granulomas after rituximab for refractory nephrotic syndrome. Pediatr Nephrol 28(1):145–9. https://doi.org/10.1007/s00467-012-2286-6 McAtee CL, Lubega J, Underbrink K, Curry K, Msaouel P, Barrow M, Muscal E, Lotze T, Srivaths P, Forbes LR, et al. (2021) Association of rituximab use with adverse events in children, adolescents, and young adults. JAMA Netw Open 4(2):e2036321. https://doi.org/10.1001/jamanetworkopen.2020.36321 Kamei K, Takahashi M, Fuyama M, Saida K, Machida H, Sato M, Ogura M, Ito S (2015) Rituximab-associated agranulocytosis in children with refractory idiopathic nephrotic syndrome: case series and review of literature. Nephrol Dial Transplant 30(1):91–6. https://doi.org/10.1093/ndt/gfu258 Parmentier C, Delbet JD, Decramer S, Boyer O, Hogan J, Ulinski T (2020) Immunoglobulin serum levels in rituximab-treated patients with steroid-dependent nephrotic syndrome. Pediatr Nephrol 35(3):455–62. https://doi.org/10.1007/s00467-019-04398-1 Colucci M, Carsetti R, Serafinelli J, Rocca S, Massella L, Gargiulo A, Lo Russo A, Capponi C, Cotugno N, Porzio O, et al. (2019) Prolonged impairment of immunological memory after anti-CD20 treatment in pediatric idiopathic nephrotic syndrome. Front Immunol 10:1653. https://doi.org/10.3389/fimmu.2019.01653 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 16 Sep, 2025 Read the published version in Egyptian Pediatric Association Gazette → Version 1 posted Editorial decision: Revision requested 17 Jul, 2025 Reviews received at journal 17 Jul, 2025 Reviews received at journal 12 Jul, 2025 Reviews received at journal 10 Jul, 2025 Reviews received at journal 06 Jul, 2025 Reviewers agreed at journal 06 Jul, 2025 Reviewers agreed at journal 03 Jul, 2025 Reviewers agreed at journal 02 Jul, 2025 Reviewers agreed at journal 30 Jun, 2025 Reviews received at journal 29 Jun, 2025 Reviewers agreed at journal 13 Jun, 2025 Reviewers invited by journal 11 Jun, 2025 Submission checks completed at journal 11 Jun, 2025 First submitted to journal 08 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6736011","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":470609595,"identity":"4feff1f2-9277-4854-aac3-b44d7a272ba9","order_by":0,"name":"Shrouq Badr","email":"","orcid":"","institution":"Alexandria University","correspondingAuthor":false,"prefix":"","firstName":"Shrouq","middleName":"","lastName":"Badr","suffix":""},{"id":470609596,"identity":"93f7e4c5-04df-4064-b360-8fd175419ded","order_by":1,"name":"Mahmoud Mohi El-Din El-Kersh","email":"","orcid":"","institution":"Alexandria University","correspondingAuthor":false,"prefix":"","firstName":"Mahmoud","middleName":"Mohi El-Din","lastName":"El-Kersh","suffix":""},{"id":470609597,"identity":"36945226-1893-4e3a-bd7b-8b13824dd7a6","order_by":2,"name":"Samar Atef Elshafey","email":"","orcid":"","institution":"Alexandria University","correspondingAuthor":false,"prefix":"","firstName":"Samar","middleName":"Atef","lastName":"Elshafey","suffix":""},{"id":470609598,"identity":"9fa5c767-d1a3-404f-8a3d-d1a12b3e90d5","order_by":3,"name":"Nancy Abdel-Salam","email":"data:image/png;base64,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","orcid":"","institution":"Alexandria University","correspondingAuthor":true,"prefix":"","firstName":"Nancy","middleName":"","lastName":"Abdel-Salam","suffix":""}],"badges":[],"createdAt":"2025-05-24 00:38:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6736011/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6736011/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s43054-025-00426-y","type":"published","date":"2025-09-16T15:56:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84818751,"identity":"5102aaca-736b-46d8-8f70-8e6c13f9050d","added_by":"auto","created_at":"2025-06-17 15:54:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44790,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6736011/v1/a651d91bacfa0fc6047d0884.png"},{"id":84816940,"identity":"047c9458-3b35-42da-81e2-725d50a840e9","added_by":"auto","created_at":"2025-06-17 15:46:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":94838,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6736011/v1/d8e583174dce6cd83c7417bb.png"},{"id":84818752,"identity":"da96a39e-84db-4be6-87a6-49a507f0e3de","added_by":"auto","created_at":"2025-06-17 15:54:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":55740,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6736011/v1/fcb160f4c26c85af2c24fe9f.png"},{"id":91889802,"identity":"f5e252d0-16a8-4c17-b420-b01f0c265b41","added_by":"auto","created_at":"2025-09-22 16:02:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":912771,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6736011/v1/f708e934-48b9-46a5-8b57-e7bc97d91f99.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eRituximab in Childhood Steroid-dependent Nephrotic Syndrome: A Single-center Experience\u003c/p\u003e","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eIdiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in childhood. Fortunately, the majority of INS children (between 80\u0026ndash;90%) have steroid-sensitive nephrotic syndrome (SSNS). However, 60\u0026ndash;80% of patients with SSNS experience relapse, and 50\u0026ndash;70% of them will develop frequently relapsing nephrotic syndrome (FRNS) or SDNS [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. To minimize the side effects of long-term high-dose steroid therapy in children with FRNS/SDNS, other immunosuppressants are prescribed [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. These usually include levamisole, cyclophosphamide, calcineurin inhibitors (CNIs), and mycophenolate mofetil (MMF). However, the lack of efficacy and/or serious side effects of these common steroid-sparing agents highlights the need for alternative options, presumably with a more favorable profile, such as rituximab.\u003c/p\u003e \u003cp\u003eRituximab is a chimeric anti-CD20 monoclonal antibody with documented efficacy in several kidney disorders. It mediates its effects through multiple mechanisms, including B-cell depletion, direct and indirect actions on T-cells, and direct action on podocytes [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Unfortunately, there is currently no consensus on the optimal rituximab dose per treatment (375\u0026ndash;1500 mg/m2), the number of infusions per course (1\u0026ndash;4), the redosing policy, post-rituximab immunosuppression, or long-term safety [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To address these concerns and considering the known ethnic variations in childhood INS [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], we studied the clinical profile of rituximab in a cohort of children with SDNS.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis is a retrospective study on children with confirmed SDNS [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], who received rituximab from 1/1/2021 to 30/6/2023. Children with NS receiving rituximab for other indications (secondary NS or steroid-resistant NS) were excluded.\u003c/p\u003e \u003cp\u003e A written informed consent was obtained from the parents or caregivers of the studied children. The study was conducted after approval by the Ethics Committee.\u003c/p\u003e \u003cp\u003eAll infants receive BCG and HBV vaccines as part of the national immunization program. HBV, HCV, HIV, tuberculosis, and other infections were excluded before prescribing rituximab.\u003c/p\u003e \u003cp\u003eA course of 1 to 4 weekly rituximab intravenous infusions at a dose of 375mg/m\u003csup\u003e2\u003c/sup\u003e/infusion was administered until B-cell depletion: B-cells (+\u0026thinsp;CD19) of \u0026lt;\u0026thinsp;1% of total lymphocytes at 7 days post-infusion [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Patients received pre-medication consisting of intravenous chlorpheniramine, dexamethasone, and paracetamol 30 minutes before rituximab and were closely monitored for side effects during and after rituximab infusions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. All patients received prophylaxis against Pneumocystis jiroveci with co-trimoxazole, and maintenance immunosuppression with MMF (1200 mg/m\u003csup\u003e2\u003c/sup\u003e) for at least 6 months post-rituximab.\u003c/p\u003e \u003cp\u003eWe neither prescribed routine rituximab maintenance after the repletion of CD19\u0026thinsp;+\u0026thinsp;B-cells nor regularly scheduled 3\u0026ndash;6 monthly doses to prolong B-cell depletion. Instead, the decision to prescribe another course of rituximab as maintenance before the occurrence of relapse is based on the history of relapse severity, signs of steroid and other immunosuppressant toxicity, the risk of rituximab complications, and available resources. Similarly, tapering steroids and other immunosuppressants was individualized according to the patients' clinical profiles.\u003c/p\u003e \u003cp\u003eData were collected from patients\u0026rsquo; files, including age at onset of nephrotic syndrome, renal histopathology reports, age at first rituximab dose, total dose of steroids given per year before rituximab administration, and duration of remission over one year before rituximab.\u003c/p\u003e \u003cp\u003eWhite blood cell counts, urine protein-to-creatinine ratio, and CD19+/CD20\u0026thinsp;+\u0026thinsp;B-cells were checked monthly for at least six months after each rituximab course. The time till B-cell repletion and the time till relapse were recorded. The total dose of steroids given per year after rituximab administration and the duration of remission over one year after rituximab were recorded.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using the IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp). Categorical variables are presented as numbers (percentages), and continuous variables as medians (IQR). The significance of the obtained results was judged at the 5% level.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, we studied 30 children who had SDNS for a median duration of 5.54 years and were started on rituximab treatment at a median age of 9.75 years. Out of 28 biopsied patients, seventeen (60.7%) had a minimal change pattern. Five patients (16.7%) experienced side effects after rituximab treatment, mostly mild allergic reactions. Only one patient had moderate neutropenia (neutrophil count 0.9\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) that persisted until the end of the follow-up period but was not associated with any febrile illness requiring treatment (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eDuring the study period, the 30 patients received a total of 61 rituximab treatment courses (22 patients received 31 retreatment courses). Of the 31 rituximab retreatment courses, 12 courses (38.7%) were prescribed after the occurrence of relapses, while 19 courses were prescribed as relapse prophylaxis after B-cell repletion. Complete depletion of CD19\u0026thinsp;+\u0026thinsp;B-cells was observed after a single rituximab infusion in all but one (required 2 infusions) course. B-cell repletion occurred at a median of 6 months post-rituximab (IQR 5\u0026ndash;7 months).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eStudy group characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo.\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eGender\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at onset of nephrotic syndrome (years)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.33\u0026ndash;10.08\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e3.13 (2.0\u0026ndash;5.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRenal biopsy finding (n\u0026thinsp;=\u0026thinsp;28)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo LM changes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60.7\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMesangial proliferation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28.6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFocal and segmental glomerulosclerosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIgM nephropathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.6\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDuration of nephrotic syndrome before rituximab (years)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.17\u0026ndash;13.08\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.54 (3.0\u0026ndash;8.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at first rituximab dose (years)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.50\u0026ndash;13.75\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.75 (7.0\u0026ndash;12.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eRegarding the efficacy of rituximab during the follow-up period (mean 19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.16 months), the total dose of steroids given per year was significantly lower (Fig.\u0026nbsp;1a), and the duration of remission was significantly longer (Fig.\u0026nbsp;1b) in the year after rituximab compared to the year before. In addition, 8 patients (26.7%) could eventually stop all immunosuppressive medications, including steroids, by the end of the follow-up period. However, 14 patients (46.7%) relapsed at a median of 13 months after the first rituximab course (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). There was no significant correlation between time till B-cell repletion and time till relapse (Fig.\u0026nbsp;2a), and two patients relapsed even before B-cell repletion. Those who relapsed and those who did not had similar times till B-cell repletion on the Kaplan-Meier curve (Fig.\u0026nbsp;2b).\u003c/p\u003e\n\u003cp\u003eOnly the duration of nephrotic syndrome before rituximab positively correlated with the time till relapses. However, neither biopsy findings nor age at first rituximab dose showed a similar correlation with the duration until relapses (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Notably, after excluding rituximab retreatment courses administered for actual relapses (12 courses) and the 7 courses in which B-cell repletion did not occur by the end of the study, the remaining 42 courses were evaluated regarding relapse incidence. After 19 courses, rituximab was prescribed as prophylaxis after B-cell repletion (none of these patients experienced relapses). In the remaining 23 courses, where no rituximab was given after B-cell repletion, only 3 patients (13%) relapsed (Fig.\u0026nbsp;3). This difference was statistically insignificant (p\u0026thinsp;=\u0026thinsp;0.239), raising questions about the practice of prophylactic rituximab after B-cell repletion.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eRituximab infusion details\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNo.\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e%\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eComplications\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e5\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e16.7\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild allergic reaction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere allergic reaction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate neutropenia (neutrophil count 0.9\u0026times;109/L)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDuration of follow-up after starting rituximab treatment (months)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e7\u0026ndash;36\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e19 (13-27.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTime till CD19 and CD20 repletion after all courses (months)*\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e2\u0026ndash;12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e6 (5\u0026ndash;7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTime till relapse after first rituximab course (months) (n\u0026thinsp;=\u0026thinsp;14)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e6\u0026ndash; 26\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMedian (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e13 (8\u0026ndash;18)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e*Seven patients did not experience B-cell repletion after their latest rituximab treatment course until the end of the study.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCorrelations of different patient parameters and time till first relapse after starting rituximab treatment\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eDuration till relapse (years) (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDuration of nephrotic syndrome before rituximab\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ers = 0.538\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.047*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge at first rituximab dose\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ers = 0.334\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.243\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRenal biopsy findings\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eH\u0026thinsp;=\u0026thinsp;0.054\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.815\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003e*: Statistically significant at p\u0026thinsp;\u0026le;\u0026thinsp;0.05 rs: Spearman coefficient H: H for Kruskal-Wallis test\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe clinical course and outcome of childhood FRNS/SDNS are quite heterogeneous, depending on several patient factors. Undoubtedly, these factors would also modify the response to rituximab [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. One of the patient variables we studied was the duration of SDNS before rituximab (median 5.54 years), which positively correlated with the time till relapse. One could argue that a longer duration of NS reflects an older age at the first rituximab dose. Although earlier studies did not support this observation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], several studies [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] reported a higher efficacy of rituximab with older age [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. They explained this through faster repletion of B-cells at younger ages, which increases relapse potential. However, we failed to identify a similar correlation between patients' chronological age at the first rituximab dose and time till relapse, undermining the validity of this explanation. However, a longer duration of NS would imply a more severe disease, with the use of multiple immunosuppressants before rituximab. Such severe disease was often associated with a less favorable response [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A possible final argument in this regard would be the historically reported nature of childhood SSNS, where children are less likely to relapse as they grow older from onset [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our study, 93.3% of patients underwent a kidney biopsy. In agreement with several studies [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], we have not identified the histopathology as a significant predictor of time till relapse post-rituximab.\u003c/p\u003e \u003cp\u003eIn terms of dosing, we adopted a rituximab regimen of 1\u0026ndash;4 weekly doses (375 mg/m\u0026sup2;/dose) per course until B-cell depletion. This was achieved after a single infusion on all but one occasion. Complete B-cell depletion occurred after a single rituximab infusion in 85.7% of Colucci et al [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and 10% of Sellier-Leclerc et al [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] patients. The rituximab regimen prescribed in childhood NS was four weekly infusions of 375 mg/m\u0026sup2; each [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Later, rituximab protocols described in the RCTs and retrospective studies of childhood FRNS/SDNS varied in both number of infusions (single, 2, 4, and 7) and dose (between 100\u0026ndash;1500 mg/m\u0026sup2;/infusion) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Although earlier studies reported a longer time till relapse with higher doses (1125\u0026ndash;1500 mg/m\u0026sup2;) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], a more recent study showed that only very-low doses (100 mg/m\u0026sup2; ) were linked to earlier relapses, while the 750 mg/m\u0026sup2; dose was not associated with a better response than 375 mg/m\u0026sup2; [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. A lower rituximab dose is currently promoted to minimize costs and side effects [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA significant proportion of rituximab-treated SSNS children were reported to relapse within a year [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and this occurred in 46.7% of our patients (median time till relapse after starting rituximab treatment was 13 months). All children in RITURNS RCT [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] relapsed within 6\u0026ndash;24 months, whereas 82.8% of Chan et al [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] patients relapsed, and the median time till relapse was 10.0 months after the first rituximab treatment, extending to 16 months after the fourth. The optimal strategy for combating post-rituximab relapses, such as redoing rituximab and post-rituximab immunosuppression, remains controversial, and one should carefully balance relapse control against safety concerns [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePost-rituximab relapses have historically been associated with B-cell recovery [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, in our study, the median time till B-cell repletion was only 6 months compared to a median time till relapse of 13 months, with no significant correlation between time till B-cell repletion and time till relapse. Moreover, two of our patients relapsed even before B-cell repletion. A similar discrepancy in the temporal relationship between relapse and B-cell repletion has frequently been reported [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Sato et al [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] noted patients who repeatedly relapsed during B-cell depletion, despite multiple rituximab courses and concomitant immunosuppression. These observations [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], along with ours, indicate that routine B-cell monitoring, although sometimes helpful, is not a reliable marker to guide rituximab retreatment once repletion occurs. Conversely, some studies supported the routine prescription of rituximab at regular intervals of 3\u0026ndash;6 months, regardless of B-cell counts, to induce persistent B-cell depletion [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, this approach subjects patients to an excessive number of rituximab infusions, with the highest potential for developing anti-rituximab antibodies and persistent hypogammaglobulinemia [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. None of our patients received such a regimen of rituximab redosing.\u003c/p\u003e \u003cp\u003eIn this study, we neither gave maintenance rituximab routinely after B-cell repletion nor as a routine schedule to extend B-cell depletion. Instead, we individualized rituximab retreatment based on the history of relapse severity, signs of steroids and other steroid-sparing agents\u0026rsquo; toxicity, risk of rituximab complications, and available resources. Accordingly, 22/30 of our patients (73.3%) received 31 rituximab retreatment courses (up to 3 courses), 12 of these courses were administered after actual relapses (38.7%), while the remaining were prophylactic after B-cell repletion. In Guigonis et al.'s [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] prospective study, more than half of the patients received rituximab retreatment, mostly as maintenance after B-cell repletion without relapse. In contrast, relapses were the main (87%) indication for redoing rituximab in the Chan et al [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] multicenter study. In their 2022 SSNS guidelines, the International Pediatric Nephrology Association (IPNA) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] introduced the concept of complicated relapse, which is a relapse requiring hospitalization due to one or more of: severe edema, symptomatic hypovolemia or AKI, thrombosis, or severe infections. In addition to frequency and treatment responsiveness, IPNA advised applying this new aspect of relapse classification to guide SSNS management decisions [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. We believe our approach in planning rituximab-redosing was very close to this concept.\u003c/p\u003e \u003cp\u003eAlternatively, post-rituximab immunosuppression helps to maintain remission without prolonging B-cell depletion from recurrent infusions [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Chan et al [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] compared 6 rituximab regimens: 375, 750, or 1125\u0026ndash;1500 mg/m\u003csup\u003e2\u003c/sup\u003e per course, with or without maintenance immunosuppression (steroids, MMF, and/or CNI for \u0026gt;\u0026thinsp;6 months). Only the group that received the lowest rituximab dose (375 mg/m\u003csup\u003e2\u003c/sup\u003e) without maintenance immunosuppression had earlier relapses. Unfortunately, the ideal post-rituximab immunosuppressant has not been established yet [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Although CNI was reported to be superior to MMF for this purpose [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], 26 (86.6%) of our patients had already received CNI pre-rituximab, and 15 of them (57.7%) suffered from CNI side effects. Therefore, we opted for MMF post-rituximab maintenance. Although its efficacy was not confirmed in some studies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], prospective RCTs validated the use of MMF after rituximab in children with complicated FRNS/SDNS [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe ideal therapy of FRNS/SDNS would sustain long remission with minimal steroid toxicity. As for rituximab in our patients with SDNS, these targets were successfully fulfilled. Aligning with other studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], our patients maintained longer relapse-free intervals in the post-rituximab year and were exposed to a significantly lower dose of steroids per year. Eight (26.7%) patients could eventually stop all immunosuppressants, including steroids. While all Delbet et al [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] patients stopped immunosuppression 2 months post-rituximab, this occurred in only 46.67% of the Ruggenenti et al [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] cohort. Those differences might be due to physician preferences, parents' choices, and the clinical characteristics of the cohort.\u003c/p\u003e \u003cp\u003eIn agreement with other studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], allergic reactions were the most frequent rituximab side effects. Over a mean follow-up period of 19.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.16 months, none of our patients witnessed severe infections such as the fulminant enterovirus myocarditis and atypical Pneumocystis jiroveci pneumonia previously reported in 7- and 3-year-old patients, respectively [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Only one patient (3.3%) developed moderate neutropenia (neutrophil count 0.9\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L). Despite persisting till the end of follow-up, this patient did not develop any infections. The reported incidence of post-rituximab neutropenia ranged from 1.2 to 20% [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In contrast to our study, Kamei et al [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] observed agranulocytosis (neutrophil count of \u0026lt;\u0026thinsp;500/mm\u003csup\u003e3\u003c/sup\u003e) in 9.6%, more in younger children (6.4 vs 12.5 years), who often suffered febrile illness, requiring antibiotics and granulocyte colony-stimulating factor [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Despite currently lacking a consensus, we applied Pneumocystis jiroveci prophylaxis with co-trimoxazole in all our patients. However, one cannot attribute our low rate of post-rituximab side effects only to Pneumocystis prophylaxis. Indeed, we should highlight that our patients first received rituximab at a remarkably older age (median 9.75 years) than the patients who developed the abovementioned complications [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], aligning with the concerns for rituximab safety in younger children [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study is limited by the relatively small number of patients, its retrospective nature, and the non-uniform pre-rituximab immunosuppression among our patients. Additionally, we cannot fully and confidently correlate all favorable responses obtained to rituximab, as all patients received post-rituximab MMF immunosuppression. Another limitation of this study is that we did not monitor immunoglobulin levels to address the long-term side effects of persistent hypogammaglobulinemia reported in other studies [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eRituximab is a promising, relatively safe alternative that can significantly prolong the duration of remission and reduce the cumulative dose, and thus side effects, of steroids and other cytotoxic medications in children with SDNS.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCNIs\u0026nbsp; \u0026nbsp;\u0026nbsp;Calcineurin Inhibitors\u003c/p\u003e\n\u003cp\u003eFRNS\u0026nbsp;\u0026nbsp;Frequently relapsing nephrotic syndrome\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eINS\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Idiopathic nephrotic syndrome\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMMF\u0026nbsp; \u0026nbsp;Mycophenolate Mofetil\u003c/p\u003e\n\u003cp\u003eSDNS\u0026nbsp;\u0026nbsp;Steroid-dependent nephrotic syndrome\u003c/p\u003e\n\u003cp\u003eSSNS \u0026nbsp; Steroid-sensitive Nephrotic syndrome \u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Research Ethics Committee of the Faculty of Medicine. IRB No.: 00012098-FWA No.: 00018699 (Date: 9/4/2023, Serial No: 0107661)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent for participation was obtained from all children\u0026rsquo;s parents.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eS.B. Material preparation, followed-up the patients, collected and analyzed the data. M.M.E. designed the study, interpreted the data and revised the final manuscript. S.A.E. was a major contributor in writing and editing the manuscript. N.A. suggested the manuscript\u0026rsquo;s idea, designed the study, shared in data collection and interpretation and wrote the first draft. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSinha R, Agrawal N, Xue Y, Chanchlani R, Pradhan S, Raina R, Marks SD (2021) Use of rituximab in paediatric nephrology. 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Front Immunol 10:1653. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fimmu.2019.01653\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2019.01653\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"egyptian-pediatric-association-gazette","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"epag","sideBox":"Learn more about [Egyptian Pediatric Association Gazette](https://epag.springeropen.com)","snPcode":"43054","submissionUrl":"https://submission.springernature.com/new-submission/43054/3?","title":"Egyptian Pediatric Association Gazette","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Children, Nephrotic, Rituximab, Steroid-dependent, Steroid-sparing, B-cell depletion","lastPublishedDoi":"10.21203/rs.3.rs-6736011/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6736011/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eMost children with idiopathic nephrotic syndrome are steroid-sensitive. However, the majority of them relapse. Unfortunately, 50–70% of relapsers will develop frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome (SDNS). This study focused on the effect and safety of rituximab in childhood SDNS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis retrospective study included SDNS children who received rituximab from 1/1/2021 to 30/6/2023. Data were collected about age at onset of nephrotic syndrome, age at first rituximab dose, and details of infusions. Time till CD19+B cell repletion and time till relapse post-rituximab, as well as total dose of steroids given per year and duration of remission, one year before and one year after rituximab, were analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThirty SDNS patients received rituximab treatment at a median age of 9.75 years for the first dose. During a median follow-up period of 19 months, only 16.7% developed complications, mostly allergic reactions, and 47.6% of patients relapsed. No significant correlation was observed between the time till CD19+ B-cell reconstitution and the time till relapse. A significant positive correlation was found between the time till relapse post-rituximab and the duration of nephrotic syndrome before rituximab. However, no similar correlation was found with the age at the first rituximab dose or renal biopsy findings. The total steroid dose (per year) was significantly lower, and the duration of remission was significantly longer in the year after rituximab compared to the year before.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Rituximab significantly prolongs the duration of remission and decreases the total steroid doses needed. There is a positive correlation between the time till relapse post-rituximab and the duration of nephrotic syndrome before rituximab. There is no significant difference in relapse incidence with or without routine prophylactic rituximab retreatment after B-cell repletion.\u003c/p\u003e","manuscriptTitle":"Rituximab in Childhood Steroid-dependent Nephrotic Syndrome: A Single-center Experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-17 15:46:41","doi":"10.21203/rs.3.rs-6736011/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-17T19:31:36+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-17T19:19:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-12T05:45:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-10T11:15:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-06T15:48:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"54162431260246661989729953226141294972","date":"2025-07-06T15:37:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65407577868677862416391710300590101428","date":"2025-07-03T16:48:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"83291858512353727928503349725799898281","date":"2025-07-02T21:44:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"11960571699842005377675445408013885499","date":"2025-06-30T05:11:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-29T18:11:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334702572967422428516268501251977145955","date":"2025-06-13T04:10:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-11T12:03:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-11T10:50:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Egyptian Pediatric Association Gazette","date":"2025-06-08T12:25:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"egyptian-pediatric-association-gazette","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"epag","sideBox":"Learn more about [Egyptian Pediatric Association Gazette](https://epag.springeropen.com)","snPcode":"43054","submissionUrl":"https://submission.springernature.com/new-submission/43054/3?","title":"Egyptian Pediatric Association Gazette","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f739eb65-9d89-4f23-a05e-834ab232d283","owner":[],"postedDate":"June 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T16:00:05+00:00","versionOfRecord":{"articleIdentity":"rs-6736011","link":"https://doi.org/10.1186/s43054-025-00426-y","journal":{"identity":"egyptian-pediatric-association-gazette","isVorOnly":false,"title":"Egyptian Pediatric Association Gazette"},"publishedOn":"2025-09-16 15:56:50","publishedOnDateReadable":"September 16th, 2025"},"versionCreatedAt":"2025-06-17 15:46:41","video":"","vorDoi":"10.1186/s43054-025-00426-y","vorDoiUrl":"https://doi.org/10.1186/s43054-025-00426-y","workflowStages":[]},"version":"v1","identity":"rs-6736011","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6736011","identity":"rs-6736011","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}