{"paper_id":"0a1ffe7b-b09a-40f4-9f6f-0623c74fb80d","body_text":"Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset refractory steroid-resistant nephrotic syndrome: a multicenter study | 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 Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset refractory steroid-resistant nephrotic syndrome: a multicenter study Shunsuke Yokota, Koichi Kamei, Shuichiro Fujinaga, Riku Hamada, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3972976/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background The efficacy of rituximab in refractory steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. Methods This retrospective study included 45 patients with childhood-onset refractory SRNS treated with rituximab treatment across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. Risk factors for poor response (non-CR) were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were evaluated. Results The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively ( p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. Conclusions Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with refractory SRNS. refractory steroid-resistant nephrotic syndrome rituximab methylprednisolone pulse therapy cyclosporine chronic kidney disease stage G5 long-term prognosis Figures Figure 1 Figure 2 Introduction Among patients with childhood-onset idiopathic nephrotic syndrome, 80–90% achieve complete remission (CR) with initial steroid administration whereas the remaining patients develop steroid-resistant nephrotic syndrome (SRNS) [ 1 , 2 ]. Refractory SRNS is defined as failure to achieve CR despite standard immunosuppressive regimens such as cyclosporine A (CsA) and methylprednisolone pulse therapy (MPT). Refractory SRNS, which accounts for 1–3% of all idiopathic nephrotic syndrome cases, is likely to progress to chronic kidney disease stage G5 (CKD G5) [ 3 ]. The 10-year kidney survival rate is 30–40% for patients who do not respond to immunosuppressive drugs and 90% for those who achieve CR or partial remission (PR) with immunosuppressive drugs [ 4 – 8 ]. A recent study reported that the kidney survival of refractory SRNS could improve with rituximab treatment that targets CD20 [ 9 ]. However, standard regimens for the treatment of refractory SRNS with rituximab have not yet been established [ 10 ] and the use of rituximab remains controversial due to the low remission rate of 46.4% in patients with refractory SRNS reported in a systematic review [ 11 ]. In the previous study including the analyses of a cohort of 23 pediatric patients with refractory SRNS, we reported that CR and PR were achieved in 70% and 13% of the patients treated with rituximab in combination with MPT and immunosuppressants (CsA or mycophenolate mofetil) as post-rituximab treatment, respectively [ 12 , 13 ]. The mechanism by which B cell-targeted therapies can achieve remission has been unclear; however, the discovery of nephrin antibodies suggests autoantibodies as an etiology of minimal change disease and supports the therapeutic efficacy of rituximab [ 14 ]. In addition, in a study of six pediatric patients with refractory SRNS who were treated with rituximab within six months after the SRNS diagnosis, all patients achieved CR, illustrating the importance of early rituximab administration [ 15 ]. Despite the lack of abundant evidence, we speculate that early rituximab administration can facilitate early remission. In this multicenter study, we aimed to determine the risk factors for failure to achieve remission one year after the initiation of rituximab treatment and to evaluate long-term kidney function in pediatric patients with refractory SRNS treated with rituximab. Materials and Methods Study design and patient population This multicenter, retrospective, observational study included patients with refractory childhood-onset SRNS who received rituximab treatment between January 1, 2006 and December 31, 2020 in the National Center for Child Health and Development (NCCHD), Saitama Prefectural Medical Center, Tokyo Metropolitan Children’s Medical Center, or Yokohama City University Medical Center. Some of the patients included in the present study were overlapped in our previous reports [ 12 , 13 , 15 ]. The cases where genetic abnormalities were observed were excluded from the present study. Definitions SRNS was defined as nephrotic syndrome without remission after four weeks of prednisolone treatment. Refractory SRNS was defined in patients who failed to achieve remission despite treatment with calcineurin inhibitors and MPT for at least one month. CR was defined as a urinary protein creatinine ratio of < 0.2 g/gCr for three consecutive days. PR was defined as a urinary protein creatinine ratio of ≥ 0.2 g/gCr with a serum albumin level of ≥ 3.0 g/dL. No remission (NR) was defined as failure to remit, i.e., a urinary protein creatinine ratio of ≥ 0.2 g/gCr and a serum albumin level of < 3.0 g/dL [ 16 ]. Treatment protocol Rituximab was administered in patients in whom MPT and CsA were ineffective after the SRNS diagnosis. Mycophenolate mofetil, mizoribine, and tacrolimus were administered at the discretion of the attending physicians. Rituximab was administered at a dose of 375 mg/m 2 /dose in most patients, and between one and four doses were administered. In most patients, MPT (30 mg/kg/day of intravenous methylprednisolone for 3 consecutive days, maximum of 1 g/day) was repeatedly administered until CR. Additional rituximab doses were administered in patients who did not achieve CR after B cell recovery. Data collection and analysis The medical records were accessed to collect clinical data, including sex, SRNS type (initial or late non-responder), ages at the onset of nephrotic syndrome and SRNS diagnosis, interval between SRNS diagnosis and rituximab treatment, pathologic findings, creatinine-based estimated glomerular filtration rate (Cr-eGFR) at rituximab treatment, immunosuppressive agents administered before and after rituximab treatment, number of rituximab doses, rates of patients who achieved B cell depletion, number of MPT courses administered after rituximab treatment, and follow-up duration. The treatment efficacy was evaluated using CR, PR, and NR one year after the first rituximab treatment. Risk factors for poor response were compared between the patients with and without CR, PR, and NR. Risk factors for poor response, defined as failure to achieve CR at one year after rituximab treatment, were calculated using univariate and multivariate analyses. Data on eGFR at last observation was used to evaluate long-term prognosis. The relationship between disease status one year after the first rituximab treatment (CR, PR, or NR) and long-term prognosis was evaluated. Adverse treatment events were also evaluated. Hypogammaglobulinemia was evaluated when serum albumin was normal. Statistical analysis All data were analyzed using JMP version 14.0 (SAS Institute Japan, Tokyo, Japan). Continuous and categorical variables were compared between patients with CR and those with non-CR (poor response) at one year using the Mann–Whitney U and Fisher’s exact tests, respectively. Risk factors for poor response were calculated using univariate and multivariate logistic regression analyses. The cutoff point for the interval between SRNS diagnosis and rituximab treatment to estimate poor response was determined using receiver operating characteristic curve analysis. Statistical significance was established at a p value of < 0.05. Ethics The present study was conducted in accordance with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Biological Research Involving Human Subjects of the Ministry of Health, Labor, and Welfare, Japan. The study was approved by the Ethics Committee of the NCCHD (approval no: 2021 − 111). Informed consent was obtained in the form of opt-out by the patients or family members. In addition, in research facilities other than the NCCHD, the study was conducted after obtaining approval in the form of a comprehensive central review at the NCCHD. Results Patient characteristics and one year response The study included 45 patients with refractory SRNS, including 28, 11, 5, and 3 patients in the NCCHD, Saitama Children’s Medical Center, Tokyo Metropolitan Children’s Medical Center, and Yokohama City University Medical Center, respectively (Table 1 ), with two patients treated across two hospitals. Thirty-one patients (69%) were initial non-responders, and the median interval between SRNS diagnosis and rituximab administration was 138 (interquartile range [IQR], 79–223) days. Three patients were on dialysis with acute kidney injury at the time of rituximab administration; all three patients were weaned off dialysis. The histopathologic evaluation of the kidney biopsy before rituximab administration revealed minor glomerular abnormalities (MGA), focal segmental glomerular sclerosis (FSGS), and diffuse mesangial proliferation in 19 (42%), 19 (42%), and 3 (7%) patients, respectively, whereas the remaining 4 (9%) patients did not undergo kidney biopsy at the time of rituximab administration. Eight patients (18%) received rituximab readministration within one year after the initial treatment for remission induction. Thirty-nine patients (87%) received MPT within one year after rituximab administration. Immunosuppressants such as calcineurin inhibitors and mycophenolate mofetil were used in 93% of the patients. Table 1 Patient characteristics and treatment details (n = 45) Characteristics Male sex 23 (51) Initial non-responder 31 (69) Interval between SRNS diagnosis and rituximab administration, median (days) 138 [79–223] Age at rituximab administration 9.3 [3.7–12.7] Cr-eGFR at rituximab administration (mL/min/1.73 m 2 ) eGFR ≥ 90 32 (71) 60 ≤ eGFR < 90 5 (11) 30 ≤ eGFR < 60 5 (11) 15 ≤ eGFR < 30 0 (0) eGFR < 15 or RRT 3 (7) Findings of kidney biopsy MGA 19 (42) FSGS 19 (42) DMP 3 (7) Not done 4 (9) Immunosuppressive agents at rituximab administration CsA 24 (53) MMF 2 (4) MZR 2 (4) CsA + MMF 9 (20) CsA + MZR 6 (13) Tac + MMF 2 (4) Number of rituximab doses One dose 29 (64) Two doses 11 (24) Three doses 1 (2) Four doses 4 (9) Patients who achieved B cell depletion (a) 43 (98) Rituximab readministration for remission within one year 8 (18) MPT within one year after rituximab administration 39 (87) Number of MPT courses within one year after rituximab administration 1 10 (22) 2 5 (11) 3 2 (4) 4 5 (11) 5 5 (11) 6 2 (4) 7 3 (7) 8 1 (2) 9 2 (4) 10 1 (2) 11 0 (0) 12 1 (2) 13 2 (4) Immunosuppressive agents after rituximab administration CsA 18 (40) MMF 5 (11) CsA + MMF 14 (31) CsA + MZR 3 (7) Tac + MMF 2 (4) None 3 (7) Outcome after one year of rituximab administration CR 31 (69) PR 11 (24) NR 2 (7) Interval between rituximab administration and CR in the CR group (days) 90 [44–160] Follow-up period after rituximab administration (years) 7.4 [2.8–8.8] Data are expressed as numbers (%) or medians [interquartile range]. CR, complete remission; Cr-eGFR, creatinine-based estimated glomerular filtration rate; CsA, cyclosporine A; DMP, diffuse mesangial proliferation; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; MGA, minor glomerular abnormalities; MMF, mycophenolate mofetil; MPT, methylprednisolone pulse therapy; MZR, mizoribine; NR, no remission; PR, partial remission; RRT, renal replacement therapy; SRNS, steroid-resistant nephrotic syndrome; Tac, tacrolimus a CD19 or CD20 < 1.0%, One patient was not analyzed B-cells after rituximab treatment. The rates of CR, PR, and NR on year after rituximab administration were 69%, 24%, and 7%, respectively. Figure 1 shows the changes in the rate of CR during the first year after rituximab administration. The median time to CR was 90 (IQR, 44–160) days, and the median follow-up period was 7.4 (IQR, 2.8–8.8) years. Risk factors for poor response after rituximab treatment for refractory SRNS Table 2 shows the comparison of clinical factors between the patients with and without CR. The rates of FSGS and initial non-response were significantly higher and the interval between SRNS diagnosis and rituximab administration was significantly longer in the non-CR group than in the CR group. Multivariate logistic regression analyses including these three variables (Table 3 ) revealed that FSGS (odds ratio, 10.0; 95% confidence interval, 1.00–109.0; p = 0.0498) and the interval between SRNS diagnosis and rituximab administration (odds ratio, 3.6; 95% confidence interval, 1.20–11.0; p = 0.02) were significant independent risk factors for poor response. Table 2 Comparison between patients with and without CR CR group (n = 31) Non-CR group (n = 14) P value Male sex 14 (45) 9 (64) 0.23 FSGS 8 (29) 11 (85) < 0.001 Initial non-responder 18 (58) 13 (93) 0.01 Cr-eGFR < 60 mL/min/1.73 m 2 at rituximab administration 5 (16) 3 (21) 0.67 Age at rituximab administration (years) 6.6 [2.9–11.8] 11.0 [4.7–12.8] 0.11 Interval between SRNS diagnosis and rituximab administration (days) 96 [74–151] 298 [192–1,090] < 0.001 Additional rituximab administration within one year 18 (58) 6 (43) 0.52 Data are expressed as numbers (%) or medians [interquartile range]. CR, complete remission; Cr-eGFR, creatinine-based estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; SRNS, steroid-resistant nephrotic syndrome Table 3 Risk factors for non-CR in univariate and multivariate analysis Univariate analysis Multivariate analysis Odds ratio 95% CI p value Odds ratio 95% CI p value FSGS 13.8 2.5–76.4 0.003 10.0 1.0–109.0 0.0498 Initial non-responder 9.4 1.1–81.0 0.04 5.3 0.3–95.0 0.26 Interval between SRNS diagnosis and rituximab administration (years) 3.0 1.2–7.4 < 0.001 3.6 1.2–11.0 0.02 CI, confidence interval; CR, complete remission; FSGS, focal segmental glomerulosclerosis; SRNS, steroid-resistant nephrotic syndrome Determination of the interval between SRNS diagnosis and rituximab treatment to predict poor response The receiver operating characteristic curve analysis was performed to determine whether poor response (non-CR) could be predicted by the interval between SRNS diagnosis and rituximab administration. As shown in Fig. 2 , the cutoff interval of 0.53 years had the best performance, with a sensitivity of 77% and a specificity of 90%. The rate of CR was higher in patients treated with rituximab within six months following SRNS diagnosis than in those treated with rituximab after six months following SRNS diagnosis (90.3% versus 21.4%; p < 0.001). Association of one year disease status with long-term prognosis At last observation, five patients were diagnosed with CKD G5. Table 4 shows the relationship between disease status one year after rituximab administration and Cr-eGFR at last follow-up. None of the 31 patients with CR had a Cr-eGFR of < 60 mL/min/1.73 m 2 , whereas 2 of the 11 patients with PR and all 3 patients with NR had CKD G5 at last observation. Table 4 The relationship between treatment response one year after rituximab treatment and kidney function at last follow-up Cr-eGFR at last follow-up (mL/min/1.73 m 2 ) ≥ 90 60 ≤ eGFR < 90 30 ≤ eGFR < 60 15 ≤ eGFR < 30 < 15 or RRT Total Outcome one year after rituximab administration CR 29 2 0 0 0 31 PR 6 2 1 0 2 11 NR 0 0 0 0 3 3 Total 35 4 1 0 5 45 CR, complete remission; Cr-eGFR, creatinine-based estimated glomerular filtration rate; eGFR, estimated glomerular filtration rate; NR, no remission PR, partial remission; RRT, renal replacement therapy Table 5 shows the characteristics of the five patients with CKD G5 at last observation. Four of the five patients were initial non-responders with the kidney pathology of FSGS. Genetic testing was performed in three of the five patients (Patients 2, 4, and 5), revealing no relevant abnormalities. Kidney function was normal in two of the five patients (Patients 2 and 4) at the time of rituximab treatment. The interval between SRNS diagnosis and rituximab administration was more than one year in all five cases, with the longest period of 8.1 years in Patient 5. Table 5 Details of the five patients who developed CKD G5 at last follow-up Patient no Sex Effects one year after rituximab administration Initial or late non-responder Findings of kidney biopsy before rituximab administration Duration from kidney biopsy to rituximab administration Age at rituximab administration Duration from SRNS diagnosis to rituximab administration (years) Cr-eGFR at rituximab administration (mL/min/1.73 m 2 ) 1 Male PR Initial FSGS 22 days 5.8 1.1 62.5 2 Male PR Initial FSGS 2.4 years 15.2 4.5 114.5 3 Male NR Initial FSGS 1.7 years 15.0 1.8 46.8 4 Male NR Late MGA 10.1 years 14.3 over 3.6 136.7 5 Male NR Initial FSGS 0.6 years 19.9 8.1 59.4 CKD G5, chronic kidney disease stage G5; Cr-eGFR, creatinine-based estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; MGA, minor glomerular abnormalities; NR, no remission; PR, partial remission; SRNS, steroid-resistant nephrotic syndrome Adverse events associated with rituximab treatment Table 6 summarizes the adverse events associated with rituximab treatment during the follow-up period. Nine patients (20%) experienced persistent severe hypogammaglobulinemia with a serum IgG level of < 200 mg/dL or required globulin replacement, and 5 patients (11%) had neutropenia with < 500 neutrophils/mm 3 . Thirteen cases of hypogammaglobulinemia or neutropenia requiring hospitalization or treatment occurred in 7 patients (16%). Table 6 Adverse events observed during the follow-up of patients treated with rituximab (n = 45) Characteristics Severe hypogammaglobulinemia (serum IgG < 200 mg/dL) or immunoglobulin replacement treatment 9 (20) Neutropenia (neutrophil count < 500/mm 3 ) 5 (11) Number of patients presenting with infections associated with severe hypogammaglobulinemia or neutropenia requiring hospitalization or antiviral/antibiotic drugs 7 (16) Number of infectious events associated with severe hypogammaglobulinemia or neutropenia requiring hospitalization or antiviral/antibiotic drugs Febrile neutropenia 3 Pneumonia 5 Herpes gingivitis 2 Invasive pulmonary aspergillosis 1 Sinusitis 1 Otitis media 1 Data are expressed as numbers (%). IgG, immunoglobulin G Discussion In the present study including 45 patients with refractory SRNS treated with rituximab, 69%, 24%, and 7% of the patients achieved CR, PR, and NR, respectively, at one year after treatment. The median time to CR was 90 days. Multivariate analysis revealed that the kidney pathology of FSGS and a long interval between SRNS diagnosis and rituximab administration, especially a period of more than six months, were significant risk factors for poor response. At last follow-up, none of the 31 patients in the CR group developed CKD G5, whereas 2 of the 11 patients in the PR group and all 3 patients in the NR group developed CKD G5, suggesting that early CR was associated with good long-term kidney prognosis. The therapeutic effect of rituximab in refractory SRNS remains controversial. In the only randomized controlled trial evaluating the efficacy of rituximab in patients with refractory SRNS [ 17 ], 31 pediatric patients with refractory SRNS were divided into the rituximab (n = 16) and standard therapy (n = 15) groups. The analyses revealed that rituximab did not reduce proteinuria three months after treatment initiation. However, three months might be too short to evaluate the efficacy of treatment in patients with refractory SRNS. Additionally, rituximab was administered at least 6 months (median, 1.3 years) after SRNS diagnosis, which was longer than that in the present study (median, 138 days). Moreover, immunosuppressive treatment after rituximab, such as MPT and calcineurin inhibitors, is crucial for successful therapeutic outcome for refractory SRNS [ 12 , 13 , 18 ]. In the present study, MPT was added to the treatment regimen in 87% of the patients and calcineurin inhibitors (CsA or tacrolimus) were continued as post-rituximab treatment in 82% of the patients; these might have contributed to the excellent results observed in our study cohort. In the present study, the shorter interval between the SRNS diagnosis and rituximab administration was associated with higher remission, as reflected in the higher rate of CR in patients treated with rituximab within six months following SRNS diagnosis compared to those treated with rituximab after six months. All five patients who developed CKD G5 received rituximab treatment more than one year after SRNS diagnosis. Sinha et al. also reported that the interval between SRNS diagnosis and rituximab administration was significantly shorter in patients with CR or PR than in those with NR (8 versus 13 months; p = 0.04) [ 19 ] and concluded that rituximab should be administered within 12 months after the diagnosis of SRNS. We suggest that the early administration of rituximab in combination with MPT and immunosuppressive drugs was associated with the favorable outcomes observed in our cohort. Our analyses also revealed FSGS as a significant risk factor for treatment failure in patients with refractory SRNS, a detail speculated by two systematic reviews [ 10 , 11 ]. MGA and FSGS are considered as identical to idiopathic nephrotic syndrome, although glomerular sclerosis is an irreversible change that worsens with long-term proteinuria [ 20 ]. In the present study, two of the three patients with NR had FSGS. The remaining one patient was diagnosed with MGA 10 years before the rituximab administration and might have had FSGS at the time of rituximab treatment. We did not identify kidney dysfunction at the time of rituximab administration as a risk factor in the present study. Two of the three patients receiving hemodialysis at the time of rituximab administration achieved CR, whereas the remaining one patient achieved PR one year later; none of the three patients had kidney dysfunction at last follow-up. Conversely, one of the three patients with NR one year later who had normal kidney function after rituximab treatment eventually developed CKD G5. The optimal time to initiate rituximab treatment after SRNS diagnosis is unknown. In a study by Hamasaki et al., 61% and 93% of the patients with MGA/DMP treated with CsA achieved CR or PR within 1 and 4 months, respectively, whereas 71% and 86% of the patients with FSGS treated with CsA and MPT achieved CR or PR within 1 and 4 months, respectively [ 21 ]. Therefore, observation for 1–4 months might be sufficient to evaluate the efficacy of CsA and MPT. In patients with SRNS resistant to combination treatment with CsA and MPT, rituximab should be added within six months after diagnosis before the progression of irreversible sclerotic lesions. Adverse events associated with rituximab include hypogammaglobulinemia and neutropenia. In the present study cohort, 20%, 11%, and 16% of the patients experienced hypogammaglobulinemia, neutropenia, and infectious episodes related to these adverse events, respectively. In a previous observational study of 140 patients treated with rituximab for idiopathic nephrotic syndrome, we found that the incidence of infections in patients with normal, mildly low, and severely low IgG levels were 0.028, 0.071, and 0.096 per person-years, respectively, suggesting that the incidence of infections was relatively low even in patients with severe hypogammaglobulinemia [ 22 ]. In another study including 213 rituximab administrations given to114 patients with refractory nephrotic syndrome, we reported neutropenia in 9.6% of all patients and 5.2% of all rituximab infusions [ 23 ]. Altogether, accumulating evidence suggest that rituximab can be safely used if potential side effects are not overlooked. Our findings should be interpreted with consideration of the study limitations. First, this was a retrospective observational study and the treatment protocol was not predetermined. Second, genetic testing was not performed in all patients. Three of the five patients with CKD G5 at last follow-up did not harbor genetic abnormalities, whereas one patient without genetic testing had a history of remission and recurrence after transplantation and was clinically considered to have nonhereditary FSGS. In the remaining one patient who developed CKD G5 and was initiated on hemodialysis, the possibility of genetic FSGS cannot be ruled out. Immunosuppressive therapy is considered to be ineffective in hereditary SRNS, although some patients have been reported to respond to immunosuppressive drugs [ 24 ]. In conclusion, in this multicenter, retrospective, observational study, combination treatment with rituximab, MPT, and immunosuppressive agents for refractory SRNS was associated with favorable outcomes. Risk factors for poor response were the pathologic finding of FSGS and a long interval between SRNS diagnosis and rituximab treatment, especially a period of more than six months. Early administration of rituximab in combination with CsA and MPT as post-rituximab immunosuppression might improve long-term prognosis in patients with refractory SRNS. Declarations Competing Interests: Koichi Kamei has received research funding from the Public Foundation of Vaccination Research Center and the Taiju Life Social Welfare Foundation; donations from Chugai Pharmaceutical, Teijin Pharma, Kyowa Kirin, Shionogi, Daiichi Sankyo, Mitsubishi Tanabe Pharma, and Otsuka Pharmaceutical; and lecture fees from Terumo, Baxter, and Zenyaku Kogyo. Ethics approval: This study was approved by the Ethics Committee of the National Center for Child Health and Development (approval no: 2021 − 111). Consent to participate: Not applicable Consent for publication: Not applicable Funding: This study did not receive any external funding. Author contributions: All authors were physicians treating the patients reported in the present study. Shunsuke Yokota prepared the manuscript and performed data collection and analysis. Kentaro Nishi, Mai Sato, Masao Ogura, Koji Sakuraya, Shuichiro Fujinaga, Riku Hamada, and Aya Inaba edited and reviewed the manuscript. Shuichi Ito advised the study protocol and revised the manuscript. Koichi Kamei oversaw the work as the corresponding author and revised the manuscript. All authors read and approved the final manuscript. Acknowledgments: We thank Enago for editing a draft of this manuscript. Data availability: The datasets generated during and/or analyzed during the current study are not publicly available because permission for their publication was not obtained from the participants or approved by the Ethics Committee. 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J Pediatr 197: 191-197. http://doi.org/10.1016/j.jpeds.2018.01.008 Kamei K, Okada M, Sato M, Fujimaru T, Ogura M, Nakayama M, Kaito H, Iijima K, Ito S (2014) Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome. Pediatr Nephrol 29: 1181-1187. http://doi.org/10.1007/s00467-014-2765-z Kamei K, Ishikura K (2016) Rituximab treatment for refractory steroid-resistant nephrotic syndrome. Pediatr Nephrol 31: 337-338. http://doi.org/10.1007/s00467-015-3205-4 Andrew JBW, Keith HK, Gabriel L, IVY R, Bernard AC, Miroslav S, Sushrut SW, Anil C, Leonardo VR, Mariam PA, Jonathan PT, Junbo C, Damian F, Jennifer LY, Matthew GS, Laurence HB Jr, Joel MH, Anna G, Helmut GR, Astrid W (2022) Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel etiology. J Am Soc Nephrol 33: 238-252. http://doi.10.1681/ASN.2021060794. Fujinaga S, Nishino T, Umeda C, Tomii Y, Watanabe Y, Sakuraya K (2019) Long-term outcomes after treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome. Pediatr Nephrol 34: 353-357. http://doi.org/10.1007/s00467-018-4145-6 Agnes T, Olivia B, Elisabeth H, Arvind B, Debbie SG, Susan S, Jack W, Khalid A, Sushmita B, Rajendra B, Melvin BF, Francisco C, Martin C, Deirdre H, Hee GK, Nakanishi K, Hesham S, Howard T, Hong X, Wendy C, Marina V, Dieter H; International Pediatric Nephrology Association (2023) IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome. Pediatr Nephrol 38: 877-919. http://doi.org/10.1007/s00467-022-05739-3 Magnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, Benetti E, Murtas C, Messina G, Massella L, Porcellini MG, Montagna M, Regazzi M, Scolari F, Ghiggeri GM (2012) Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 23: 1117-1124. http://doi.org/10.1681/ASN.2011080775 Suyama K, Kawasaki Y, Miyazaki K, Kanno S, Ono A, Suzuki Y, Ohara S, Hosoya M (2016) Rituximab and low-dose cyclosporine combination therapy for steroid-resistant focal segmental glomerulosclerosis. Pediatr Int 58: 219-223. http://doi.org/10.1111/ped.12804 Sinha R, Banerjee S, Mukherjee A, Pradhan S, Akhtar S (2020) Early use of rituximab in calcineurin inhibitor-refractory and steroid-resistant nephrotic syndrome. Kidney Int Rep 5: 2354-2357. http://doi.org/10.1016/j.ekir.2020.09.021 Watanabe Y, Fujinaga S, Endo A, Nakagawa M, Sakuraya K (2020) Baseline characteristics and long-term outcomes of steroid-resistant nephrotic syndrome in children: impact of initial kidney histology. Pediatr Nephrol 35: 2377-2381. https://doi.org/10.1007/s00467-020-04760-8 Hamasaki Y, Yoshikawa N, Hattori S, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Ishikura K, Yata N, Kaneko T, Honda M, Japanese Study Group of Renal Disease (2009) Prospective 5-year follow-up of cyclosporine treatment in children with steroid-resistant nephrosis. Pediatr Nephrol 24: 2177-2185. http://doi.org/10.1007/s00467-009-1264-0 Inoki Y, Nishi K, Sato M, Ogura M, Kamei K (2023) The association between hypogammaglobulinemia severity and infection risk in rituximab-treated patients with childhood-onset idiopathic nephrotic syndrome. Pediatr Nephrol 38: 451-460. http://doi.org/10.1007/s00467-022-05652-9 Kamei K, Takahashi M, Fuyama M, Saida K, Machida H, Sato M, Ogura M, Ito S (2014) Rituximab-associated agranulocytosis in children with refractory idiopathic nephrotic syndrome: case series and review of literature. Nephrol Dial Transplant 30: 91-96. http://doi.org/10.1093/ndt/gfu258 Büscher AK, Beck BB, Melk A, Hoefele J, Kranz B, Bamborschke D, Baig S, Lange-Sperandio B, Jungraithmayr T, Weber LT, Kemper MJ, Tönshoff B, Hoyer PF, Konrad M, Weber S, German Pediatric Nephrology Association (GPN) (2016) Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus genetic steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 11: 245-253. http://doi.org/10.2215/CJN.07370715 Supplementary Files GraphicalAbstract.pptx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major Revisions Needed 25 Mar, 2024 Reviewers agreed at journal 26 Feb, 2024 Reviewers invited by journal 20 Feb, 2024 Editor assigned by journal 20 Feb, 2024 First submitted to journal 19 Feb, 2024 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3972976\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":274177960,\"identity\":\"4e910c3b-6db7-406d-be0f-736c187b3bea\",\"order_by\":0,\"name\":\"Shunsuke Yokota\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Division of Nephrology, Saitama Children's Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shunsuke\",\"middleName\":\"\",\"lastName\":\"Yokota\",\"suffix\":\"\"},{\"id\":274177961,\"identity\":\"d26e892d-478d-4138-a2bf-bfec6ddca94f\",\"order_by\":1,\"name\":\"Koichi Kamei\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYBACCRCRwJAgB6TYGHjAYgeI02JMohagpsQGhBYCQLL9dOKDBwxp6dvZDz978IahVo6B8Sx+a6R5cjcbJDDk5O7sSTM3nMNwHOjCcwl4tcgx5G6TSPxXkbvhBg+bNA/DMaALzxjg18L/dvuPBIaKdAOitUhL5G4DhlhOAlRLDWEtkjPebpZIYEgz3HAmzUxyjsEBYzZCfpE4n7vx4w+GZHmD44efSbypqJPjlyAQYmjA4DADm8QZUnQwMNQxMPD3kKZlFIyCUTAKhj0AACAeQ6wBOp/+AAAAAElFTkSuQmCC\",\"orcid\":\"https://orcid.org/0000-0003-3528-6961\",\"institution\":\"Division of Nephrology and Rheumatology, National Center for Child Health and Development\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Koichi\",\"middleName\":\"\",\"lastName\":\"Kamei\",\"suffix\":\"\"},{\"id\":274177962,\"identity\":\"b71795f5-21b0-4aa7-9b64-d7f44e99660c\",\"order_by\":2,\"name\":\"Shuichiro Fujinaga\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Division of Nephrology, Saitama Children's Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shuichiro\",\"middleName\":\"\",\"lastName\":\"Fujinaga\",\"suffix\":\"\"},{\"id\":274177963,\"identity\":\"754a61e4-8f7e-4377-8b64-7f33093d89c7\",\"order_by\":3,\"name\":\"Riku Hamada\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Division of Nephrology and Rheumatology, Tokyo Metropolitan Children's Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Riku\",\"middleName\":\"\",\"lastName\":\"Hamada\",\"suffix\":\"\"},{\"id\":274177964,\"identity\":\"cc30ba59-3279-47f6-981b-d2c86e595e80\",\"order_by\":4,\"name\":\"Aya Inaba\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Department of Pediatrics, Yokohama City University Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Aya\",\"middleName\":\"\",\"lastName\":\"Inaba\",\"suffix\":\"\"},{\"id\":274177965,\"identity\":\"093ab37c-d0a8-45e4-a561-d9e4d73b637e\",\"order_by\":5,\"name\":\"Kentaro Nishi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Division of Nephrology and Rheumatology, National Center for Child Health and Development\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Kentaro\",\"middleName\":\"\",\"lastName\":\"Nishi\",\"suffix\":\"\"},{\"id\":274177966,\"identity\":\"fa44b7b8-283d-4b8c-a164-027947034eaf\",\"order_by\":6,\"name\":\"Mai Sato\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Division of Nephrology and Rheumatology, National Center for Child Health and Development\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mai\",\"middleName\":\"\",\"lastName\":\"Sato\",\"suffix\":\"\"},{\"id\":274177967,\"identity\":\"95025bf1-a093-4571-8401-1d40916135cc\",\"order_by\":7,\"name\":\"Masao Ogura\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Division of Nephrology and Rheumatology, National Center for Child Health and Development\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Masao\",\"middleName\":\"\",\"lastName\":\"Ogura\",\"suffix\":\"\"},{\"id\":274177968,\"identity\":\"ecc9d72b-8d3a-44f0-9e20-33dd4de0d8c5\",\"order_by\":8,\"name\":\"Koji Sakuraya\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Division of Nephrology, Saitama Children's Medical Center\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Koji\",\"middleName\":\"\",\"lastName\":\"Sakuraya\",\"suffix\":\"\"},{\"id\":274177969,\"identity\":\"97f73853-af3c-4a6d-9050-89c9665d615b\",\"order_by\":9,\"name\":\"Shuichi Ito\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Department of Pediatrics, Graduate School of Medicine, Yokohama City University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Shuichi\",\"middleName\":\"\",\"lastName\":\"Ito\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-02-20 14:15:05\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-3972976/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-3972976/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":51560532,\"identity\":\"776eb299-5427-4b00-a3c7-982304f7a329\",\"added_by\":\"auto\",\"created_at\":\"2024-02-23 17:48:22\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":25397,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eKaplan–Meier curve showing the relationship between the time from rituximab treatment and the achievement of CR in patients who achieved CR.\\u003c/p\\u003e\\n\\u003cp\\u003eThe median time to complete remission was 90 days.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3972976/v1/b7a96de31450a475bdb2cb3c.png\"},{\"id\":51560533,\"identity\":\"a91961fc-ef22-4774-af59-3bb11d563e55\",\"added_by\":\"auto\",\"created_at\":\"2024-02-23 17:48:22\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":25588,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eReceiver operating characteristic analysis curve to determine the cutoff point for the interval between SRNS diagnosis and rituximab administration to predict non-CR.\\u003c/p\\u003e\\n\\u003cp\\u003eThe area under the curve is 0.85, and the cutoff value of 0.53 year has a sensitivity of 77% and a specificity of 90%. CR, complete remission; SRNS, steroid-resistant nephrotic syndrome\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3972976/v1/2d87b2fa5775b14c30ddb1db.png\"},{\"id\":51560732,\"identity\":\"1d50d458-f1a1-4e55-8b28-e065536c43b7\",\"added_by\":\"auto\",\"created_at\":\"2024-02-23 17:56:23\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":528698,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3972976/v1/16cb43fb-83c1-4ae1-aa9e-e51294de91d1.pdf\"},{\"id\":51560534,\"identity\":\"c8a563c2-dc27-4757-b460-3f22754c7880\",\"added_by\":\"auto\",\"created_at\":\"2024-02-23 17:48:22\",\"extension\":\"pptx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":54723,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"GraphicalAbstract.pptx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3972976/v1/d13681765e570e67d85a573a.pptx\"}],\"financialInterests\":\"\",\"formattedTitle\":\"Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset refractory steroid-resistant nephrotic syndrome: a multicenter study\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eAmong patients with childhood-onset idiopathic nephrotic syndrome, 80\\u0026ndash;90% achieve complete remission (CR) with initial steroid administration whereas the remaining patients develop steroid-resistant nephrotic syndrome (SRNS) [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e]. Refractory SRNS is defined as failure to achieve CR despite standard immunosuppressive regimens such as cyclosporine A (CsA) and methylprednisolone pulse therapy (MPT). Refractory SRNS, which accounts for 1\\u0026ndash;3% of all idiopathic nephrotic syndrome cases, is likely to progress to chronic kidney disease stage G5 (CKD G5) [\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e]. The 10-year kidney survival rate is 30\\u0026ndash;40% for patients who do not respond to immunosuppressive drugs and 90% for those who achieve CR or partial remission (PR) with immunosuppressive drugs [\\u003cspan additionalcitationids=\\\"CR5 CR6 CR7\\\" citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eA recent study reported that the kidney survival of refractory SRNS could improve with rituximab treatment that targets CD20 [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e]. However, standard regimens for the treatment of refractory SRNS with rituximab have not yet been established [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e] and the use of rituximab remains controversial due to the low remission rate of 46.4% in patients with refractory SRNS reported in a systematic review [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eIn the previous study including the analyses of a cohort of 23 pediatric patients with refractory SRNS, we reported that CR and PR were achieved in 70% and 13% of the patients treated with rituximab in combination with MPT and immunosuppressants (CsA or mycophenolate mofetil) as post-rituximab treatment, respectively [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]. The mechanism by which B cell-targeted therapies can achieve remission has been unclear; however, the discovery of nephrin antibodies suggests autoantibodies as an etiology of minimal change disease and supports the therapeutic efficacy of rituximab [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]. In addition, in a study of six pediatric patients with refractory SRNS who were treated with rituximab within six months after the SRNS diagnosis, all patients achieved CR, illustrating the importance of early rituximab administration [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. Despite the lack of abundant evidence, we speculate that early rituximab administration can facilitate early remission.\\u003c/p\\u003e \\u003cp\\u003eIn this multicenter study, we aimed to determine the risk factors for failure to achieve remission one year after the initiation of rituximab treatment and to evaluate long-term kidney function in pediatric patients with refractory SRNS treated with rituximab.\\u003c/p\\u003e\"},{\"header\":\"Materials and Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy design and patient population\\u003c/h2\\u003e \\u003cp\\u003eThis multicenter, retrospective, observational study included patients with refractory childhood-onset SRNS who received rituximab treatment between January 1, 2006 and December 31, 2020 in the National Center for Child Health and Development (NCCHD), Saitama Prefectural Medical Center, Tokyo Metropolitan Children\\u0026rsquo;s Medical Center, or Yokohama City University Medical Center. Some of the patients included in the present study were overlapped in our previous reports [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e]. The cases where genetic abnormalities were observed were excluded from the present study.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eDefinitions\\u003c/h2\\u003e \\u003cp\\u003eSRNS was defined as nephrotic syndrome without remission after four weeks of prednisolone treatment. Refractory SRNS was defined in patients who failed to achieve remission despite treatment with calcineurin inhibitors and MPT for at least one month. CR was defined as a urinary protein creatinine ratio of \\u0026lt;\\u0026thinsp;0.2 g/gCr for three consecutive days. PR was defined as a urinary protein creatinine ratio of \\u0026ge;\\u0026thinsp;0.2 g/gCr with a serum albumin level of \\u0026ge;\\u0026thinsp;3.0 g/dL. No remission (NR) was defined as failure to remit, i.e., a urinary protein creatinine ratio of \\u0026ge;\\u0026thinsp;0.2 g/gCr and a serum albumin level of \\u0026lt;\\u0026thinsp;3.0 g/dL [\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e].\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eTreatment protocol\\u003c/h2\\u003e \\u003cp\\u003eRituximab was administered in patients in whom MPT and CsA were ineffective after the SRNS diagnosis. Mycophenolate mofetil, mizoribine, and tacrolimus were administered at the discretion of the attending physicians. Rituximab was administered at a dose of 375 mg/m\\u003csup\\u003e2\\u003c/sup\\u003e/dose in most patients, and between one and four doses were administered. In most patients, MPT (30 mg/kg/day of intravenous methylprednisolone for 3 consecutive days, maximum of 1 g/day) was repeatedly administered until CR. Additional rituximab doses were administered in patients who did not achieve CR after B cell recovery.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eData collection and analysis\\u003c/h2\\u003e \\u003cp\\u003eThe medical records were accessed to collect clinical data, including sex, SRNS type (initial or late non-responder), ages at the onset of nephrotic syndrome and SRNS diagnosis, interval between SRNS diagnosis and rituximab treatment, pathologic findings, creatinine-based estimated glomerular filtration rate (Cr-eGFR) at rituximab treatment, immunosuppressive agents administered before and after rituximab treatment, number of rituximab doses, rates of patients who achieved B cell depletion, number of MPT courses administered after rituximab treatment, and follow-up duration. The treatment efficacy was evaluated using CR, PR, and NR one year after the first rituximab treatment. Risk factors for poor response were compared between the patients with and without CR, PR, and NR. Risk factors for poor response, defined as failure to achieve CR at one year after rituximab treatment, were calculated using univariate and multivariate analyses. Data on eGFR at last observation was used to evaluate long-term prognosis. The relationship between disease status one year after the first rituximab treatment (CR, PR, or NR) and long-term prognosis was evaluated. Adverse treatment events were also evaluated. Hypogammaglobulinemia was evaluated when serum albumin was normal.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e \\u003cp\\u003eAll data were analyzed using JMP version 14.0 (SAS Institute Japan, Tokyo, Japan). Continuous and categorical variables were compared between patients with CR and those with non-CR (poor response) at one year using the Mann\\u0026ndash;Whitney \\u003cem\\u003eU\\u003c/em\\u003e and Fisher\\u0026rsquo;s exact tests, respectively. Risk factors for poor response were calculated using univariate and multivariate logistic regression analyses. The cutoff point for the interval between SRNS diagnosis and rituximab treatment to estimate poor response was determined using receiver operating characteristic curve analysis. Statistical significance was established at a \\u003cem\\u003ep\\u003c/em\\u003e value of \\u0026lt;\\u0026thinsp;0.05.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eEthics\\u003c/h2\\u003e \\u003cp\\u003e The present study was conducted in accordance with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Biological Research Involving Human Subjects of the Ministry of Health, Labor, and Welfare, Japan. The study was approved by the Ethics Committee of the NCCHD (approval no: 2021\\u0026thinsp;\\u0026minus;\\u0026thinsp;111). Informed consent was obtained in the form of opt-out by the patients or family members. In addition, in research facilities other than the NCCHD, the study was conducted after obtaining approval in the form of a comprehensive central review at the NCCHD.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003ePatient characteristics and one year response\\u003c/h2\\u003e \\u003cp\\u003eThe study included 45 patients with refractory SRNS, including 28, 11, 5, and 3 patients in the NCCHD, Saitama Children\\u0026rsquo;s Medical Center, Tokyo Metropolitan Children\\u0026rsquo;s Medical Center, and Yokohama City University Medical Center, respectively (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e), with two patients treated across two hospitals. Thirty-one patients (69%) were initial non-responders, and the median interval between SRNS diagnosis and rituximab administration was 138 (interquartile range [IQR], 79\\u0026ndash;223) days. Three patients were on dialysis with acute kidney injury at the time of rituximab administration; all three patients were weaned off dialysis. The histopathologic evaluation of the kidney biopsy before rituximab administration revealed minor glomerular abnormalities (MGA), focal segmental glomerular sclerosis (FSGS), and diffuse mesangial proliferation in 19 (42%), 19 (42%), and 3 (7%) patients, respectively, whereas the remaining 4 (9%) patients did not undergo kidney biopsy at the time of rituximab administration. Eight patients (18%) received rituximab readministration within one year after the initial treatment for remission induction. Thirty-nine patients (87%) received MPT within one year after rituximab administration. Immunosuppressants such as calcineurin inhibitors and mycophenolate mofetil were used in 93% of the patients.\\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\\u003ePatient characteristics and treatment details (n\\u0026thinsp;=\\u0026thinsp;45)\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"3\\\"\\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 \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eCharacteristics\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eMale sex\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e23 (51)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eInitial non-responder\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e31 (69)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eInterval between SRNS diagnosis and rituximab administration, median (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e138 [79\\u0026ndash;223]\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eAge at rituximab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9.3 [3.7\\u0026ndash;12.7]\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"4\\\" rowspan=\\\"5\\\"\\u003e \\u003cp\\u003eCr-eGFR at rituximab administration (mL/min/1.73 m\\u003csup\\u003e2\\u003c/sup\\u003e)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eeGFR\\u0026thinsp;\\u0026ge;\\u0026thinsp;90\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e32 (71)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e60\\u0026thinsp;\\u0026le;\\u0026thinsp;eGFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;90\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (11)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e30\\u0026thinsp;\\u0026le;\\u0026thinsp;eGFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;60\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (11)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e15\\u0026thinsp;\\u0026le;\\u0026thinsp;eGFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;30\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eeGFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;15 or RRT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3 (7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"3\\\" rowspan=\\\"4\\\"\\u003e \\u003cp\\u003eFindings of kidney biopsy\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMGA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e19 (42)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eFSGS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e19 (42)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eDMP\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3 (7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNot done\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4 (9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"5\\\" rowspan=\\\"6\\\"\\u003e \\u003cp\\u003eImmunosuppressive agents at rituximab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCsA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e24 (53)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMMF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMZR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCsA\\u0026thinsp;+\\u0026thinsp;MMF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9 (20)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCsA\\u0026thinsp;+\\u0026thinsp;MZR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6 (13)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTac\\u0026thinsp;+\\u0026thinsp;MMF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"3\\\" rowspan=\\\"4\\\"\\u003e \\u003cp\\u003eNumber of rituximab doses\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eOne dose\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e29 (64)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTwo doses\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11 (24)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eThree doses\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eFour doses\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e4 (9)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003ePatients who achieved B cell depletion\\u003csup\\u003e(a)\\u003c/sup\\u003e\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e43 (98)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eRituximab readministration for remission within one year\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e8 (18)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eMPT within one year after rituximab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e39 (87)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"12\\\" rowspan=\\\"13\\\"\\u003e \\u003cp\\u003eNumber of MPT courses within one year after rituximab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e10 (22)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (11)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (11)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (11)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e7\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3 (7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e10\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0 (0)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e12\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1 (2)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e13\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"5\\\" rowspan=\\\"6\\\"\\u003e \\u003cp\\u003eImmunosuppressive agents after rituximab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCsA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e18 (40)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMMF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (11)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCsA\\u0026thinsp;+\\u0026thinsp;MMF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e14 (31)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCsA\\u0026thinsp;+\\u0026thinsp;MZR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3 (7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTac\\u0026thinsp;+\\u0026thinsp;MMF\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (4)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNone\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3 (7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"2\\\" rowspan=\\\"3\\\"\\u003e \\u003cp\\u003eOutcome after one year of rituximab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e31 (69)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11 (24)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2 (7)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eInterval between rituximab administration and CR in the CR group (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e90 [44\\u0026ndash;160]\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eFollow-up period after rituximab administration (years)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7.4 [2.8\\u0026ndash;8.8]\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003eData are expressed as numbers (%) or medians [interquartile range].\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003eCR, complete remission; Cr-eGFR, creatinine-based estimated glomerular filtration rate; CsA, cyclosporine A; DMP, diffuse mesangial proliferation; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; MGA, minor glomerular abnormalities; MMF, mycophenolate mofetil; MPT, methylprednisolone pulse therapy; MZR, mizoribine; NR, no remission; PR, partial remission; RRT, renal replacement therapy; SRNS, steroid-resistant nephrotic syndrome; Tac, tacrolimus\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003e\\u003csup\\u003ea\\u003c/sup\\u003e CD19 or CD20\\u0026thinsp;\\u0026lt;\\u0026thinsp;1.0%, One patient was not analyzed B-cells after rituximab treatment.\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eThe rates of CR, PR, and NR on year after rituximab administration were 69%, 24%, and 7%, respectively. Figure\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e shows the changes in the rate of CR during the first year after rituximab administration. The median time to CR was 90 (IQR, 44\\u0026ndash;160) days, and the median follow-up period was 7.4 (IQR, 2.8\\u0026ndash;8.8) years.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eRisk factors for poor response after rituximab treatment for refractory SRNS\\u003c/h2\\u003e \\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e shows the comparison of clinical factors between the patients with and without CR. The rates of FSGS and initial non-response were significantly higher and the interval between SRNS diagnosis and rituximab administration was significantly longer in the non-CR group than in the CR group. Multivariate logistic regression analyses including these three variables (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e) revealed that FSGS (odds ratio, 10.0; 95% confidence interval, 1.00\\u0026ndash;109.0; \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.0498) and the interval between SRNS diagnosis and rituximab administration (odds ratio, 3.6; 95% confidence interval, 1.20\\u0026ndash;11.0; \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.02) were significant independent risk factors for poor response.\\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\\u003eComparison between patients with and without CR\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"4\\\"\\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 \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCR group\\u003c/p\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;31)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNon-CR group\\u003c/p\\u003e \\u003cp\\u003e(n\\u0026thinsp;=\\u0026thinsp;14)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u003cem\\u003eP\\u003c/em\\u003e value\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eMale sex\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e14 (45)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9 (64)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.23\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eFSGS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e8 (29)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11 (85)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eInitial non-responder\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e18 (58)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e13 (93)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.01\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eCr-eGFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;60 mL/min/1.73 m\\u003csup\\u003e2\\u003c/sup\\u003e at rituximab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e5 (16)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3 (21)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.67\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAge at rituximab administration (years)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e6.6 [2.9\\u0026ndash;11.8]\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e11.0 [4.7\\u0026ndash;12.8]\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.11\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eInterval between SRNS diagnosis and rituximab administration (days)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e96 [74\\u0026ndash;151]\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e298 [192\\u0026ndash;1,090]\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003eAdditional rituximab administration within one year\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003e18 (58)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6 (43)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0.52\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eData are expressed as numbers (%) or medians [interquartile range].\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"4\\\"\\u003eCR, complete remission; Cr-eGFR, creatinine-based estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; SRNS, steroid-resistant nephrotic syndrome\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\n\\u003ctable id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e\\n \\u003ccaption language=\\\"En\\\"\\u003e\\n \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e\\n \\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n \\u003cp\\u003eRisk factors for non-CR in univariate and multivariate analysis \\u003c/p\\u003e\\n \\u003c/div\\u003e\\n \\u003c/caption\\u003e\\n \\u003cthead\\u003e\\n \\u003ctr\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 19.9812%;\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"5\\\" style=\\\"width: 12.5764%;\\\"\\u003e\\n \\u003cp\\u003eUnivariate analysis\\u003c/p\\u003e\\n \\u003c/th\\u003e\\n \\u003cth align=\\\"left\\\" colspan=\\\"6\\\" style=\\\"width: 13.2816%;\\\"\\u003e\\n \\u003cp\\u003eMultivariate analysis\\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\\\" colspan=\\\"2\\\" style=\\\"width: 19.9812%;\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.7612%;\\\"\\u003e\\n \\u003cp\\u003eOdds ratio\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 4.5839%;\\\"\\u003e\\n \\u003cp\\u003e95% CI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" style=\\\"width: 4.2313%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003ep\\u003c/em\\u003e value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 4.4076%;\\\"\\u003e\\n \\u003cp\\u003eOdds ratio\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 4.4076%;\\\"\\u003e\\n \\u003cp\\u003e95% CI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 4.4664%;\\\"\\u003e\\n \\u003cp\\u003e\\u003cem\\u003ep\\u003c/em\\u003e value\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 21.8618%;\\\"\\u003e\\n \\u003cp\\u003eFSGS\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.291%;\\\"\\u003e\\n \\u003cp\\u003e13.8\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 5.2891%;\\\"\\u003e\\n \\u003cp\\u003e2.5\\u0026ndash;76.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" style=\\\"width: 3.291%;\\\"\\u003e\\n \\u003cp\\u003e0.003\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.5849%;\\\"\\u003e\\n \\u003cp\\u003e10.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.4086%;\\\"\\u003e\\n \\u003cp\\u003e1.0\\u0026ndash;109.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" style=\\\"width: 2.7621%;\\\"\\u003e\\n \\u003cp\\u003e0.0498\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 21.8618%;\\\"\\u003e\\n \\u003cp\\u003eInitial non-responder\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.291%;\\\"\\u003e\\n \\u003cp\\u003e9.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 5.2891%;\\\"\\u003e\\n \\u003cp\\u003e1.1\\u0026ndash;81.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" style=\\\"width: 3.291%;\\\"\\u003e\\n \\u003cp\\u003e0.04\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.5849%;\\\"\\u003e\\n \\u003cp\\u003e5.3\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.4086%;\\\"\\u003e\\n \\u003cp\\u003e0.3\\u0026ndash;95.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" style=\\\"width: 2.7621%;\\\"\\u003e\\n \\u003cp\\u003e0.26\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 21.8618%;\\\"\\u003e\\n \\u003cp\\u003eInterval between SRNS diagnosis and rituximab administration (years)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.291%;\\\"\\u003e\\n \\u003cp\\u003e3.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 5.2891%;\\\"\\u003e\\n \\u003cp\\u003e1.2\\u0026ndash;7.4\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" style=\\\"width: 3.291%;\\\"\\u003e\\n \\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.5849%;\\\"\\u003e\\n \\u003cp\\u003e3.6\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" style=\\\"width: 3.4086%;\\\"\\u003e\\n \\u003cp\\u003e1.2\\u0026ndash;11.0\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd align=\\\"left\\\" style=\\\"width: 2.7621%;\\\"\\u003e\\n \\u003cp\\u003e0.02\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\u003cp\\u003eCI, confidence interval; CR, complete remission; FSGS, focal segmental glomerulosclerosis; SRNS, steroid-resistant nephrotic syndrome\\u003c/p\\u003e\\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eDetermination of the interval between SRNS diagnosis and rituximab treatment to predict poor response\\u003c/h2\\u003e \\u003cp\\u003eThe receiver operating characteristic curve analysis was performed to determine whether poor response (non-CR) could be predicted by the interval between SRNS diagnosis and rituximab administration. As shown in Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e, the cutoff interval of 0.53 years had the best performance, with a sensitivity of 77% and a specificity of 90%. The rate of CR was higher in patients treated with rituximab within six months following SRNS diagnosis than in those treated with rituximab after six months following SRNS diagnosis (90.3% versus 21.4%; \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAssociation of one year disease status with long-term prognosis\\u003c/h2\\u003e \\u003cp\\u003eAt last observation, five patients were diagnosed with CKD G5. Table\\u0026nbsp;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e shows the relationship between disease status one year after rituximab administration and Cr-eGFR at last follow-up. None of the 31 patients with CR had a Cr-eGFR of \\u0026lt;\\u0026thinsp;60 mL/min/1.73 m\\u003csup\\u003e2\\u003c/sup\\u003e, whereas 2 of the 11 patients with PR and all 3 patients with NR had CKD G5 at last observation.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eThe relationship between treatment response one year after rituximab treatment and kidney function at last follow-up\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"8\\\"\\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 \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" morerows=\\\"1\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\" rowspan=\\\"2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"6\\\" nameend=\\\"c8\\\" namest=\\\"c3\\\"\\u003e \\u003cp\\u003eCr-eGFR at last follow-up (mL/min/1.73 m\\u003csup\\u003e2\\u003c/sup\\u003e)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e\\u0026ge;\\u0026thinsp;90\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e60\\u0026thinsp;\\u0026le;\\u0026thinsp;eGFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;90\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e30\\u0026thinsp;\\u0026le;\\u0026thinsp;eGFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;60\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e15\\u0026thinsp;\\u0026le;\\u0026thinsp;eGFR\\u0026thinsp;\\u0026lt;\\u0026thinsp;30\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e\\u0026lt;\\u0026thinsp;15 or RRT\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eTotal\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"3\\\" rowspan=\\\"4\\\"\\u003e \\u003cp\\u003eOutcome one year after rituximab administration\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eCR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e29\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e31\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e11\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eNR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eTotal\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e35\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e45\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"8\\\"\\u003eCR, complete remission; Cr-eGFR, creatinine-based estimated glomerular filtration rate; eGFR, estimated glomerular filtration rate; NR, no remission PR, partial remission; RRT, renal replacement therapy\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab5\\\" class=\\\"InternalRef\\\"\\u003e5\\u003c/span\\u003e shows the characteristics of the five patients with CKD G5 at last observation. Four of the five patients were initial non-responders with the kidney pathology of FSGS. Genetic testing was performed in three of the five patients (Patients 2, 4, and 5), revealing no relevant abnormalities. Kidney function was normal in two of the five patients (Patients 2 and 4) at the time of rituximab treatment. The interval between SRNS diagnosis and rituximab administration was more than one year in all five cases, with the longest period of 8.1 years in Patient 5.\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab5\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 5\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eDetails of the five patients who developed CKD G5 at last follow-up\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"9\\\"\\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 \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e \\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003ePatient no\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSex\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eEffects one year after rituximab administration\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInitial or late non-responder\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eFindings of kidney biopsy before rituximab administration\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003eDuration from kidney biopsy to rituximab administration\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003eAge at rituximab administration\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eDuration from SRNS diagnosis to rituximab administration (years)\\u003c/p\\u003e \\u003c/th\\u003e \\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003eCr-eGFR at rituximab administration\\u003c/p\\u003e \\u003cp\\u003e(mL/min/1.73 m\\u003csup\\u003e2\\u003c/sup\\u003e)\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInitial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eFSGS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e22 days\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e5.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e1.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e62.5\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003ePR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInitial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eFSGS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e2.4 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e15.2\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e4.5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e114.5\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInitial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eFSGS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e1.7 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e15.0\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e1.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e46.8\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e4\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eLate\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eMGA\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e10.1 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e14.3\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003eover 3.6\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e136.7\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e \\u003cp\\u003e5\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eMale\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003eNR\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e \\u003cp\\u003eInitial\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c5\\\"\\u003e \\u003cp\\u003eFSGS\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e \\u003cp\\u003e0.6 years\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c7\\\"\\u003e \\u003cp\\u003e19.9\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c8\\\"\\u003e \\u003cp\\u003e8.1\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c9\\\"\\u003e \\u003cp\\u003e59.4\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"9\\\"\\u003eCKD G5, chronic kidney disease stage G5; Cr-eGFR, creatinine-based estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; MGA, minor glomerular abnormalities; NR, no remission; PR, partial remission; SRNS, steroid-resistant nephrotic syndrome\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec14\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eAdverse events associated with rituximab treatment\\u003c/h2\\u003e \\u003cp\\u003eTable\\u0026nbsp;\\u003cspan refid=\\\"Tab6\\\" class=\\\"InternalRef\\\"\\u003e6\\u003c/span\\u003e summarizes the adverse events associated with rituximab treatment during the follow-up period. Nine patients (20%) experienced persistent severe hypogammaglobulinemia with a serum IgG level of \\u0026lt;\\u0026thinsp;200 mg/dL or required globulin replacement, and 5 patients (11%) had neutropenia with \\u0026lt;\\u0026thinsp;500 neutrophils/mm\\u003csup\\u003e3\\u003c/sup\\u003e. Thirteen cases of hypogammaglobulinemia or neutropenia requiring hospitalization or treatment occurred in 7 patients (16%).\\u003c/p\\u003e \\u003cp\\u003e \\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab6\\\" border=\\\"1\\\"\\u003e \\u003ccaption language=\\\"En\\\"\\u003e \\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 6\\u003c/div\\u003e \\u003cdiv class=\\\"CaptionContent\\\"\\u003e \\u003cp\\u003eAdverse events observed during the follow-up of patients treated with rituximab (n\\u0026thinsp;=\\u0026thinsp;45)\\u003c/p\\u003e \\u003c/div\\u003e \\u003c/caption\\u003e \\u003ccolgroup cols=\\\"3\\\"\\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 \\u003cthead\\u003e \\u003ctr\\u003e \\u003cth align=\\\"left\\\" colspan=\\\"3\\\" nameend=\\\"c3\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eCharacteristics\\u003c/p\\u003e \\u003c/th\\u003e \\u003c/tr\\u003e \\u003c/thead\\u003e \\u003ctbody\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eSevere hypogammaglobulinemia (serum IgG\\u0026thinsp;\\u0026lt;\\u0026thinsp;200 mg/dL) or immunoglobulin replacement treatment\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e9 (20)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eNeutropenia (neutrophil count\\u0026thinsp;\\u0026lt;\\u0026thinsp;500/mm\\u003csup\\u003e3\\u003c/sup\\u003e)\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5 (11)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colspan=\\\"2\\\" nameend=\\\"c2\\\" namest=\\\"c1\\\"\\u003e \\u003cp\\u003eNumber of patients presenting with infections associated with severe hypogammaglobulinemia or neutropenia requiring hospitalization or antiviral/antibiotic drugs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e7 (16)\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c1\\\" morerows=\\\"5\\\" rowspan=\\\"6\\\"\\u003e \\u003cp\\u003eNumber of infectious events associated with severe hypogammaglobulinemia or neutropenia requiring hospitalization or antiviral/antibiotic drugs\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eFebrile neutropenia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e3\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003ePneumonia\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e5\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eHerpes gingivitis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e2\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eInvasive pulmonary aspergillosis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eSinusitis\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003ctr\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e \\u003cp\\u003eOtitis media\\u003c/p\\u003e \\u003c/td\\u003e \\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e \\u003cp\\u003e1\\u003c/p\\u003e \\u003c/td\\u003e \\u003c/tr\\u003e \\u003c/tbody\\u003e \\u003c/colgroup\\u003e \\u003ctfoot\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003eData are expressed as numbers (%).\\u003c/td\\u003e\\u003c/tr\\u003e \\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003eIgG, immunoglobulin G\\u003c/td\\u003e\\u003c/tr\\u003e \\u003c/tfoot\\u003e \\u003c/table\\u003e\\u003c/div\\u003e \\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn the present study including 45 patients with refractory SRNS treated with rituximab, 69%, 24%, and 7% of the patients achieved CR, PR, and NR, respectively, at one year after treatment. The median time to CR was 90 days. Multivariate analysis revealed that the kidney pathology of FSGS and a long interval between SRNS diagnosis and rituximab administration, especially a period of more than six months, were significant risk factors for poor response. At last follow-up, none of the 31 patients in the CR group developed CKD G5, whereas 2 of the 11 patients in the PR group and all 3 patients in the NR group developed CKD G5, suggesting that early CR was associated with good long-term kidney prognosis.\\u003c/p\\u003e \\u003cp\\u003eThe therapeutic effect of rituximab in refractory SRNS remains controversial. In the only randomized controlled trial evaluating the efficacy of rituximab in patients with refractory SRNS [\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e], 31 pediatric patients with refractory SRNS were divided into the rituximab (n\\u0026thinsp;=\\u0026thinsp;16) and standard therapy (n\\u0026thinsp;=\\u0026thinsp;15) groups. The analyses revealed that rituximab did not reduce proteinuria three months after treatment initiation. However, three months might be too short to evaluate the efficacy of treatment in patients with refractory SRNS. Additionally, rituximab was administered at least 6 months (median, 1.3 years) after SRNS diagnosis, which was longer than that in the present study (median, 138 days). Moreover, immunosuppressive treatment after rituximab, such as MPT and calcineurin inhibitors, is crucial for successful therapeutic outcome for refractory SRNS [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. In the present study, MPT was added to the treatment regimen in 87% of the patients and calcineurin inhibitors (CsA or tacrolimus) were continued as post-rituximab treatment in 82% of the patients; these might have contributed to the excellent results observed in our study cohort.\\u003c/p\\u003e \\u003cp\\u003eIn the present study, the shorter interval between the SRNS diagnosis and rituximab administration was associated with higher remission, as reflected in the higher rate of CR in patients treated with rituximab within six months following SRNS diagnosis compared to those treated with rituximab after six months. All five patients who developed CKD G5 received rituximab treatment more than one year after SRNS diagnosis. Sinha et al. also reported that the interval between SRNS diagnosis and rituximab administration was significantly shorter in patients with CR or PR than in those with NR (8 versus 13 months; \\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.04) [\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e] and concluded that rituximab should be administered within 12 months after the diagnosis of SRNS. We suggest that the early administration of rituximab in combination with MPT and immunosuppressive drugs was associated with the favorable outcomes observed in our cohort.\\u003c/p\\u003e \\u003cp\\u003eOur analyses also revealed FSGS as a significant risk factor for treatment failure in patients with refractory SRNS, a detail speculated by two systematic reviews [\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]. MGA and FSGS are considered as identical to idiopathic nephrotic syndrome, although glomerular sclerosis is an irreversible change that worsens with long-term proteinuria [\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]. In the present study, two of the three patients with NR had FSGS. The remaining one patient was diagnosed with MGA 10 years before the rituximab administration and might have had FSGS at the time of rituximab treatment.\\u003c/p\\u003e \\u003cp\\u003eWe did not identify kidney dysfunction at the time of rituximab administration as a risk factor in the present study. Two of the three patients receiving hemodialysis at the time of rituximab administration achieved CR, whereas the remaining one patient achieved PR one year later; none of the three patients had kidney dysfunction at last follow-up. Conversely, one of the three patients with NR one year later who had normal kidney function after rituximab treatment eventually developed CKD G5.\\u003c/p\\u003e \\u003cp\\u003eThe optimal time to initiate rituximab treatment after SRNS diagnosis is unknown. In a study by Hamasaki et al., 61% and 93% of the patients with MGA/DMP treated with CsA achieved CR or PR within 1 and 4 months, respectively, whereas 71% and 86% of the patients with FSGS treated with CsA and MPT achieved CR or PR within 1 and 4 months, respectively [\\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e]. Therefore, observation for 1\\u0026ndash;4 months might be sufficient to evaluate the efficacy of CsA and MPT. In patients with SRNS resistant to combination treatment with CsA and MPT, rituximab should be added within six months after diagnosis before the progression of irreversible sclerotic lesions.\\u003c/p\\u003e \\u003cp\\u003eAdverse events associated with rituximab include hypogammaglobulinemia and neutropenia. In the present study cohort, 20%, 11%, and 16% of the patients experienced hypogammaglobulinemia, neutropenia, and infectious episodes related to these adverse events, respectively. In a previous observational study of 140 patients treated with rituximab for idiopathic nephrotic syndrome, we found that the incidence of infections in patients with normal, mildly low, and severely low IgG levels were 0.028, 0.071, and 0.096 per person-years, respectively, suggesting that the incidence of infections was relatively low even in patients with severe hypogammaglobulinemia [\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e]. In another study including 213 rituximab administrations given to114 patients with refractory nephrotic syndrome, we reported neutropenia in 9.6% of all patients and 5.2% of all rituximab infusions [\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e]. Altogether, accumulating evidence suggest that rituximab can be safely used if potential side effects are not overlooked.\\u003c/p\\u003e \\u003cp\\u003eOur findings should be interpreted with consideration of the study limitations. First, this was a retrospective observational study and the treatment protocol was not predetermined. Second, genetic testing was not performed in all patients. Three of the five patients with CKD G5 at last follow-up did not harbor genetic abnormalities, whereas one patient without genetic testing had a history of remission and recurrence after transplantation and was clinically considered to have nonhereditary FSGS. In the remaining one patient who developed CKD G5 and was initiated on hemodialysis, the possibility of genetic FSGS cannot be ruled out. Immunosuppressive therapy is considered to be ineffective in hereditary SRNS, although some patients have been reported to respond to immunosuppressive drugs [\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003eIn conclusion, in this multicenter, retrospective, observational study, combination treatment with rituximab, MPT, and immunosuppressive agents for refractory SRNS was associated with favorable outcomes. Risk factors for poor response were the pathologic finding of FSGS and a long interval between SRNS diagnosis and rituximab treatment, especially a period of more than six months. Early administration of rituximab in combination with CsA and MPT as post-rituximab immunosuppression might improve long-term prognosis in patients with refractory SRNS.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eCompeting Interests:\\u003c/h2\\u003e \\u003cp\\u003eKoichi Kamei has received research funding from the Public Foundation of Vaccination Research Center and the Taiju Life Social Welfare Foundation; donations from Chugai Pharmaceutical, Teijin Pharma, Kyowa Kirin, Shionogi, Daiichi Sankyo, Mitsubishi Tanabe Pharma, and Otsuka Pharmaceutical; and lecture fees from Terumo, Baxter, and Zenyaku Kogyo.\\u003c/p\\u003e\\u003ch2\\u003eEthics approval:\\u003c/h2\\u003e \\u003cp\\u003eThis study was approved by the Ethics Committee of the National Center for Child Health and Development (approval no: 2021\\u0026thinsp;\\u0026minus;\\u0026thinsp;111).\\u003c/p\\u003e\\u003cp\\u003e \\u003cstrong\\u003eConsent to participate:\\u003c/strong\\u003e \\u003c/p\\u003e\\u003cp\\u003eNot applicable\\u003c/p\\u003e \\u003cp\\u003e \\u003cstrong\\u003eConsent for publication:\\u003c/strong\\u003e \\u003cp\\u003eNot applicable\\u003c/p\\u003e \\u003c/p\\u003e\\u003ch2\\u003eFunding:\\u003c/h2\\u003e \\u003cp\\u003eThis study did not receive any external funding.\\u003c/p\\u003e\\u003ch2\\u003eAuthor contributions:\\u003c/h2\\u003e \\u003cp\\u003eAll authors were physicians treating the patients reported in the present study. Shunsuke Yokota prepared the manuscript and performed data collection and analysis. Kentaro Nishi, Mai Sato, Masao Ogura, Koji Sakuraya, Shuichiro Fujinaga, Riku Hamada, and Aya Inaba edited and reviewed the manuscript. Shuichi Ito advised the study protocol and revised the manuscript. Koichi Kamei oversaw the work as the corresponding author and revised the manuscript. All authors read and approved the final manuscript.\\u003c/p\\u003e\\u003ch2\\u003eAcknowledgments:\\u003c/h2\\u003e \\u003cp\\u003eWe thank Enago for editing a draft of this manuscript.\\u003c/p\\u003e\\u003ch2\\u003eData availability:\\u003c/h2\\u003e \\u003cp\\u003eThe datasets generated during and/or analyzed during the current study are not publicly available because permission for their publication was not obtained from the participants or approved by the Ethics Committee. However, the datasets are available from the corresponding author on reasonable request.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eSinha A, Hari P, Sharma PK, Gulati A, Kalaivani M, Mantan M, Dinda AK, Srivastava RN, Bagga A (2012) Disease course in steroid sensitive nephrotic syndrome. Indian Pediatr 49: 881-887. http://doi.org/10.1007/s13312-012-0220-4\\u003c/li\\u003e\\n\\u003cli\\u003eTarshish P, Tobin JN, Bernstein J, Edelmann Jr CM (1997) Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children. J Am Soc Nephol 8: 769-776. http://doi.org/10.1681/ASN.V85769\\u003c/li\\u003e\\n\\u003cli\\u003eIijima K, Sako M, Nozu K (2017) Rituximab for nephrotic syndrome in children. Clin Exp Nephrol 21: 193-202, http://doi.org/10.1007/s10157-016-1313-5\\u003c/li\\u003e\\n\\u003cli\\u003eMekahli D, LiutkusA, Ranchin B, Yu A, Bessenay L, Girardin E, Damme-Lombaerts RV, Palcoux JB, Cachat F, Lavocat MP, Bourdat-Michel G, Nobili F, Cochat P (2009) Long-term outcome of idiopathic steroid-resistance nephrotic syndrome: a multicenter study. Pediatr Nephrol 24: 1525-1532. http://doi.org/10.1007/s00467-009-1138-5\\u003c/li\\u003e\\n\\u003cli\\u003ePaik KH, Lee BH, Cho HY, Kang HG, Ha IS, Cheong HI, Jin DK, Moon KC, Choi Y (2007) Primary focal segmental glomerular sclerosis in children: clinical course and prognosis. Pediatr Nephrol 22: 389-395. http://doi.org/10.1007/s00467-006-0301-5\\u003c/li\\u003e\\n\\u003cli\\u003eZagury A, Oliveira AL, Montalv\\u0026atilde;o JAA, Novaes RHL, S\\u0026aacute; VM, Moraes CAP, Tavares MS (2013) Steroid-resistance idiopathic nephrotic syndrome in children: long-term follow-up and risk factors for end-stage renal disease. J Bras Nefrol 35: 191-199. http://doi.org/10.5935/0101-2800.20130031\\u003c/li\\u003e\\n\\u003cli\\u003eGipson DS, Chin H, Presler TP, Jennette C, Ferris ME, Massengill S, Gibson K, Thomas DB (2006) Differential risk of remission and ESRD in childhood FSGS. Pediatr Nephrol 21: 344-349. http://doi.org/10.1007/s00467-005-2097-0\\u003c/li\\u003e\\n\\u003cli\\u003eAbeyagunawardena AS, Sebire NJ, Risdon RA, Dillon MJ, Rees L, Hoff WV, Kumarasiri PV, Trompeter RS (2007) Predictors of long-term outcome of children with idiopathic focal segmental glomerulosclerosis. Pediatr Nephrol 22: 215-221. http://doi.org/10.1007/s00467-006-0264-6\\u003c/li\\u003e\\n\\u003cli\\u003eLee JM, Kronbichler A, Shin JI, Oh J (2021) Current understandings in treating children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 36: 747-761. http://doi.org/10.1007/s00467-020-04476-9\\u003c/li\\u003e\\n\\u003cli\\u003eKamei K, Ishikura K, Sako M, Ito S, Nozu K, Iijima K (2020) Rituximab therapy for refractory steroid-resistant nephrotic syndrome in children. Pediatr Nephrol 35: 17-24. http://doi.org/10.1007/s00467-018-4166-1\\u003c/li\\u003e\\n\\u003cli\\u003eJellouli M, Charfi R, Maalej B, Mahfoud A, Trabelsi S, Gargah T (2018) Rituximab in the management of pediatric steroid-resistant nephrotic syndrome: a systematic review. J Pediatr 197: 191-197. http://doi.org/10.1016/j.jpeds.2018.01.008\\u003c/li\\u003e\\n\\u003cli\\u003eKamei K, Okada M, Sato M, Fujimaru T, Ogura M, Nakayama M, Kaito H, Iijima K, Ito S (2014) Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome. Pediatr Nephrol 29: 1181-1187. http://doi.org/10.1007/s00467-014-2765-z\\u003c/li\\u003e\\n\\u003cli\\u003eKamei K, Ishikura K (2016) Rituximab treatment for refractory steroid-resistant nephrotic syndrome. Pediatr Nephrol 31: 337-338. http://doi.org/10.1007/s00467-015-3205-4\\u003c/li\\u003e\\n\\u003cli\\u003eAndrew JBW, Keith HK, Gabriel L, IVY R, Bernard AC, Miroslav S, Sushrut SW, Anil C, Leonardo VR, Mariam PA, Jonathan PT, Junbo C, Damian F, Jennifer LY, Matthew GS, Laurence HB Jr, Joel MH, Anna G, Helmut GR, Astrid W (2022) Discovery of autoantibodies targeting nephrin in minimal change disease supports a novel etiology. J Am Soc Nephrol 33: 238-252. http://doi.10.1681/ASN.2021060794.\\u003c/li\\u003e\\n\\u003cli\\u003eFujinaga S, Nishino T, Umeda C, Tomii Y, Watanabe Y, Sakuraya K (2019) Long-term outcomes after treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome. Pediatr Nephrol 34: 353-357. http://doi.org/10.1007/s00467-018-4145-6\\u003c/li\\u003e\\n\\u003cli\\u003eAgnes T, Olivia B, Elisabeth H, Arvind B, Debbie SG, Susan S, Jack W, Khalid A, Sushmita B, Rajendra B, Melvin BF, Francisco C, Martin C, Deirdre H, Hee GK, Nakanishi K, Hesham S, Howard T, Hong X, Wendy C, Marina V, Dieter H; International Pediatric Nephrology Association (2023) IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome. Pediatr Nephrol 38: 877-919. http://doi.org/10.1007/s00467-022-05739-3\\u003c/li\\u003e\\n\\u003cli\\u003eMagnasco A, Ravani P, Edefonti A, Murer L, Ghio L, Belingheri M, Benetti E, Murtas C, Messina G, Massella L, Porcellini MG, Montagna M, Regazzi M, Scolari F, Ghiggeri GM (2012) Rituximab in children with resistant idiopathic nephrotic syndrome. J Am Soc Nephrol 23: 1117-1124. http://doi.org/10.1681/ASN.2011080775\\u003c/li\\u003e\\n\\u003cli\\u003eSuyama K, Kawasaki Y, Miyazaki K, Kanno S, Ono A, Suzuki Y, Ohara S, Hosoya M (2016) Rituximab and low-dose cyclosporine combination therapy for steroid-resistant focal segmental glomerulosclerosis. Pediatr Int 58: 219-223. http://doi.org/10.1111/ped.12804\\u003c/li\\u003e\\n\\u003cli\\u003eSinha R, Banerjee S, Mukherjee A, Pradhan S, Akhtar S (2020) Early use of rituximab in calcineurin inhibitor-refractory and steroid-resistant nephrotic syndrome. Kidney Int Rep 5: 2354-2357. http://doi.org/10.1016/j.ekir.2020.09.021\\u003c/li\\u003e\\n\\u003cli\\u003eWatanabe Y, Fujinaga S, Endo A, Nakagawa M, Sakuraya K (2020) Baseline characteristics and long-term outcomes of steroid-resistant nephrotic syndrome in children: impact of initial kidney histology. Pediatr Nephrol 35: 2377-2381. https://doi.org/10.1007/s00467-020-04760-8\\u003c/li\\u003e\\n\\u003cli\\u003eHamasaki Y, Yoshikawa N, Hattori S, Sasaki S, Iijima K, Nakanishi K, Matsuyama T, Ishikura K, Yata N, Kaneko T, Honda M, Japanese Study Group of Renal Disease (2009) Prospective 5-year follow-up of cyclosporine treatment in children with steroid-resistant nephrosis. Pediatr Nephrol 24: 2177-2185. http://doi.org/10.1007/s00467-009-1264-0\\u003c/li\\u003e\\n\\u003cli\\u003eInoki Y, Nishi K, Sato M, Ogura M, Kamei K (2023) The association between hypogammaglobulinemia severity and infection risk in rituximab-treated patients with childhood-onset idiopathic nephrotic syndrome. Pediatr Nephrol 38: 451-460. http://doi.org/10.1007/s00467-022-05652-9\\u003c/li\\u003e\\n\\u003cli\\u003eKamei K, Takahashi M, Fuyama M, Saida K, Machida H, Sato M, Ogura M, Ito S (2014) Rituximab-associated agranulocytosis in children with refractory idiopathic nephrotic syndrome: case series and review of literature. Nephrol Dial Transplant 30: 91-96. http://doi.org/10.1093/ndt/gfu258\\u003c/li\\u003e\\n\\u003cli\\u003eB\\u0026uuml;scher AK, Beck BB, Melk A, Hoefele J, Kranz B, Bamborschke D, Baig S, Lange-Sperandio B, Jungraithmayr T, Weber LT, Kemper MJ, T\\u0026ouml;nshoff B, Hoyer PF, Konrad M, Weber S, German Pediatric Nephrology Association (GPN) (2016) Rapid response to cyclosporin A and favorable renal outcome in nongenetic versus genetic steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 11: 245-253. http://doi.org/10.2215/CJN.07370715\\u003c/li\\u003e\\n\\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\":true,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"pediatric-nephrology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"pnep\",\"sideBox\":\"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)\",\"snPcode\":\"467\",\"submissionUrl\":\"https://www.editorialmanager.com/pnep/default2.aspx\",\"title\":\"Pediatric Nephrology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"refractory steroid-resistant nephrotic syndrome, rituximab, methylprednisolone pulse therapy, cyclosporine, chronic kidney disease stage G5, long-term prognosis\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-3972976/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-3972976/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eThe efficacy of rituximab in refractory steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eThis retrospective study included 45 patients with childhood-onset refractory SRNS treated with rituximab treatment across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. Risk factors for poor response (non-CR) were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were evaluated.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eThe rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (\\u003cem\\u003ep\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5.\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003eEarly administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with refractory SRNS.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset refractory steroid-resistant nephrotic syndrome: a multicenter study\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-02-23 17:48:18\",\"doi\":\"10.21203/rs.3.rs-3972976/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Major Revisions Needed\",\"date\":\"2024-03-25T11:30:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2024-02-26T16:02:24+00:00\",\"index\":0,\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2024-02-20T18:30:51+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2024-02-20T17:05:14+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Pediatric Nephrology\",\"date\":\"2024-02-19T09:59:42+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"pediatric-nephrology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"pnep\",\"sideBox\":\"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)\",\"snPcode\":\"467\",\"submissionUrl\":\"https://www.editorialmanager.com/pnep/default2.aspx\",\"title\":\"Pediatric Nephrology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"b9976d15-2afb-4f42-a9dd-ae75e9de48dc\",\"owner\":[],\"postedDate\":\"February 23rd, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-05-11T23:57:15+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2024-02-23 17:48:18\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-3972976\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-3972976\",\"identity\":\"rs-3972976\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}