A comparison of two and multiple doses of rituximab in pediatric patients with frequent relapses and steroid- dependent nephrotic syndrome. A single-center study

A comparison of two and multiple doses of rituximab in pediatric patients with frequent relapses and steroid- dependent nephrotic syndrome. 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A single-center study Farah Roujouleh, Nabil Aleysae, Naffa Alharbi, May Salem, Alaa Bamahmoud, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4372759/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim. Compare the efficacy and safety of two different rituximab regimens in children suffering from frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). Methods. We included all pediatric patients diagnosed with FR/SDNS who received two or more doses of rituximab infusions and were followed up for at least 12 months from the initiation of therapy at a single referral center in Saudi Arabia between January 2010 and September 2021. Patients were categorized into two groups: those who received 2 doses (Group A) and those who received 3 or more doses (Group B) of rituximab therapy. The primary outcome was the proportion of patients maintaining remission at 6-, 10-, and 12-month intervals following the beginning of the first course of rituximab therapy. Result. The study included 28 patients, 13 (46.5%) in group A and 15 (53.5%) in group B. The average disease onset was 3 years old. Both groups achieved similar remission rates at various follow-up points (100% at 6 months, then decreasing over time). While relapse rates were similar, the time between relapses was longer in group B (86.6 weeks) compared to group A (55 weeks, p = 0.02). Minor side effects occurred in 6 patients (16%), but none were serious. Conclusion. While two doses of rituximab are comparable in effectiveness to multiple doses over a 12-month period, receiving more than two doses may significantly extend the duration of relapse-free survival. Steroid-dependent/frequently-relapsing nephrotic syndrome Rituximab proteinuria Introduction Idiopathic nephrotic syndrome (INS) is the most common cause of nephrotic syndrome in children. 1 The steroid is administered as the first-line therapy, while other immunosuppressants are used as a second-line drug in combination with the steroid when sufficient efficacy is not achieved with the steroid alone. According to the International Study of Kidney Disease in Children, the standard regimen of steroids includes the administration of prednisolone at a dose of 60 mg/m2/day for 4–6 weeks, followed by 40 mg/m2 (1.5 mg/kg) provide on alternate days for 2–5 months, then gradual dose reduction by 5 mg (10 mg/m2) once a week until total discontinuation of the drug. 2 Despite the fact that 80–90% of children with INS have a successful long-term response to oral steroid therapy (steroid-sensitive), 40% of these patients have repeated flare-ups (frequent relapsers) or become dependent on steroid medication (steroid-dependent). 3 Children with frequent relapses and steroid-dependent nephrotic syndrome (FR/SDNS) can have side effects from long-term steroids therapy such as moon face, systemic infections, hypertension, Cushing's syndrome, obesity, slow growth, poor glucose tolerance, cataracts, and stomach ulcers. Finding effective and long-lasting treatments for children with FR/SDNS continues to be a major focus of research and clinical practice. In modern practice, treatment with steroid-sparing agents and immunosuppressants is carried out in those patients to limit the negative effects of long-term steroid therapy. 4 The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis recommends alkylating agents, levamisole, calcineurin inhibitors (CNIs), and mycophenolate mofetil (MMF) for these patients. 5 Although these steroid-sparing agents are generally effective at preventing relapses in most patients with FR/SDNS, the bulk of these agents also have numerous possible adverse effects that require regular monitoring. Rituximab (RTX), a chimeric monoclonal antibody targeting CD20, plays a key role in the treatment of autoimmune disorders such as nephrotic syndrome, lupus nephritis, and certain vasculitis by rapidly depleting B-cell populations, which are crucial for both disease development and maintaining a healthy immune response. 6–7 RTX is preferred for FR/SDNS treatment due to its potential for longer remission and fewer side effects compared to steroids and alkylating agents, despite variable response rates observed in children with FR/SDNS. 8,9 The 2004 case report by Benz et al. marked the first successful treatment of childhood nephrotic syndrome using RTX, initially administered for idiopathic thrombocytopenia in a child with a history of SDNS, leading to no further relapse of the nephrotic range proteinuria at the time of reporting. 10 Subsequent literature, including studies by Gilbert et al. and Francois et al., has supported the efficacy of RTX in maintaining remission in pediatric FR/SDNS patients. 11,12 Guigonis et al.'s 2008 large-scale study further confirmed this, with a majority of children achieving complete remission after 2–4 doses. 13 Two years later, Gulati et al. found that 20 out of 24 cases with complex SDNS achieved prolonged remission after receiving two doses of RTX therapy. 14 Single doses of RTX have been effective in treating FR/SDNS. 15,16 A randomized controlled trial by Ravani et al. showing a significant 70% reduction in proteinuria compared to standard therapy. 17 However, despite these optimistic evidences, there is still debate over the optimal dose and frequency of RTX administration for children with FR/SDNS. The aim of this study is to compare the therapeutic efficacy and safety of two different RTX treatment schedules administered to pediatric subjects with FR and SDNS. Methods Study design and population Our study is a single-center retrospective analysis comparing two-dose versus multiple-dose RTX treatments in children under 14 with FR/SDNS who followed up for at least 12 months from the initiation of therapy at the King Faisal Specialist Hospital & Research Center-Jeddah (KFSH&RC-J) between January 2010 and September 2021. Patients already on other steroid-sparing medications (CNIs, MMF) were still eligible for the study. Patients who were older than 14 years at the time of diagnosis or first RTX infusion, as well as those with steroid-resistant nephrotic syndrome or congenital nephrotic syndrome, were excluded from the study. The included patients were divided into 2 groups: group A included subjects who received 2 doses, whereas group B included those who received 3 or more doses of RTX. Patient demographics, disease characteristics, medication history, RTX therapy doses, outcomes, and potential adverse effects were systematically recorded. A list of the exact collected data is provided in a pre-identified collection form (see appendix). Three consultant pediatric nephrologists, including the study's primary and co-principal investigators, are part of the associated care team tasked with tracking rituximab's efficacy. The primary investigator and five other study staff members retrieved the necessary information from the KFSH&RC-J database and analyzed it retrospectively. Definitions of nephrotic syndrome relapse, remission, frequent relapse, steroid dependence, and steroid resistance were all in accordance with the KDIGO 2020 guidelines {5}. Dipstick results of proteinuria are expressed semiquantitatively as follows: negative: 0 to < 15 mg/dL, trace: 15 to < 30 mg/dL, 1+: 30 to < 100 mg/dL, 2+: 100 to < 300 mg/dL, 3+: 300 to < 1000 mg/dL, or 4+: ≥1000 mg/dL. The study protocol was approved by the Institutional Review Board of KFSH&RC-J, and the study was conducted in accordance with the Declaration of Helsinki. Outcomes The primary outcome was the proportion of patients maintaining remission at 6, 10, and 12 months after the beginning of the first course of RTX therapy. The secondary outcomes are 1) the mean time to the first relapse in weeks, 2) the overall average duration of the relapse-free period in weeks, and 3) the number of patients who had adverse effects related to the RTX treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Statistical analysis. Categorical variables were compiled into tables and frequencies (percentages). The Shapiro-Wilk test was used to test the normality of the data. The mean and standard deviation (SD) and the independent samples t-test were used in the case of normally distributed variables, while the median, interquartile range (IQR), and Wilcoxon two-sample test were used for the non-normally distributed variables. Fisher’s exact test was used to assess the significance of study parameters on categorical data between the two groups. Significance was assessed at a 5% level. The statistical software SPSS was used to analyze the data. Results Clinical characteristics of the patients Within the initially selected group of 33 candidates for the study, 5 individuals were excluded on the grounds of not fulfilling the inclusion criteria, resulting in a final sample size of 28 pediatric subjects for this research. There were 13 (46.5%) subjects had received the first course as 2 doses (group A) and 15 (53.5%) subjects received a course of 3 or 4 doses (group B) of RTX therapy. The main characteristics of all patients and both groups are summarized in Table 1 . Other than the duration of follow-up after RTX, there is no significant difference in the baseline characteristics of the two groups. Male patients (n = 20) were slightly predominated. All patients were Arabic-ethnic, with disease onset at 1–8 years of age. The median onset age of the disease was 3.0 years (IQR: 2.0–3.5), and the average age at RTX treatment was 9.3 years (SD: ±2.9), with no significant difference between groups A and B. The median duration of nephrotic syndrome before initial RTX therapy was 6.3 (IQR: 3.0–9.5) years. All patients were on steroids or another immunosuppressant (MMF or tacrolimus) or both (Table 1 ) at the time of initiation of RTX therapy. No one in this cohort received cyclophosphamide or cyclosporine. Thirteen (46%) children underwent kidney biopsies. The most prevalent histologic finding was minimal change disease (92%), with a comparable proportion between both groups (Table 2 ). Genetic testing was not done for all the included patients. In our practice, RTX is administered as a single infusion (375 mg/m2) every 1–3 weeks for 2–4 doses, dissolved in saline, and given intravenously over 3–4 hours, with premedication including acetaminophen, diphenhydramine, and methylprednisolone. All patients were in remission (20 with complete and 8 with partial remission) at the time of the first RTX infusion, with a mean baseline serum albumin of 30.1 (SD: ± 10.7) g/L and a mean serum creatinine of 32.6 (SD: ± 11) mmol/L. The mean SD duration of follow-up after RTX therapy was 35.1 (± 14) months for the whole sample, 26.2 (± 9.9) for group A, and 42.9 (± 12.6) months for group B, with a significant difference between both groups (p < 0.001). Table 1 The baseline clinical and histologic characteristics of 28 patients with FR/SDNS. Patients’ characteristics All patients 1 (n = 28) Group A 1 (n = 13) Group B 1 (n = 15) p-value Sex (M: F) ratio 2.50:1 2.25:1 2.75:1 - Age at onset of NS (yrs.) 3.0 (2.0-3.5) 3.0 (3.0–3.0) 3.0 (2.0–5.0) 0. 34 Age at initiation of RTX (yrs) 9.3 ± 2.9 8.8 ± 3.1 9.8 ± 2.8 0.34 Duration of NS (yrs) 6.3 (3.0-9.5) 5.0 (2.0–8.0) 8.0 (4.0–10.0) 0.36 Duration of FU after RTX (mon) 35.1 ± 14.0 26.2 ± 9.9 42.9 ± 12.6 < 0.001 Weight (kg) 36.5 ± 13.4 35.6 ± 16.0 37.3 ± 11.3 0.74 Height (cm) 129.6 ± 14.6 126.2 ± 15.1 132.6 ± 14.0 0.25 BMI 21.2 ± 5.2 21.4 ± 6.2 20.9 ± 4.3 0.81 BSA (± SD) 1.1 (± 0.3) 1.1 (± 0.3) 1.2 (± 0.2) 0.49 Systolic BP mmHg 112.4 ± 9.6 113.4 ± 11.4 111.5 ± 8.2 0.62 Diastolic BP mmHg 64.6 ± 8.6 65.9 ± 9.9 63.6 ± 7.7 0.50 Prednisolone; n (%) 27 (96.4%) 12 (92.3%) 15 (100%) 0.46 Prednisolone dose (mg/m2/day) 16.9 (10.9–27.6) 22.2 (7.5–28.5) 15 (11-26.6) 0.82 Prednisolone with MMF 21 (75.0) 10 (76.9) 11 (73.3) 1.00 Prednisolone with Tacrolimus 3 (10.7) 2 (15.4 1 (6.7) 0.58 MMF and Tacrolimus) 2 (7.1) 2 (15.4) 0 (0.0) 0.21 Only Tacrolimus 1 (3.7) 1 (7.7) 0 (0.0) 0.46 In remission at the initiation of RTX; n (%) 20 (71.4) 11 (84.6) 9 (60.0) 0.22 Hemoglobin; g/L 137.3 ± 15.1 135.4 ± 14.4 138.9 ± 16.1 0.55 White Blood Cells (× 10 9 /L) 8.8 (7.7–11.2) 8.5 (8.0–9.0) 8.8 (7.1–12.0) 0.68 Platelet count (× 10 9 /L) 382.4 ± 88.1 411.8 ± 105.8 357.0 ± 62.4 0.11 Serum creatinine (umol/L) 32.6 ± 11.0 33.0 ± 14.1 32.3 ± 7.9 0.87 Serum albumin (g/L) 30.1 ± 10.7 31.1 ± 10.0 29.3 ± 11.6 0.66 Renal histology 13 (46.4) 7 (53.9) 6 (40.0) - Not done 15 (53.6) 6 (46.1) 9 (60.0) - MCD/FSGS 12/1 7/0 5/1 0.46 Abbreviations: BMI = body mass index; BSA = body surface area; BP = blood pressure; cm = centimeter; F = female; FSGS = focal segmental glomerulosclerosis; kg = kilograms; M = male; MCD = minimum change disease; MMF = mycophenolate mofetil; mon = months; n = number; NS; Nephrotic syndrome, RTX = rituximab; wt = weight; yrs = years Footnote: 1 n(%) or Mean ± SD or Median (IQR) reported according to the distribution of the variable Table 2 Clinical outcome after the first dose of rituximab infusion for both groups Outcome All patients 1 Group A 1 Group B 1 p-value At 6 Months: Total follow-up; n 25 11 13 - Relapsed; n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0.63 Relapse-free; n (%) 25 (100) 12 (100) 13 (100) - At 10 Months Total follow-up; n 23 11 12 - Relapsed; n (%) 3 ( 13 ) 2 ( 18 ) 1 ( 8 ) - Relapse-free; n (%) 20 (87) 9 (82) 11 (92) 0.48 At 12 months Total follow-up; n 27 13 14 - Relapsed; n (%) 4 ( 15 ) 3 ( 23 ) 1 ( 7 ) - Relapse-free; n (%) 23 (85) 10 (77) 13 (92) 0.24 At the last follow-up. Total follow-up; n Relapsed; n (%) Relapse-free; n (%) 27 10 (37) 17 (63) 0 5 (38) 8 (62) 14 5 (36) 9 (64) - - 0.88 Time to the first relapse among relapsers per week; mean (SD) 70.8 (34.5) 55 (11.2) 86.6 (44) 0.15 Overall relapse-free duration per week; median (IQR) 97.5 (70.0-180.0) 76.0 (59.0–97.0) 169.0 (92.5–196.0) 0.02 Time to the first relapse among relapsers per week; mean (SD) 70.8 (34.5) 55 (11.2) 86.6 (44) 0.15 Patients with adverse effects 6 ( 21 ) 3 ( 23 ) 3 ( 20 ) 1.00 Number of adverse events 6 3 3 1.00 Abbreviations : n = number, IQR = interquartile range. Footnotes : 1 n (%) and Mean ± SD or Median (IQR) were reported according to the distribution of the variable among cases whose data were available at the time of each follow-up period. Response to the treatment. The clinical outcomes for all patients and for both groups are shown in Table 2 . For all subjects, data available at the end of the 6-, 10-, and 12-month intervals following initial RTX treatment as well as at the final follow-up showed remission rates of 100%, 87%, 85%, and 63%, respectively. At these respective time endpoints, the remission rates for groups A and B were 100% compared to 100%, 82% compared to 92%, 77% compared to 92%, and 62% compared to 64%, with no notable differences between the groups at any time point. The median (IQR) relapse-free period after the first RTX treatment was 97.5 (70 to 180) weeks. The mean duration to the first relapse among relapsers for the whole sample, group A, and group B, were 70.8, 55, and 86.6 weeks, respectively, without significant difference. The duration of the relapse-free period was notably longer for patients in group B than for those in group A, with durations of 169 vs. 76 weeks, respectively (p = 0.02). Regarding adverse events, six (16%) out of 28 patients experienced adverse events (Table 2 ). There were no significant differences between the two groups regarding the overall incidence of adverse events. All reported adverse events were mild. Only two children had infections, including upper respiratory tract and eyelid infections. One patient had high liver enzymes, normal synthetic liver function, and negative hepatitis serology tests. Other reported adverse events included headaches, blurred vision, and a transient ataxic gait. No one died in this cohort, and no one had acute infusion reactions. Discussion This retrospective study evaluated the outcome of 28 patients with childhood-onset FR/SDNS, and every patient was followed for at least 12 months after RTX treatment. We have shown that RTX, when administered in association with other immunosuppressive agents (CNI or MMF), is efficacious in maintaining a longer proteinuria-free duration and is safe in these patients. We also found that the relapse-free period was prolonged with more frequent doses of RTX infusions. Patients given a 2-dose regimen and those given 3 or 4 doses experienced the same benefits in terms of recurrence rate of the nephrotic range proteinuria. Adverse effects were observed only in 16% of our cases; all of them were mild and transient. The overall relapse-free rates at 6-, 10-, and 12-months post-rituximab therapy in our study are in concordance with several previous observations. In the largest randomized clinical trials, which enrolled 120 children, Basu et al. reported that a single course of 2 infusions of rituximab treatment for SDNS was associated with a relapse-free survival of 100% and 90% at 6-months and 12 months, respectively. 18 Likewise, Kemper et al. analyzed the data of 37 patients and found that 70.3% of them remained in remission after 12 months of initial RTX infusion. 19 Somewhat lower remission rates were observed in some studies. For instance, Ravani et al. reported that 48% of his study cohort (N = 46) who received one- to five doses of RTX were in remission without oral immunosuppressant agents at 6 months, and only 20% were still in remission after 1 year from any RTX treatment. 17 Hogan et al. also found that the one-year relapse-free survival of the entire cohort (n = 61) was 60%. This lower remission rate in previously mentioned studies may be attributed to the definition criteria used to categorize the efficacy or to the fact that RTX was usually administered as a last therapeutic option in included patients who had high disease activity and not responded well to other steroid-sparing therapies. 20 We found that the efficacy of two-dose RTX treatment in FR/SDNS was comparable to the efficacy of multiple doses (≥ 3 doses). Although 10- and 12-month relapse-free survival rates among those receiving multiple doses were higher than the 2-dosing group, the difference did not reach statistical significance. A recent German study demonstrated that there is no association between the number of RTX infusions and the duration of remission. 20 By comparing four doses versus a single dose of RTX, Maxted et al. showed that a single dose of RTX had similar effects on inducing remission at 6-month follow-up. However, it was less effective at 12- and 24-month follow-up periods. 21 Similar to this finding, Ravani et al. showed that there was no significant difference between patients who received two, three, or four RTX infusions. 18 In contrast, Kemper et al. reported that the time to first relapse was significantly shorter in patients receiving one or two compared to three or four doses of RTX infusion. 19 Hogan et al. also reported that one-year relapse-free survival was 59% and 72% in those received a single injection and those received two injections of 375 mg/m2 respectively, therefore, they concluded that there was a trend towards a higher risk of relapse with single dose of RTX in compared to multiple doses (risk rate of 1.67). 20 Although a single dosage of RTX might help patients with refractory FR/SDNS, its ability to prevent relapses was short-lived. Even though some protocols for the administration of RTX have evolved in this direction in recent years, there has been a decrease from four to only two infusions for the first course of RTX therapy. In literature, the median relapse-free intervals is 9 to 40 months, with variations attributed to study designs, patient demographics, and RTX and immunosuppressive treatments. In our study, the overall median relapse-free duration was 97.5 weeks (IQR: 70–180), with the mean time to first relapse at 70.8 weeks, and Group A experienced a notably shorter relapse-free survival compared to Group B (76 vs. 169 weeks). Likewise, Kemper et al. reported a shorter time to first relapse with lower RTX doses, with significant differences between one or two doses (10.3 ± 3.5 months) and three or four doses (23.3 ± 18.7 months). 19 Iijima et al. found a 267-day relapse-free interval with four doses, corroborating the findings of two meta-analyses on improved outcomes with higher doses. 22–24 In concurring with several published reports, we found that RTX is safe in these children. None of our patients developed life-threatening adverse events, and no one had acute infusion reactions. However, a recent systematic review of six RCTs indicated fewer serious adverse reactions to RTX, yet serious complications, including infusion-related reactions, have occurred. 25 The main limitations of our study include the retrospective design, single-center study, small sample size, loss of follow-up of some patients, and the fact that the fact that we didn’t concentrate on maintenance therapy after RTX therapy. Our study included children with FR/SDNS, as this is the group of children most in need of an effective and safe therapeutic option. We also excluded patients with initial steroid resistance due to a higher relapse risk. This patient selection is likely to influence treatment outcomes. Conclusion While two doses of RTX are comparable in effectiveness to multiple doses over a 12-month period, receiving three or four doses may significantly extend the duration of relapse-free survival, suggesting that a higher number of doses could be more beneficial in sustaining longer remission periods. Abbreviations CNIs: Calcineurin Inhibitors F: Female FR/SDNS: Frequent Relapses/Steroid-Dependent Nephrotic Syndrome IQR: Interquartile Range INS: Idiopathic Nephrotic Syndrome KDIGO: The Kidney Disease: Improving Global Outcomes KFSH&RC-J: King Faisal Specialist Hospital & Research Center – Jeddah M: Male MMF: Mycophenolate Mofetil RTX: Rituximab SD: Standard Deviation Declarations Competing Interests. The authors have no competing interests to declare that are relevant to the content of this article. Author Contribution Dr. N.N.A, F.R, and N.A.A conceptualized the study framework. F.R, N.A.A, M.B, A.K, A.A, and R.B, were contribute in the data collection process and offered valuable insights during the manuscript review. A.B,N.N. A, M.S, and made significant contributions to the design of the study, provided critical revisions of the manuscript, and endorsed the final draft for publication. Acknowledgement Our team extends its heartfelt appreciation to the Research Center at KFSH&RC-Jeddah, with special recognition to Nada Alzahrani and Hawazin Abdulbagi for their exceptional research assistance and organizational efforts. Our gratitude also goes to PhD. Emily Heaphy for her significant input in the statistical analysis. We are thankful to the members of our pediatric department's research committee, particularly Dr. Noman Ahmed, for their motivational guidance and valuable insights. Lastly, our profound thanks to Najla Saleh for her generous support. Data Availability Data is provided assupplementary information file References Veltkamp F, Rensma LR, Bouts AHM; LEARNS consortium. Incidence and Relapse of Idiopathic Nephrotic Syndrome: Meta-analysis. Pediatrics. 2021;148(1):e2020029249. doi: 10.1542/peds.2020-029249 . Epub 2021 Jun 30. Lombel RM, Gipson DS, Hodson EM. Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr Nephrol. 2013 Mar. 28(3):415–26. Kyrieleis HA, Löwik MM, Pronk I, Cruysberg HR, Kremer JA, Oyen WJ, van den Heuvel BL, Wetzels JF, Levtchenko EN: Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin J Am Soc Nephrol 2009; 4: 1593–1600 Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9:30. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. Chapter 3: a steroid-sensitive nephrotic syndrome in children. Kidney Int Suppl. 2012;2(2):163–71. Christiane S. Hampe. B Cells in Autoimmune Diseases. Scientifica (Cairo). 2012; 2012: 215308. Kallash M, Smoyer WE, Mahan JD. Rituximab use in the management of childhood nephrotic syndrome. Front Pediatr 2019; 7: 178. Ishikura K, Ikeda M, Hattori S, et al. 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Kidney Int. 2013; 84, 1025–1033; doi: 10.1038/ki.2013.211 Basu B, Sander A, Roy B, et al. Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome: A Randomized Clinical Trial. JAMA Pediatr. 2018;172(8):757–764. doi: 10.1001/jamapediatrics.2018.1323 Kemper MJ, Gellermann J, Habbig S, et al. Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. Nephrol Dial Transplant. 2011;27:1910–1915. Hogan J, Dossier C, Kwon T, et al. Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome. Pediatr Nephrol. 2019;34:253–259. Maxted AP, Dalrymple RA, Chisholm D, McColl J, Tse Y, Christian MT, et al. Low-dose rituximab is no less effective for nephrotic syndrome measured by 12-month outcome. Pediatr Nephrol. 2019;34(5):855–63. Iijima K, Sako M, Nozu K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicenter, double blind, randomized, placebo-controlled trial. Lancet. 2014;384: 1273–1281. Zhao Z, Liao G, Li Y, Zhou S, Zou H. The efficacy and safety of rituximab in treating childhood refractory nephrotic syndrome: a meta-analysis. Sci Rep. 2015;5:8219. https://doi.org/10.1038/srep0 8219 . Maratea D, Bettio M, Corti MG, Montini G, Venturini F. The efficacy and safety of rituximab in treating childhood nephrotic syndrome: an Italian perspective. Ital J Pediatr. 2016;42(1):63. https://doi.org/10.1186/s13052-016-0271-6 . Gao X, Wang Y, Xu Z, Deng H, Yang H, Zhong F. Systematic Review and Meta-Analysis of Rituximab for Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome in Children. Front Pediatr. 2021;9:626323. Additional Declarations No competing interests reported. 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Aleysae","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYFAC5gYwxcbexvCBEcI2IKAFqoyN5xjjDNK0MEikEanFnP1gA8OHP3ZyfJLPEht/7rgnz8DevE2C4Y8dTi2WPYkNjDPbko3ZpNMONvOeKTZs4DlWJsHYloxTi8GBxPbfvA3MiW3S6e2PGdsSEhgkcswkGBuYcWs5/7CB+c+f+vo2yeONjT9BWuTfmAEdVo9by41EoIFshxPYJNgONvCCbeEBamE7jEfLwwbG3rbjhm08aYnNQC0gRrFFYttxPA5LPsDw40+1vHz7MUOQw+T52Q9vvPHhTzVOLZiADUQkkKBhFIyCUTAKRgEmAAB0NFF4ElLj/wAAAABJRU5ErkJggg==","orcid":"","institution":"King Faisal Specialist Hospital and Research Center- Jeddah","correspondingAuthor":true,"prefix":"","firstName":"Nabil","middleName":"","lastName":"Aleysae","suffix":""},{"id":301390148,"identity":"d9053733-bb0e-476f-bc4b-0e725ba5488c","order_by":2,"name":"Naffa Alharbi","email":"","orcid":"","institution":"King Faisal Specialist Hospital and Research Center- Jeddah","correspondingAuthor":false,"prefix":"","firstName":"Naffa","middleName":"","lastName":"Alharbi","suffix":""},{"id":301390149,"identity":"275c3355-cfcd-40d5-af58-b8ccbb9bcc7c","order_by":3,"name":"May Salem","email":"","orcid":"","institution":"King Faisal Specialist Hospital and Research Center- Jeddah","correspondingAuthor":false,"prefix":"","firstName":"May","middleName":"","lastName":"Salem","suffix":""},{"id":301390150,"identity":"ea3ef1d1-0eff-44e7-8014-9224b4effd21","order_by":4,"name":"Alaa Bamahmoud","email":"","orcid":"","institution":"King Faisal Specialist Hospital and Research Center- Jeddah","correspondingAuthor":false,"prefix":"","firstName":"Alaa","middleName":"","lastName":"Bamahmoud","suffix":""},{"id":301390151,"identity":"45aa4d8a-1368-4c01-9838-9a463a1e9c95","order_by":5,"name":"Manal Bajamal","email":"","orcid":"","institution":"King Faisal Specialist Hospital and Research Center- Jeddah","correspondingAuthor":false,"prefix":"","firstName":"Manal","middleName":"","lastName":"Bajamal","suffix":""},{"id":301390152,"identity":"7f3cdffd-ba40-4747-a975-793e62f27df2","order_by":6,"name":"Abdullah Kimawi","email":"","orcid":"","institution":"King Faisal Specialist Hospital and Research Center- Jeddah","correspondingAuthor":false,"prefix":"","firstName":"Abdullah","middleName":"","lastName":"Kimawi","suffix":""},{"id":301390153,"identity":"21d86787-0211-476a-a5d9-b7abb6121216","order_by":7,"name":"Alanoud Almehmadi","email":"","orcid":"","institution":"King Faisal Specialist Hospital and Research Center- Jeddah","correspondingAuthor":false,"prefix":"","firstName":"Alanoud","middleName":"","lastName":"Almehmadi","suffix":""},{"id":301390154,"identity":"af0057ee-b22d-45b7-bdbf-e7ad8f363e17","order_by":8,"name":"Rayan Bawayan","email":"","orcid":"","institution":"King Faisal Specialist Hospital and Research Center- Jeddah","correspondingAuthor":false,"prefix":"","firstName":"Rayan","middleName":"","lastName":"Bawayan","suffix":""}],"badges":[],"createdAt":"2024-05-05 18:23:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4372759/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4372759/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57028852,"identity":"c492e215-fb74-4996-972f-158d128ddba6","added_by":"auto","created_at":"2024-05-23 15:59:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":626567,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4372759/v1/b2e2cdd4-1eaf-435c-af7a-db67e7a75874.pdf"},{"id":56401859,"identity":"8af5fc96-31e5-4f0d-a555-100205f5f6cf","added_by":"auto","created_at":"2024-05-13 16:54:46","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25147,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfile.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4372759/v1/4dd9d2c54cb62e94a76b1733.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A comparison of two and multiple doses of rituximab in pediatric patients with frequent relapses and steroid- dependent nephrotic syndrome. A single-center study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIdiopathic nephrotic syndrome (INS) is the most common cause of nephrotic syndrome in children.\u003csup\u003e1\u003c/sup\u003e The steroid is administered as the first-line therapy, while other immunosuppressants are used as a second-line drug in combination with the steroid when sufficient efficacy is not achieved with the steroid alone. According to the International Study of Kidney Disease in Children, the standard regimen of steroids includes the administration of prednisolone at a dose of 60 mg/m2/day for 4\u0026ndash;6 weeks, followed by 40 mg/m2 (1.5 mg/kg) provide on alternate days for 2\u0026ndash;5 months, then gradual dose reduction by 5 mg (10 mg/m2) once a week until total discontinuation of the drug.\u003csup\u003e2\u003c/sup\u003e Despite the fact that 80\u0026ndash;90% of children with INS have a successful long-term response to oral steroid therapy (steroid-sensitive), 40% of these patients have repeated flare-ups (frequent relapsers) or become dependent on steroid medication (steroid-dependent).\u003csup\u003e3\u003c/sup\u003e Children with frequent relapses and steroid-dependent nephrotic syndrome (FR/SDNS) can have side effects from long-term steroids therapy such as moon face, systemic infections, hypertension, Cushing's syndrome, obesity, slow growth, poor glucose tolerance, cataracts, and stomach ulcers. Finding effective and long-lasting treatments for children with FR/SDNS continues to be a major focus of research and clinical practice. In modern practice, treatment with steroid-sparing agents and immunosuppressants is carried out in those patients to limit the negative effects of long-term steroid therapy.\u003csup\u003e4\u003c/sup\u003e The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis recommends alkylating agents, levamisole, calcineurin inhibitors (CNIs), and mycophenolate mofetil (MMF) for these patients.\u003csup\u003e5\u003c/sup\u003e Although these steroid-sparing agents are generally effective at preventing relapses in most patients with FR/SDNS, the bulk of these agents also have numerous possible adverse effects that require regular monitoring. Rituximab (RTX), a chimeric monoclonal antibody targeting CD20, plays a key role in the treatment of autoimmune disorders such as nephrotic syndrome, lupus nephritis, and certain vasculitis by rapidly depleting B-cell populations, which are crucial for both disease development and maintaining a healthy immune response.\u003csup\u003e6\u0026ndash;7\u003c/sup\u003e RTX is preferred for FR/SDNS treatment due to its potential for longer remission and fewer side effects compared to steroids and alkylating agents, despite variable response rates observed in children with FR/SDNS.\u003csup\u003e8,9\u003c/sup\u003e The 2004 case report by Benz et al. marked the first successful treatment of childhood nephrotic syndrome using RTX, initially administered for idiopathic thrombocytopenia in a child with a history of SDNS, leading to no further relapse of the nephrotic range proteinuria at the time of reporting.\u003csup\u003e10\u003c/sup\u003e Subsequent literature, including studies by Gilbert et al. and Francois et al., has supported the efficacy of RTX in maintaining remission in pediatric FR/SDNS patients.\u003csup\u003e11,12\u003c/sup\u003e Guigonis et al.'s 2008 large-scale study further confirmed this, with a majority of children achieving complete remission after 2\u0026ndash;4 doses.\u003csup\u003e13\u003c/sup\u003e Two years later, Gulati et al. found that 20 out of 24 cases with complex SDNS achieved prolonged remission after receiving two doses of RTX therapy.\u003csup\u003e14\u003c/sup\u003e Single doses of RTX have been effective in treating FR/SDNS.\u003csup\u003e15,16\u003c/sup\u003e A randomized controlled trial by Ravani et al. showing a significant 70% reduction in proteinuria compared to standard therapy.\u003csup\u003e17\u003c/sup\u003e However, despite these optimistic evidences, there is still debate over the optimal dose and frequency of RTX administration for children with FR/SDNS.\u003c/p\u003e \u003cp\u003eThe aim of this study is to compare the therapeutic efficacy and safety of two different RTX treatment schedules administered to pediatric subjects with FR and SDNS.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eOur study is a single-center retrospective analysis comparing two-dose versus multiple-dose RTX treatments in children under 14 with FR/SDNS who followed up for at least 12 months from the initiation of therapy at the King Faisal Specialist Hospital \u0026amp; Research Center-Jeddah (KFSH\u0026amp;RC-J) between January 2010 and September 2021. Patients already on other steroid-sparing medications (CNIs, MMF) were still eligible for the study. Patients who were older than 14 years at the time of diagnosis or first RTX infusion, as well as those with steroid-resistant nephrotic syndrome or congenital nephrotic syndrome, were excluded from the study. The included patients were divided into 2 groups: group A included subjects who received 2 doses, whereas group B included those who received 3 or more doses of RTX. Patient demographics, disease characteristics, medication history, RTX therapy doses, outcomes, and potential adverse effects were systematically recorded. A list of the exact collected data is provided in a pre-identified collection form (see appendix). Three consultant pediatric nephrologists, including the study's primary and co-principal investigators, are part of the associated care team tasked with tracking rituximab's efficacy. The primary investigator and five other study staff members retrieved the necessary information from the KFSH\u0026amp;RC-J database and analyzed it retrospectively. Definitions of nephrotic syndrome relapse, remission, frequent relapse, steroid dependence, and steroid resistance were all in accordance with the KDIGO 2020 guidelines {5}. Dipstick results of proteinuria are expressed semiquantitatively as follows: negative: 0 to \u0026lt;\u0026thinsp;15 mg/dL, trace: 15 to \u0026lt;\u0026thinsp;30 mg/dL, 1+: 30 to \u0026lt;\u0026thinsp;100 mg/dL, 2+: 100 to \u0026lt;\u0026thinsp;300 mg/dL, 3+: 300 to \u0026lt;\u0026thinsp;1000 mg/dL, or 4+: \u0026ge;1000 mg/dL. The study protocol was approved by the Institutional Review Board of KFSH\u0026amp;RC-J, and the study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome was the proportion of patients maintaining remission at 6, 10, and 12 months after the beginning of the first course of RTX therapy. The secondary outcomes are 1) the mean time to the first relapse in weeks, 2) the overall average duration of the relapse-free period in weeks, and 3) the number of patients who had adverse effects related to the RTX treatment. Safety was assessed using the Common Terminology Criteria for Adverse Events, version 4.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis.\u003c/h2\u003e \u003cp\u003eCategorical variables were compiled into tables and frequencies (percentages). The Shapiro-Wilk test was used to test the normality of the data. The mean and standard deviation (SD) and the independent samples t-test were used in the case of normally distributed variables, while the median, interquartile range (IQR), and Wilcoxon two-sample test were used for the non-normally distributed variables. Fisher\u0026rsquo;s exact test was used to assess the significance of study parameters on categorical data between the two groups. Significance was assessed at a 5% level. The statistical software SPSS was used to analyze the data.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eClinical characteristics of the patients\u003c/h2\u003e \u003cp\u003eWithin the initially selected group of 33 candidates for the study, 5 individuals were excluded on the grounds of not fulfilling the inclusion criteria, resulting in a final sample size of 28 pediatric subjects for this research. There were 13 (46.5%) subjects had received the first course as 2 doses (group A) and 15 (53.5%) subjects received a course of 3 or 4 doses (group B) of RTX therapy. The main characteristics of all patients and both groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Other than the duration of follow-up after RTX, there is no significant difference in the baseline characteristics of the two groups. Male patients (n\u0026thinsp;=\u0026thinsp;20) were slightly predominated. All patients were Arabic-ethnic, with disease onset at 1\u0026ndash;8 years of age. The median onset age of the disease was 3.0 years (IQR: 2.0\u0026ndash;3.5), and the average age at RTX treatment was 9.3 years (SD: \u0026plusmn;2.9), with no significant difference between groups A and B. The median duration of nephrotic syndrome before initial RTX therapy was 6.3 (IQR: 3.0\u0026ndash;9.5) years. All patients were on steroids or another immunosuppressant (MMF or tacrolimus) or both (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) at the time of initiation of RTX therapy. No one in this cohort received cyclophosphamide or cyclosporine. Thirteen (46%) children underwent kidney biopsies. The most prevalent histologic finding was minimal change disease (92%), with a comparable proportion between both groups (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Genetic testing was not done for all the included patients. In our practice, RTX is administered as a single infusion (375 mg/m2) every 1\u0026ndash;3 weeks for 2\u0026ndash;4 doses, dissolved in saline, and given intravenously over 3\u0026ndash;4 hours, with premedication including acetaminophen, diphenhydramine, and methylprednisolone. All patients were in remission (20 with complete and 8 with partial remission) at the time of the first RTX infusion, with a mean baseline serum albumin of 30.1 (SD: \u0026plusmn; 10.7) g/L and a mean serum creatinine of 32.6 (SD: \u0026plusmn; 11) mmol/L. The mean SD duration of follow-up after RTX therapy was 35.1 (\u0026plusmn;\u0026thinsp;14) months for the whole sample, 26.2 (\u0026plusmn;\u0026thinsp;9.9) for group A, and 42.9 (\u0026plusmn;\u0026thinsp;12.6) months for group B, with a significant difference between both groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe baseline clinical and histologic characteristics of 28 patients with FR/SDNS.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients\u0026rsquo; characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup A\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup B\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (M: F) ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.50:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.25:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.75:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at onset of NS (yrs.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.0 (2.0-3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0 (3.0\u0026ndash;3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.0 (2.0\u0026ndash;5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.\u0026nbsp;34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at initiation of RTX (yrs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of NS (yrs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.3 (3.0-9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0 (2.0\u0026ndash;8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.0 (4.0\u0026ndash;10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of FU after RTX (mon)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.3\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e129.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e126.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBSA (\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1 (\u0026plusmn;\u0026thinsp;0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1 (\u0026plusmn;\u0026thinsp;0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.2 (\u0026plusmn;\u0026thinsp;0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystolic BP mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e112.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e113.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e111.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiastolic BP mmHg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.6\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63.6\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrednisolone; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (96.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (92.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrednisolone dose (mg/m2/day)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.9 (10.9\u0026ndash;27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.2 (7.5\u0026ndash;28.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (11-26.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrednisolone with MMF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (76.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (73.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrednisolone with Tacrolimus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (15.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (6.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMF and Tacrolimus)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnly Tacrolimus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn remission at the initiation of RTX; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (71.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (84.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin; g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e135.4\u0026thinsp;\u0026plusmn;\u0026thinsp;14.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e138.9\u0026thinsp;\u0026plusmn;\u0026thinsp;16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite Blood Cells (\u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.8 (7.7\u0026ndash;11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5 (8.0\u0026ndash;9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.8 (7.1\u0026ndash;12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet count (\u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e382.4\u0026thinsp;\u0026plusmn;\u0026thinsp;88.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e411.8\u0026thinsp;\u0026plusmn;\u0026thinsp;105.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e357.0\u0026thinsp;\u0026plusmn;\u0026thinsp;62.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum creatinine (umol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.3\u0026thinsp;\u0026plusmn;\u0026thinsp;7.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum albumin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.3\u0026thinsp;\u0026plusmn;\u0026thinsp;11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal histology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (46.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (53.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot done\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (53.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (46.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCD/FSGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAbbreviations: BMI\u0026thinsp;=\u0026thinsp;body mass index; BSA\u0026thinsp;=\u0026thinsp;body surface area; BP\u0026thinsp;=\u0026thinsp;blood pressure; cm\u0026thinsp;=\u0026thinsp;centimeter; F\u0026thinsp;=\u0026thinsp;female; FSGS\u0026thinsp;=\u0026thinsp;focal segmental glomerulosclerosis; kg\u0026thinsp;=\u0026thinsp;kilograms; M\u0026thinsp;=\u0026thinsp;male; MCD\u0026thinsp;=\u0026thinsp;minimum change disease; MMF\u0026thinsp;=\u0026thinsp;mycophenolate mofetil; mon\u0026thinsp;=\u0026thinsp;months; n\u0026thinsp;=\u0026thinsp;number; NS; Nephrotic syndrome, RTX\u0026thinsp;=\u0026thinsp;rituximab; wt\u0026thinsp;=\u0026thinsp;weight; yrs\u0026thinsp;=\u0026thinsp;years\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eFootnote: 1 n(%) or Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or Median (IQR) reported according to the distribution of the variable\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical outcome after the first dose of rituximab infusion for both groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup A\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup B\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt 6 Months:\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal follow-up; n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapsed; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.63\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse-free; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAt 10 Months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal follow-up; n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapsed; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse-free; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAt 12 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal follow-up; n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapsed; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse-free; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAt the last follow-up.\u003c/p\u003e \u003cp\u003eTotal follow-up; n\u003c/p\u003e \u003cp\u003eRelapsed; n (%)\u003c/p\u003e \u003cp\u003eRelapse-free; n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003cp\u003e10 (37)\u003c/p\u003e \u003cp\u003e17 (63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e5 (38)\u003c/p\u003e \u003cp\u003e8 (62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003cp\u003e5 (36)\u003c/p\u003e \u003cp\u003e9 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime to the first relapse among relapsers per week; mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.8 (34.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86.6 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOverall relapse-free duration per week; median (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97.5\u003c/p\u003e \u003cp\u003e(70.0-180.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.0\u003c/p\u003e \u003cp\u003e(59.0\u0026ndash;97.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e169.0\u003c/p\u003e \u003cp\u003e(92.5\u0026ndash;196.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime to the first relapse among relapsers per week; mean (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.8 (34.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55 (11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86.6 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.15\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatients with adverse effects\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.00\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of adverse events\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e1.00\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: \u003cem\u003en\u0026thinsp;=\u0026thinsp;number, IQR\u0026thinsp;=\u0026thinsp;interquartile range.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eFootnotes\u003c/b\u003e: \u003cem\u003e1 n (%) and Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or Median (IQR) were reported according to the distribution of the variable among cases whose data were available at the time of each follow-up period.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eResponse to the treatment.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe clinical outcomes for all patients and for both groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. For all subjects, data available at the end of the 6-, 10-, and 12-month intervals following initial RTX treatment as well as at the final follow-up showed remission rates of 100%, 87%, 85%, and 63%, respectively. At these respective time endpoints, the remission rates for groups A and B were 100% compared to 100%, 82% compared to 92%, 77% compared to 92%, and 62% compared to 64%, with no notable differences between the groups at any time point. The median (IQR) relapse-free period after the first RTX treatment was 97.5 (70 to 180) weeks. The mean duration to the first relapse among relapsers for the whole sample, group A, and group B, were 70.8, 55, and 86.6 weeks, respectively, without significant difference. The duration of the relapse-free period was notably longer for patients in group B than for those in group A, with durations of 169 vs. 76 weeks, respectively (p\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e \u003cp\u003eRegarding adverse events, six (16%) out of 28 patients experienced adverse events (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There were no significant differences between the two groups regarding the overall incidence of adverse events. All reported adverse events were mild. Only two children had infections, including upper respiratory tract and eyelid infections. One patient had high liver enzymes, normal synthetic liver function, and negative hepatitis serology tests. Other reported adverse events included headaches, blurred vision, and a transient ataxic gait. No one died in this cohort, and no one had acute infusion reactions.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e This retrospective study evaluated the outcome of 28 patients with childhood-onset FR/SDNS, and every patient was followed for at least 12 months after RTX treatment. We have shown that RTX, when administered in association with other immunosuppressive agents (CNI or MMF), is efficacious in maintaining a longer proteinuria-free duration and is safe in these patients. We also found that the relapse-free period was prolonged with more frequent doses of RTX infusions. Patients given a 2-dose regimen and those given 3 or 4 doses experienced the same benefits in terms of recurrence rate of the nephrotic range proteinuria. Adverse effects were observed only in 16% of our cases; all of them were mild and transient.\u003c/p\u003e \u003cp\u003eThe overall relapse-free rates at 6-, 10-, and 12-months post-rituximab therapy in our study are in concordance with several previous observations. In the largest randomized clinical trials, which enrolled 120 children, Basu et al. reported that a single course of 2 infusions of rituximab treatment for SDNS was associated with a relapse-free survival of 100% and 90% at 6-months and 12 months, respectively.\u003csup\u003e18\u003c/sup\u003e Likewise, Kemper et al. analyzed the data of 37 patients and found that 70.3% of them remained in remission after 12 months of initial RTX infusion.\u003csup\u003e19\u003c/sup\u003e Somewhat lower remission rates were observed in some studies. For instance, Ravani et al. reported that 48% of his study cohort (N\u0026thinsp;=\u0026thinsp;46) who received one- to five doses of RTX were in remission without oral immunosuppressant agents at 6 months, and only 20% were still in remission after 1 year from any RTX treatment.\u003csup\u003e17\u003c/sup\u003e Hogan et al. also found that the one-year relapse-free survival of the entire cohort (n\u0026thinsp;=\u0026thinsp;61) was 60%. This lower remission rate in previously mentioned studies may be attributed to the definition criteria used to categorize the efficacy or to the fact that RTX was usually administered as a last therapeutic option in included patients who had high disease activity and not responded well to other steroid-sparing therapies.\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe found that the efficacy of two-dose RTX treatment in FR/SDNS was comparable to the efficacy of multiple doses (\u0026ge;\u0026thinsp;3 doses). Although 10- and 12-month relapse-free survival rates among those receiving multiple doses were higher than the 2-dosing group, the difference did not reach statistical significance. A recent German study demonstrated that there is no association between the number of RTX infusions and the duration of remission.\u003csup\u003e20\u003c/sup\u003e By comparing four doses versus a single dose of RTX, Maxted et al. showed that a single dose of RTX had similar effects on inducing remission at 6-month follow-up. However, it was less effective at 12- and 24-month follow-up periods.\u003csup\u003e21\u003c/sup\u003e Similar to this finding, Ravani et al. showed that there was no significant difference between patients who received two, three, or four RTX infusions.\u003csup\u003e18\u003c/sup\u003e In contrast, Kemper et al. reported that the time to first relapse was significantly shorter in patients receiving one or two compared to three or four doses of RTX infusion.\u003csup\u003e19\u003c/sup\u003e Hogan et al. also reported that one-year relapse-free survival was 59% and 72% in those received a single injection and those received two injections of 375 mg/m2 respectively, therefore, they concluded that there was a trend towards a higher risk of relapse with single dose of RTX in compared to multiple doses (risk rate of 1.67).\u003csup\u003e20\u003c/sup\u003e Although a single dosage of RTX might help patients with refractory FR/SDNS, its ability to prevent relapses was short-lived. Even though some protocols for the administration of RTX have evolved in this direction in recent years, there has been a decrease from four to only two infusions for the first course of RTX therapy.\u003c/p\u003e \u003cp\u003eIn literature, the median relapse-free intervals is 9 to 40 months, with variations attributed to study designs, patient demographics, and RTX and immunosuppressive treatments. In our study, the overall median relapse-free duration was 97.5 weeks (IQR: 70\u0026ndash;180), with the mean time to first relapse at 70.8 weeks, and Group A experienced a notably shorter relapse-free survival compared to Group B (76 vs. 169 weeks). Likewise, Kemper et al. reported a shorter time to first relapse with lower RTX doses, with significant differences between one or two doses (10.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5 months) and three or four doses (23.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7 months).\u003csup\u003e19\u003c/sup\u003e Iijima et al. found a 267-day relapse-free interval with four doses, corroborating the findings of two meta-analyses on improved outcomes with higher doses. \u003csup\u003e22\u0026ndash;24\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn concurring with several published reports, we found that RTX is safe in these children. None of our patients developed life-threatening adverse events, and no one had acute infusion reactions. However, a recent systematic review of six RCTs indicated fewer serious adverse reactions to RTX, yet serious complications, including infusion-related reactions, have occurred.\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe main limitations of our study include the retrospective design, single-center study, small sample size, loss of follow-up of some patients, and the fact that the fact that we didn\u0026rsquo;t concentrate on maintenance therapy after RTX therapy. Our study included children with FR/SDNS, as this is the group of children most in need of an effective and safe therapeutic option. We also excluded patients with initial steroid resistance due to a higher relapse risk. This patient selection is likely to influence treatment outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWhile two doses of RTX are comparable in effectiveness to multiple doses over a 12-month period, receiving three or four doses may significantly extend the duration of relapse-free survival, suggesting that a higher number of doses could be more beneficial in sustaining longer remission periods.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCNIs: Calcineurin Inhibitors\u003c/p\u003e\n\u003cp\u003eF: Female\u003c/p\u003e\n\u003cp\u003eFR/SDNS: Frequent Relapses/Steroid-Dependent Nephrotic Syndrome\u003c/p\u003e\n\u003cp\u003eIQR: Interquartile Range\u003c/p\u003e\n\u003cp\u003eINS: Idiopathic Nephrotic Syndrome\u003c/p\u003e\n\u003cp\u003eKDIGO: The Kidney Disease: Improving Global Outcomes\u003c/p\u003e\n\u003cp\u003eKFSH\u0026amp;RC-J: King Faisal Specialist Hospital \u0026amp; Research Center \u0026ndash; Jeddah\u003c/p\u003e\n\u003cp\u003eM: Male\u003c/p\u003e\n\u003cp\u003eMMF: Mycophenolate Mofetil\u003c/p\u003e\n\u003cp\u003eRTX: Rituximab\u003c/p\u003e\n\u003cp\u003eSD: Standard Deviation\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests.\u003c/strong\u003e \u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDr. N.N.A, F.R, and N.A.A conceptualized the study framework. F.R, N.A.A, M.B, A.K, A.A, and R.B, were contribute in the data collection process and offered valuable insights during the manuscript review. A.B,N.N. A, M.S, and made significant contributions to the design of the study, provided critical revisions of the manuscript, and endorsed the final draft for publication.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eOur team extends its heartfelt appreciation to the Research Center at KFSH\u0026amp;RC-Jeddah, with special recognition to Nada Alzahrani and Hawazin Abdulbagi for their exceptional research assistance and organizational efforts. Our gratitude also goes to PhD. Emily Heaphy for her significant input in the statistical analysis. We are thankful to the members of our pediatric department's research committee, particularly Dr. Noman Ahmed, for their motivational guidance and valuable insights. Lastly, our profound thanks to Najla Saleh for her generous support.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided assupplementary information file\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVeltkamp F, Rensma LR, Bouts AHM; LEARNS consortium. Incidence and Relapse of Idiopathic Nephrotic Syndrome: Meta-analysis. Pediatrics. 2021;148(1):e2020029249. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1542/peds.2020-029249\u003c/span\u003e\u003cspan address=\"10.1542/peds.2020-029249\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2021 Jun 30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLombel RM, Gipson DS, Hodson EM. Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. 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Front Pediatr. 2021;9:626323.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Steroid-dependent/frequently-relapsing nephrotic syndrome, Rituximab, proteinuria","lastPublishedDoi":"10.21203/rs.3.rs-4372759/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4372759/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAim.\u003c/h2\u003e \u003cp\u003eCompare the efficacy and safety of two different rituximab regimens in children suffering from frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS).\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e \u003cp\u003eWe included all pediatric patients diagnosed with FR/SDNS who received two or more doses of rituximab infusions and were followed up for at least 12 months from the initiation of therapy at a single referral center in Saudi Arabia between January 2010 and September 2021. Patients were categorized into two groups: those who received 2 doses (Group A) and those who received 3 or more doses (Group B) of rituximab therapy. The primary outcome was the proportion of patients maintaining remission at 6-, 10-, and 12-month intervals following the beginning of the first course of rituximab therapy.\u003c/p\u003e\u003ch2\u003eResult.\u003c/h2\u003e \u003cp\u003eThe study included 28 patients, 13 (46.5%) in group A and 15 (53.5%) in group B. The average disease onset was 3 years old. Both groups achieved similar remission rates at various follow-up points (100% at 6 months, then decreasing over time). While relapse rates were similar, the time between relapses was longer in group B (86.6 weeks) compared to group A (55 weeks, p\u0026thinsp;=\u0026thinsp;0.02). Minor side effects occurred in 6 patients (16%), but none were serious. Conclusion. While two doses of rituximab are comparable in effectiveness to multiple doses over a 12-month period, receiving more than two doses may significantly extend the duration of relapse-free survival.\u003c/p\u003e","manuscriptTitle":"A comparison of two and multiple doses of rituximab in pediatric patients with frequent relapses and steroid- dependent nephrotic syndrome. 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