Application of rituximab to treat minimal change disease with refractory nephrotic syndrome in the remission maintenance phase with long-term follow-up

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Rituximab has been confirmed to be an effective treatment for refractory MCD. However, in the remission maintenance phase, the effects of multiple factors remain unclear, including the dose or infusion interval of rituximab, the use of concomitant immunosuppressants, the relapse rate, the relationship between B-cell reconstruction and relapse, and relapse-related factors. Methods: We reviewed 14 refractory MCD patients receiving rituximab with a mean follow-up duration of 25.9±8.9 months. Three patients were in partial remission, and 11 patients achieved complete remission before RTX treatment. RTX was administered intravenously at a dose of 375 mg/m 2 body surface area or 1000 mg initially. In the subsequent treatment, RTX was administered at 375 mg/m 2 body surface area or 1000 mg every infusion. Result: Nine patients with a mean annual RTX dose of 1929±504 mg remained in remission. Five patients experience a relapse, and their mean annual RTX dose significantly decreased to 940±111 mg (P<0.05). Eleven patients stopped steroids or immunosuppressants, and 3 patients had a reduction in steroids or immunosuppressants. The relapse frequency significantly decreased from 1.87 (0.43, 2.69) to 0 (0, 1.33). B-cell reconstruction was not associated with relapse. The cumulative annual dose of RTX was significantly negatively correlated with relapse. Conclusion: RTX significantly reduced the relapse rate and facilitated earlier withdrawal of corticosteroids and immunosuppressants during the remission maintenance phase in refractory MCD patients. Serious side effects were not reported. During the remission phase, we can extend the infusion interval appropriately but cannot ignore the case of an accumulated annual dose of RTX. Minimal change disease (MCD) Rituximab (RTX) Refractory nephrotic syndrome Relapse Figures Figure 1 Background Minimal change disease (MCD) affects approximately 10–15% of adult patients with idiopathic nephrotic syndrome. Glucocorticoids are recommended as first-line therapies for MCD according to Kidney Disease: Improving Global Outcomes (KDIGO)[1]. The response rate is reported to be 75%[2]. Cyclosporine A, cyclophosphamide, mycophenolate mofetil, azathioprine, tacrolimus, and levamisole are used as second-line therapeutic approaches[3, 4]. However, MCD has a high recurrence rate. Although corticosteroids and the aforementioned immunosuppressive agents can be employed to manage refractory minimal change disease, their use is often met with significant apprehension due to the spectrum of potential adverse effects, such as steroid-induced diabetes, hypertension, water‒sodium retention, dyslipidemia, increased cardiovascular events, and decreased bone mineralization, such as femoral head necrosis, renal function damage with CNI, infections from mycophenolate, and infertility with cyclophosphamide. Therefore, a therapy with a higher level of patient satisfaction is desirable. Rituximab is a chimeric murine/human monoclonal immunoglobulin antibody that binds to CD20-positive lymphocytes and inhibits their proliferation and differentiation. It is used to treat non-Hodgkin lymphoma, rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis. It has already been frequently used in the pediatric population. Rituximab has been proven to be a safe and effective therapy for adult MCD, especially for frequently relapsing or steroid-dependent MCD[5–9]. However, long-term outcomes, particularly in the remission maintenance phase of MCD, are in doubt. This study aimed to observe the infusion dose, infusion interval, and relapse rate and to identify relapse-related factors in the maintenance remission phase. Study design and population In this retrospective study, we recruited 14 patients who had an estimated glomerular filtration rate (eGFR) of more than 60 mL/min, as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation, and were diagnosed with MCD with biopsy confirmation. These patients are clinically classified as having refractory nephrotic syndrome. They were treated with RTX and were in remission at the Second Hospital of Hebei Medical University between May 2021 and October 2024. Clinical characteristics We retrieved the following clinical and laboratory data: baseline characteristics (age at disease diagnosis, age at RTX start, sex, comorbidities, systolic blood pressure (SP), diastolic blood pressure (DP), renal biopsy, NS type, relapse rate before RTX, relapse rate after RTX, and previous treatments), and clinical data (RTX first dose, RTX total dose, RTX infusion interval, and concomitant use of steroids and immunosuppressants (ISs)). Treatment protocol RTX was initially administered at 375 mg/m 2 body surface area or 1000 mg in all patients. Eight patients received a second RTX infusion 1 month after the first infusion. We defined RTX infusions twice a month as the first treatment. Most patients received a second treatment at six-month intervals. In subsequent infusion treatments, the intervals were usually more than 6 months. We evaluated all patients before RTX infusion to exclude patients who had contraindications. Routine blood parameters, electrolytes, cardiac enzymes, troponin, chest CT images and ECG findings were collected prior to infusion. To minimize infusion reactions, methylprednisolone and diphenhydramine hydrochloride were given before drug infusion. ECG monitoring was performed during infusion. Statistical analysis Statistical analysis was performed using Statistical Product and Service Solutions (SPSS) 20.0 (IBM Corp., NY, USA). The normality of the distribution of quantitative variables was evaluated using the Shapiro–Wilk test. All continuous variables are expressed as the mean±SD or median (minimum, maximum). We used nonparametric statistical methods to compare the correlations between two variables. All p values were two-sided. P < 0.05 was considered significant. Results Baseline characteristics The baseline characteristics of the study population are summarized in Table 1. The median age at disease diagnosis was 18.3 years (10.2–47.5 years), and the median age at the start of RTX treatment was 21.7 years (15.3–48.5 years). Kidney biopsy revealed minimal change disease without acute tubular necrosis. The use of previous steroids or immunosuppressants and the types of refractory nephrotic syndrome are displayed in Table 2. Thirteen patients had received corticosteroids before RTX infusion. Most patients used other immunosuppressants, such as calcineurin inhibitors (n=8), cyclophosphamide (n=1), leflunomide (n=2), Tripterygium glycosides (n=1), and mycophenolate mofetil (n=1). Some patients (4/14) had received three or more immunosuppressive regimens prior to RTX. The baseline 24-hour urine protein level was 0.13 g (0.01–2.4 g). The serum ALB concentration was 42.08±3.83 g/L. The serum creatinine level was 69.50±12.57 µmol/L. The baseline eGFR was 123.01±13.50 mL/min per 1.73 m 2 . The CHOL concentration was 4.51±0.90 mmol/L. The number of CD19+ B cells was /μL. The mean follow-up time was 25.9±8.9 months. RTX dose The clinical courses of the 14 patients are summarized in Table 3. RTX (375 mg/m 2 body surface area) was given to 6 patients. The other 8 patients initially received 1000 mg RTX. Eight patients (Patient 1, Patient 3, Patient 4, Patient 5, Patient 7, Patient 9, Patient 11, and Patient 14) received the same dose of RTX one month after the first infusion. RTX was administered at 375 mg/m 2 body surface area or 1000 mg of every infusion. The cumulative dose of RTX in all patients ranged from 600 to 2000 mg within six months. We calculated the annual cumulative dose of RTX (Table 4). In addition to the patients who relapsed (Patient 4, Patient 6, Patient 9, Patient 10, Patient 14) and Patient 8, who did not receive a second dose of RTX, the average annual cumulative dose of RTX was 1929±504 mg. In contrast, the annual cumulative dose of RTX in the patients who relapsed was significantly lower, at 940±111 mg (P<0.001, Figure 1). The total RTX dose for all patients ranged from 1000 to 4500 mg until the end of follow-up. RTX interval of infusion Eight patients received a second RTX infusion one month after the first infusion. We defined two infusions within 1 month as the first treatment. The second treatment interval was 8.7±3.7 months, with the exception of 3 patients who experienced relapse (Patient 6, Patient 10, Patient 14), whose infusion intervals were 9, 12 and 22 months. Some patients who received the third RTX treatment had infusion intervals of 12±3.1 months. Three patients agreed to the fourth RTX treatment, but unfortunately, one patient experienced a relapse; this patient had an infusion interval of 20 months. The other two patients had infusion intervals of 7 and 8 months. Concomitant use of steroids and ISs Eleven patients stopped steroids or immunosuppressants during RTX treatment. The remaining 3 patients had a reduction in the use of steroids or immunosuppressants. Dadas are summarized in Table 5. The duration of discontinuation of steroids or immunosuppressants was 8.5±4.3 months after RTX treatment. CD19‑positive B‑cells In all patients, CD19-positive B cells were completely eradicated during the first infusion of RTX. B-cell reconstruction occurred approximately 6 months after the administration of rituximab. Among the 5 patients who experienced relapse, the number of CD19-positive B cells was elevated during recurrence. However, among patients without recurrence, B-cell reconstruction occurred in most patients. A CD19-positive B-cell count was not associated with recurrence. The relapse rate and relapse-related factors Nine patients were in sustained remission, and the remaining 5 patients (Patient 4, Patient 6, Patient 9, Patient 10, and Patient 14) experienced relapse. In addition to Patient 10, the remaining patients who experienced relapse continued to receive RTX treatment and were in stable remission. The relapse frequency significantly decreased from 1.87 (0.43, 2.69) to 0 (0, 1.33). To determine the cause of recurrence, we performed a correlation analysis to examine the association of relapse with the age at disease diagnosis, age of RTX application, sex, comorbidities, blood pressure, type of nephrotic syndrome, immunosuppressive use, CD19+ B-cell count, prerecurrence rate, RTX dose, RTX frequency, average annual usage of RTX, and RTX infusion interval. The results revealed that cumulative annual dose of RTX and the combination of multiple immunosuppressants are associated with relapse. According to logistic regression, the annual dose of RTX was significantly negatively correlated with recurrence. AEs In our study, RTX was well tolerated. No serious adverse events were observed during or after rituximab infusion. Three of the 14 patients experienced transient skin rash on the body, which was resolved with a second dose of 40 mg of methylprednisolone, slowing the infusion rate. One of the 14 patients experienced thoracic pain, which was relieved by slowing the infusion rate. No infection-related diseases appeared. Discussion MCD represents approximately 10–15% of patients with idiopathic nephrotic syndrome in adults. Glucocorticoid monotherapy is recommended as the initial treatment. Patients with refractory minimal change disease, including steroid-dependent nephrotic syndrome (SDNS), steroid-resistant nephrotic syndrome (SRNS), and frequently relapsing nephrotic syndrome (FRNS), require long-term therapeutic strategies involving either prolonged corticosteroid maintenance therapy or combination regimens incorporating other immunosuppressive agents. Individuals often demonstrate reluctance to adhere to these immunosuppressive protocols because of these side effects. Even so, recurrences often occur, thus accelerating disease progression and relapse episodes. Rituximab can prevent some of these side effects and reduce the recurrence rate. An increasing number of studies have confirmed that RTX is a promising therapeutic option for MCD[5–7, 10–13]. The pathogenesis of MCD is undefined. Diffuse effacement of podocyte foot processes, the absence of electron-dense deposits or negative immunofluorescence staining are the characteristics of MCD[3]. Dysregulated T cells can produce abnormally increased circulating permeability factors, thus driving the injury of podocytes in MCD. Different lines of evidence suggest a reduced function of regulatory T cells in MCD in adult patients. B lymphocytes play a crucial role in the pathogenesis of idiopathic minimal change disease[14, 15]. RTX can eliminate B cells and disrupt B-cell–T-cell interactions, thus reducing the production of permeability factors. Additionally, rituximab plays a role in B-cell-independent mechanisms. Perosa et al. reported that rituximab might cross-react with sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL-3b) rather than acting directly on antibody production. Rituximab might prevent actin cytoskeleton remodeling in podocytes by preserving sphingolipid-related enzymes, SMPDL-3b and ASMase activity[16]. The podocyte cytoskeleton may be a direct target for RTX through a B lymphocyte-independent mechanism[17]. The recent discovery of nephrin autoantibodies in a subset with minimal change disease provides further support for MCD etiology, which may lead to a new molecular classification of nephrin autoantibody minimal change disease and instigate new therapeutics for MCD. Patients with anti-slit antibodies show a good response to second-line immunosuppressants and a favorable long-term outcomes. The detection of anti-slit antibodies in kidney biopsies, in addition to the measurement of anti- nephrin antibodies in the serum of patients with steroid-resistant NS, enables the identification of patients who are more likely to respond to intense immunosuppression. In the remission maintenance period of MCD, the regimens of RTX are confusing. There is no treatment guidance for the dose or infusion interval. A few studies have provided suggestions for the induction period of MCD. It varies greatly from 500 mg, 375 mg/m 2 or 1000 mg at one or two time points, even once weekly for 4 weeks[14, 18–22]. Takei et al. performed a prospective trial in 25 MCNS (steroid-dependent minimal-change nephrotic syndrome) patients who used a single dose of RTX (375 mg/m 2 body surface area) twice at an interval of 6 months[22]. Among the 13 patients with MCD who were in remission with prednisolone (PSL), immunosuppressant (IS) treatment or both, most patients received RTX two to four times at 6-month intervals with a single dose of 375 mg/m 2 body surface area (maximum 500 mg)[11]. In our study, RTX was initially administered at 375 mg/m 2 body surface area or 1000 mg, while some patients were remedicated with RTX one month after the first infusion. In the follow-up treatment, every infusion dose was 375 mg/m 2 body surface area or 1000 mg. The annual dose of RTX in patients who were in remission throughout our study was significantly greater than that in patients who experienced relapse. There are few studies on the infusion interval for MCD. Among relapsing ANCA-vasculitis patients, fixed-interval rituximab retreatment has been suggested or considered a more prolonged period of remission[23]. In previous short-term studies of RTX in MCD patients, the infusion intervals for remission maintenance were mostly fixed at 6-month intervals. However, depending on each patient's condition and economic factors, the infusion intervals used in our study differed. After the RTX first treatment, the second infusion was 8.7 ± 3.7 months after the first infusion. Among relapsed patients, the infusion intervals seemed to be longer. Some patients who received the third RTX treatment had a mean infusion interval of 12 ± 3.1 months. The infusion intervals in our study were relatively long and seemingly could have increased with increasing duration of treatment. The patient with the longest follow-up duration (41 months) did not receive rituximab for the fourth time until he relapsed. The interval between infusions was 20 months for this patient. Owing to the limitations of our follow-up period, few patients who received long-term rituximab were included. Does the infusion interval lengthen as the treatment progresses? This was the first study to explore the infusion interval. We need to design trials with more patients and longer periods of time to test this conclusion in the future. In terms of reducing the relapse rate or reducing the steroid dose, RTX greatly contributes. Takei et al. confirmed that rituximab therapy was associated with a reduction in relapse frequency and in the total dose of PSL needed. Munyentwali et al. analyzed 17 patients with steroid-dependent or frequently relapsing minimal change nephrotic syndrome. Some of them stopped or had a reduction in the use of steroid and IS drugs[24]. Recently, a report verified that RTX treatment resulted in an 80.3% remission rate[6]. In another systematic review and meta-analysis, RTX treatment resulted in a 91.6% CR rate, and 27.4% of patients experienced at least one relapse after RTX treatment. RTX is associated with trivial adverse events and good tolerance[7]. RTX has the potential to maintain prolonged remission. In our study, the median relapse frequency significantly decreased from 1.87 (0.43, 2.69) to 0 (0, 1.33) times/year, which was the same as that reported in some previous studies. Five patients experienced relapse, and 11 patients stopped steroids or immunosuppressants during RTX treatment. The remaining 3 patients experienced a reduction. This finding reinforced the role of rituximab as a glucocorticoid (GC) or IS-sparing agent. Early termination of immunosuppressants could greatly reduce harm to the body. Rituximab has also been shown to be effective in treating steroid-resistant nephrotic syndrome (SRNS). The relationship between relapse and CD19-positive B-cell repletion has been reported in many studies[5, 22, 24–26]. Some studies have concluded that an increase in the number of CD19-positive B cells is associated with disease relapse. However, Takei T concluded that B-cell restitution was not related to relapse[22]. In our study, relapse had no connection with B-cell reconstitution. We analyzed relapse with many possible related factors. Finally, the annual accumulative dose of RTX and the combination of multiple immunosuppressants were associated with relapse. According to logistic regression, the annual dose of RTX was significantly negatively correlated with recurrence. Neither the frequency nor the dose of rituximab was related to relapse. On the basis of experience with the infusion interval for other diseases (membranous nephropathy or ANCA-associated vasculitis), we recommend trying an infusion interval of six months or more; however, we cannot ignore the annual use of RTX in the early maintenance period. Extending the infusion period can not only reduce drug-related side effects but also relieve the financial burden on patients. Additionally, the blood concentration of RTX affects disease function. A few studies have suggested that urinary loss of RTX shortens the B-cell depletion period, which leads to relapse[24, 27]. Unfortunately, rituximab concentrations were not measured in our study. The type of disease, age, concomitant use of immunosuppressants, and dose and frequency of RTX are factors affecting the duration of B-cell depletion[28, 29]. There are several limitations to our study. First, this was a retrospective study lacking comparisons and concomitant therapy. The objects of the study were limited. Second, all MCD patients included in our research were identified on the basis of initial biopsy. Whether these patients potentially progress to FSGS remains unknown. Conclusions In conclusion, RTX could significantly reduce the relapse rate and facilitate earlier withdrawal of corticosteroids and immunosuppressants, which are well tolerated during the remission maintenance phase in refractory MCD. In the remission phase, we can extend the infusion interval appropriately but cannot ignore the case of an accumulated annual dose of RTX. The optimal rituximab dosage, infusion interval, subsequent treatment or more profound mechanisms associated with RTX are confusing. We hope more trials explore these questions. Declarations Acknowledgments We gratefully acknowledge all the participants who contributed to this study. Author contributions Li Tian, Liying Wen, Ranjie Fu, and Xuzhi Liang collected data from MCD patients. Li Tian and Lingling Xing completed the statistical calculations. Shaomei Li was the main contributor to the writing of the manuscript. All the authors read and approved the final manuscript. Funding Not applicable. Data availability The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. Declarations Ethical approval and consent to participate This retrospective study was approved by the Research Ethics Committee of The Second Hospital of Hebei Medical University. (ethics number: 2024-r399). Consent for publication Not applicable. Clinical trial number Not applicable. Competing interests The authors declare that they have no competing interests. References Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ et al : Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int 2021, 100(4):753-779. 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Munyentwali H, Bouachi K, Audard V, Remy P, Lang P, Mojaat R, Deschênes G, Ronco PM, Plaisier EM, Dahan KY: Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease. Kidney Int 2013, 83(3):511-516. Kamei K, Ito S, Nozu K, Fujinaga S, Nakayama M, Sako M, Saito M, Yoneko M, Iijima K: Single dose of rituximab for refractory steroid-dependent nephrotic syndrome in children. Pediatr Nephrol 2009, 24(7):1321-1328. Ruggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, Marasà M, Chianca A, Rubis N, Ene-Iordache B, Rudnicki M et al : Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J Am Soc Nephrol 2014, 25 (4):850-863. Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet H et al : Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. Pediatr Nephrol 2008, 23(8):1269-1279. Thiel J, Rizzi M, Engesser M, Dufner AK, Troilo A, Lorenzetti R, Voll RE, Venhoff N: B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. Arthritis Res Ther 2017, 19(1):101. Hogan J, Dossier C, Kwon T, Macher MA, Maisin A, Couderc A, Niel O, Baudouin V, Deschênes G: Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome. Pediatr Nephrol 2019, 34(2):253-259. Tables Table 1 The baseline characteristics of the study population Characteristics Patients of refractory MCD Age years, Median (IQR) age at disease diagnosis 18.3(10.2-47.5) age at RTX start 21.7(15.3-48.5) Sex ratio (F/M) 3/11 Comorbidities Diabetes,n (%) 1（7.1） Thromboembolic disease,n (%) 1（7.1） coronary heart disease 1（7.1） Blood-Pressure,mmHg, Mean ± SD Systolic 121.7±9.1 Diastolic 84.5±9.5 renal biopsy MCD,n (%) 14（100） MCD+ATN,n (%) 0（0） NS type SDNS , n (%) 8（57.1） FRNS , n (%) 4（28.6） SRNS, n (%) 2（14.3） Previous IS treatments Steroid, n (%) 13（92.9） calcineurin inhibitor,n, (%) 8（57.1） cyclophosphamide,n (%) 1（7.1） leflunomide 2（14.3） tripterygium glycosides 1（7.1） mycophenolate mofetil 1（7.1） three or more immunosuppressants,n (%) 4（28.6） relapse times before RTX, times/year，Mean ± SD 1.67±0.69 24-hour urinary protein excretion, g,Median (IQR) 0.13（0.01-2.4） Serum albumin, g/L, Mean ± SD 42.08±3.83 Serum creatinine,µmol/L, Mean ± SD 69.50±12.57 eGFR (CKD-EPI), ml/min*1.73m2, Mean ± SD 123.01±13.50 CHOL，mmol/L，Mean ± SD 4.51±0.90 CD19 positive B-cells，number/ul，Median (IQR) 243（106-642） Follow-up time, months, Mean ± SD 25.9±8.9 Quantitative data were expressed as median (minimum，maximum) or mean±standard deviation (SD) categorical data were presented as frequencies eGFR, estimated glomerular filtration rate;IS, immunosupressants；SDNS, steroid-dependent NS; FRNS, frequently relapsing NS;SRNS, steriod-resistant NS Table 2 The use of previous steroids or immunosuppressants and types of refractory nephrotic syndrome patient number Types of refractory nephrotic syndrome Previous immunosuppressants Number of relapse 1 SDNS S 1 2 SDNS S，TAC 2 3 FRNS S，CSA 3 4 FRNS S，TAC，TPG 6 5 SDNS S，CSA 2 6 FRNS S，LEF，MMF，TAC 7 7 SDNS S 4 8 SDNS S,TAC 3 9 SRNS S，TAC，CSA，CTX，MMF 20 10 SDNS TAC 2 11 SRNS S，CSA 3 12 SDNS S，CSA 4 13 FRNS S，TAC，CSA，LEF 10 14 SDNS S，CSA 2 SDNS:steroid dependent nephrotic syndrome;SRNS:steroid resistaSRNSt nephrotic syndrome;FRNS:frequent relapse nephrotic syndrome; S:steroid;CSA:cyclosporin A;TAC:tacrolimus,CTX:cyclophosphamide;LEF: leflunomide; TPG:tripterygium glycosides;MMF:mycophenolate mofetil Table 3 The clinical courses for RTX dose and infusion intervals patient number The first dose of RTX ,mg The second RTX one month apart the first infusion RTX accumulated dose in six month,mg RTX total dose before relapse, mg RTX frequency before relapse， times Having a relapse during RTX administer RTX total dose 1 1000 yes 2000 3000 4 no 3000 2 1000 no 1000 2600 3 no 2600 3 1000 yes 2000 4500 5 no 4500 4 1000 yes 2000 3000 4 yes 4500 5 1000 yes 2000 3000 4 no 3000 6 600 no 600 600 1 yes 1200 7 1000 yes 2000 3100 4 no 3100 8 1000 no 1000 1000 1 no 1000 9 600 yes 1800 3600 5 yes 4200 10 1000 no 1000 1000 1 yes 1000 11 600 yes 1200 1700 3 no 1700 12 700 no 700 1500 2 no 1500 13 600 no 600 1200 2 no 1200 14 700 yes 1400 1400 2 yes 2100 Table 4 The annual cumulative dose of RTX in all patients patient number medication time,month The annual dose of RTX Having a relapse during RTX administer 1 22 3000 no 2 22 2600 no 3 31 4500 no 4 35 4500 yes 5 18 3000 no 6 9 1200 yes 7 21 3100 no 8 - 1000 no 9 34 4200 yes 10 12 1000 yes 11 9 1700 no 12 6 1500 no 13 9 1200 no 14 20 2100 yes Medicine time: The time from the first to the last application of RTX or the time from the first RTX to relapse Annual dose of RTX: The total dose of rituximab divided by year of application Table 5 The steroids and immunosuppresants during RTX treatment patient number IS in use at RTX initiaton IS in use after RTX IS stopping time 1 MP 4 S 6 2 PSL 15 TAC 2 S 8 3 CSA 100 S 6 4 MP 6 TAC 2 S 12 5 PSL 5 CSA100 S 2 6 PSL 20 R - 7 PSL 7.5 S 16 8 PSL20 S 13 9 PSL 35 TAC 3 S 24 10 TAC 2 R - 11 PSL 20 CSA 150 S 10 12 MP 16 CSA150 S 4 13 PSL30 TAC 3 R - 14 PSL 5 CSA 50 S 8 S,stop the use of immunosupressants;R,reduce the dose of immunosupressants;MP, methylprednisolone;PSL, prednisolone;CSA, cyclosporin A;TAC, tacrolimus Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5858633","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":434259824,"identity":"c6fd18d4-1b3b-4d75-b53e-c43d077e9cae","order_by":0,"name":"Li Tian","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Tian","suffix":""},{"id":434259825,"identity":"681e3cbc-ce22-4fc5-934f-85fe0c0f3628","order_by":1,"name":"Lingling Xing","email":"","orcid":"","institution":"The Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lingling","middleName":"","lastName":"Xing","suffix":""},{"id":434259826,"identity":"c8a8e01a-bf49-4c37-9136-b27024c971cc","order_by":2,"name":"Liying Wen","email":"","orcid":"","institution":"The Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liying","middleName":"","lastName":"Wen","suffix":""},{"id":434259827,"identity":"4466135e-8fd3-495c-a1ec-34af7ddd6087","order_by":3,"name":"Ranjie Fu","email":"","orcid":"","institution":"The Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ranjie","middleName":"","lastName":"Fu","suffix":""},{"id":434259828,"identity":"c144da98-8fdb-487e-8174-f914b970bdc0","order_by":4,"name":"Xuzhi Liang","email":"","orcid":"","institution":"The Second Hospital of Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xuzhi","middleName":"","lastName":"Liang","suffix":""},{"id":434259829,"identity":"7030fb6b-61e5-47a4-b671-62bcb28fa9bc","order_by":5,"name":"Shaomei Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIiWNgGAWjYBACPmYGNjCDDSogx8befgCvFja4FqgeYz6eMwn4tcDNh1KJ8yQcDPBrYWd/9uBHxTY5PvnmY5JfamzS2yQYEhiAIngcxmNu2HPmtjEbG1uatMyxtNw26cYDjEARfFrYJHjbbie2sfGYSUuwHc5tkzmQwMzYhk8L+zPJv2236yFa/h1OZ5NIMCCghcFMGmhLAhtQi+THtsMJRGgBGi5z5rZhG1tasjVjX5phGzCQD+LzCz//8WeSbypuy8s3Hz5488c3G3n59vaDwDDErQUFMPNAGQeIUw8EjD+IVjoKRsEoGAUjCQAAFdJK02dcyVoAAAAASUVORK5CYII=","orcid":"","institution":"The Second Hospital of Hebei Medical University","correspondingAuthor":true,"prefix":"","firstName":"Shaomei","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-01-19 09:23:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5858633/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5858633/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79351371,"identity":"c2a64524-70c2-4fdc-be4b-8c7dfba637ea","added_by":"auto","created_at":"2025-03-27 10:27:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":53015,"visible":true,"origin":"","legend":"\u003cp\u003eAnnual dose of RTX by different group\u003c/p\u003e","description":"","filename":"Fig.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5858633/v1/9cbccc2dc0f6b545d0737cd0.jpg"},{"id":82509033,"identity":"a44809bd-0f7c-4952-ae4b-1e9e5a0bcbb8","added_by":"auto","created_at":"2025-05-12 10:16:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":829119,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5858633/v1/08a2d84d-5779-48f3-9ac5-627160075340.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Application of rituximab to treat minimal change disease with refractory nephrotic syndrome in the remission maintenance phase with long-term follow-up","fulltext":[{"header":"Background","content":"\u003cp\u003eMinimal change disease (MCD) affects approximately 10\u0026ndash;15% of adult patients with idiopathic nephrotic syndrome. Glucocorticoids are recommended as first-line therapies for MCD according to Kidney Disease: Improving Global Outcomes (KDIGO)[1]. The response rate is reported to be 75%[2]. Cyclosporine A, cyclophosphamide, mycophenolate mofetil, azathioprine, tacrolimus, and levamisole are used as second-line therapeutic approaches[3, 4]. However, MCD has a high recurrence rate. Although corticosteroids and the aforementioned immunosuppressive agents can be employed to manage refractory minimal change disease, their use is often met with significant apprehension due to the spectrum of potential adverse effects, such as steroid-induced diabetes, hypertension, water‒sodium retention, dyslipidemia, increased cardiovascular events, and decreased bone mineralization, such as femoral head necrosis, renal function damage with CNI, infections from mycophenolate, and infertility with cyclophosphamide. Therefore, a therapy with a higher level of patient satisfaction is desirable.\u003c/p\u003e \u003cp\u003eRituximab is a chimeric murine/human monoclonal immunoglobulin antibody that binds to CD20-positive lymphocytes and inhibits their proliferation and differentiation. It is used to treat non-Hodgkin lymphoma, rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis. It has already been frequently used in the pediatric population. Rituximab has been proven to be a safe and effective therapy for adult MCD, especially for frequently relapsing or steroid-dependent MCD[5\u0026ndash;9]. However, long-term outcomes, particularly in the remission maintenance phase of MCD, are in doubt. This study aimed to observe the infusion dose, infusion interval, and relapse rate and to identify relapse-related factors in the maintenance remission phase.\u003c/p\u003e"},{"header":"Study design and population","content":"\u003cp\u003eIn this retrospective study, we recruited 14 patients who had an estimated glomerular filtration rate (eGFR) of more than 60 mL/min, as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation, and were diagnosed with MCD with biopsy\u0026nbsp;confirmation. These patients are clinically classified as\u0026nbsp;having\u0026nbsp;refractory nephrotic syndrome. They were treated with RTX\u0026nbsp;and\u0026nbsp;were in remission at\u0026nbsp;the\u0026nbsp;Second Hospital of Hebei Medical University between May 2021 and October 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003echaracteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrieved the following clinical and laboratory data: baseline characteristics (age at disease diagnosis, age at RTX start, sex, comorbidities, systolic blood pressure (SP), diastolic blood pressure (DP), renal biopsy, NS type, relapse rate before RTX,\u0026nbsp;relapse rate after RTX,\u0026nbsp;and\u0026nbsp;previous treatments),\u0026nbsp;and\u0026nbsp;clinical data (RTX first dose, RTX total dose, RTX infusion interval,\u0026nbsp;and\u0026nbsp;concomitant use of steroids and immunosuppressants (ISs)).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRTX was initially administered\u0026nbsp;at 375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area or 1000 mg\u0026nbsp;in all patients.\u0026nbsp;Eight\u0026nbsp;patients\u0026nbsp;received a\u0026nbsp;second RTX infusion 1 month after the first infusion. We defined RTX infusions twice a month as the first treatment. Most patients received\u0026nbsp;a\u0026nbsp;second treatment at six-month intervals. In subsequent infusion treatments, the intervals were usually more than 6 months.\u003c/p\u003e\n\u003cp\u003eWe evaluated all patients before RTX infusion to exclude patients who had contraindications. Routine blood parameters, electrolytes, cardiac enzymes, troponin, chest CT images and ECG findings were collected prior to infusion. To minimize infusion reactions, methylprednisolone and diphenhydramine hydrochloride were given before drug infusion. ECG monitoring was performed during infusion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using Statistical Product and Service Solutions (SPSS) 20.0 (IBM Corp., NY, USA).\u0026nbsp;The normality of the distribution of quantitative variables was evaluated using the Shapiro\u0026ndash;Wilk test. All continuous variables are expressed as the mean\u0026plusmn;SD or median (minimum, maximum). We used nonparametric statistical methods to compare the correlations between two variables. All \u003cem\u003ep\u003c/em\u003e values were two-sided. \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05 was considered significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics of the study population are summarized in Table 1. The median age at disease diagnosis was 18.3 years (10.2\u0026ndash;47.5 years), and the median age at the start of RTX treatment was 21.7 years (15.3\u0026ndash;48.5 years). Kidney biopsy revealed minimal change disease without acute tubular necrosis. The use of previous steroids or immunosuppressants and the types of refractory nephrotic syndrome are displayed in Table 2. Thirteen patients had received corticosteroids before RTX infusion. Most patients used other immunosuppressants, such as calcineurin\u0026nbsp;inhibitors (n=8), cyclophosphamide (n=1), leflunomide (n=2), Tripterygium glycosides (n=1), and mycophenolate mofetil (n=1). Some patients (4/14) had received\u0026nbsp;three or more\u0026nbsp;immunosuppressive regimens\u0026nbsp;prior to RTX.\u0026nbsp;The baseline 24-hour urine protein level was\u0026nbsp;0.13 g (0.01\u0026ndash;2.4 g). The serum ALB concentration\u0026nbsp;was 42.08\u0026plusmn;3.83 g/L.\u0026nbsp;The serum\u0026nbsp;creatinine\u0026nbsp;level\u0026nbsp;was 69.50\u0026plusmn;12.57 \u0026micro;mol/L. The baseline eGFR was 123.01\u0026plusmn;13.50 mL/min per 1.73 m\u003csup\u003e2\u003c/sup\u003e.\u0026nbsp;The\u0026nbsp;CHOL\u0026nbsp;concentration\u0026nbsp;was 4.51\u0026plusmn;0.90 mmol/L. The number of\u0026nbsp;CD19+ B\u0026nbsp;cells was\u0026nbsp;/\u0026mu;L. The mean follow-up time was 25.9\u0026plusmn;8.9 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRTX dose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical courses of the 14 patients\u0026nbsp;are summarized in Table 3. RTX (375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area) was given to 6 patients. The other 8 patients initially received 1000 mg RTX. Eight patients (Patient 1, Patient 3, Patient 4, Patient 5, Patient 7, Patient 9, Patient 11, and Patient 14) received the same dose of RTX one month after the first infusion. RTX was administered at 375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area or 1000 mg of every infusion. The cumulative dose of RTX in all patients ranged from 600 to 2000 mg within six months. We calculated the annual cumulative dose of RTX (Table 4). In addition to the patients who relapsed (Patient 4, Patient 6, Patient 9, Patient 10, Patient 14) and Patient 8,\u0026nbsp;who did not receive\u0026nbsp;a\u0026nbsp;second\u0026nbsp;dose of RTX, the average annual cumulative\u0026nbsp;dose of RTX was 1929\u0026plusmn;504 mg. In contrast, the annual\u0026nbsp;cumulative\u0026nbsp;dose of RTX in the patients who relapsed was significantly lower, at 940\u0026plusmn;111 mg (P\u0026lt;0.001, Figure 1). The total RTX dose for all patients ranged from 1000 to 4500 mg\u0026nbsp;until the end of follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRTX interval of infusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEight patients received a second RTX infusion one month after the first infusion. We defined two infusions within 1 month as the first treatment. The second treatment interval was 8.7\u0026plusmn;3.7 months, with the exception of 3 patients who experienced relapse (Patient 6, Patient 10, Patient 14), whose infusion intervals were 9, 12 and 22 months. Some patients who received the third RTX treatment had\u0026nbsp;infusion intervals\u0026nbsp;of\u0026nbsp;12\u0026plusmn;3.1 months. Three\u0026nbsp;patients\u0026nbsp;agreed to\u0026nbsp;the fourth RTX treatment, but unfortunately,\u0026nbsp;one patient experienced\u0026nbsp;a relapse; this patient had an infusion\u0026nbsp;interval of\u0026nbsp;20 months. The other two\u0026nbsp;patients had\u0026nbsp;infusion intervals of 7 and 8 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcomitant use of steroids and ISs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEleven patients stopped steroids or immunosuppressants during RTX treatment. The remaining 3 patients had a reduction\u0026nbsp;in the use\u0026nbsp;of steroids or immunosuppressants. Dadas\u0026nbsp;are\u0026nbsp;summarized in Table 5. The\u0026nbsp;duration of\u0026nbsp;discontinuation of steroids or immunosuppressants was 8.5\u0026plusmn;4.3 months after RTX treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCD19‑positive\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eB‑cells\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn all patients, CD19-positive\u0026nbsp;B\u0026nbsp;cells were completely eradicated during the first infusion of RTX.\u0026nbsp;B-cell\u0026nbsp;reconstruction occurred\u0026nbsp;approximately\u0026nbsp;6 months after the administration of rituximab. Among the 5 patients\u0026nbsp;who experienced relapse, the\u0026nbsp;number of CD19-positive B cells\u0026nbsp;was\u0026nbsp;elevated\u0026nbsp;during\u0026nbsp;recurrence.\u0026nbsp;However,\u0026nbsp;among\u0026nbsp;patients without recurrence, B-cell\u0026nbsp;reconstruction occurred\u0026nbsp;in\u0026nbsp;most\u0026nbsp;patients. A CD19-positive\u0026nbsp;B-cell count was not associated with recurrence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe relapse rate and relapse-related factors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNine patients were in sustained remission, and the remaining 5 patients (Patient 4, Patient 6, Patient 9, Patient 10, and Patient 14) experienced relapse. In addition to Patient 10, the remaining patients who experienced relapse continued to receive\u0026nbsp;RTX treatment and were in stable remission.\u003c/p\u003e\n\u003cp\u003eThe relapse frequency significantly decreased from\u0026nbsp;1.87 (0.43, 2.69) to 0 (0, 1.33).\u003c/p\u003e\n\u003cp\u003eTo determine the cause of recurrence, we performed a correlation analysis to examine the association of relapse with the age at disease diagnosis, age of RTX application, sex, comorbidities, blood pressure, type of nephrotic syndrome, immunosuppressive use, CD19+ B-cell count, prerecurrence rate, RTX dose, RTX frequency, average annual usage of RTX, and RTX infusion interval. The results revealed that\u0026nbsp;cumulative\u0026nbsp;annual dose of RTX and the\u0026nbsp;combination\u0026nbsp;of multiple immunosuppressants\u0026nbsp;are\u0026nbsp;associated with relapse.\u0026nbsp;According to\u0026nbsp;logistic regression, the annual dose of RTX\u0026nbsp;was significantly negatively correlated with recurrence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAEs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn our study, RTX was well tolerated. No serious adverse events were observed during or after rituximab infusion. Three of the 14 patients experienced transient skin rash on the body, which was resolved with a second dose of 40 mg of methylprednisolone, slowing the infusion rate. One of the 14 patients experienced thoracic pain, which was relieved by slowing the infusion rate. No infection-related diseases appeared.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMCD represents approximately 10\u0026ndash;15% of patients with idiopathic nephrotic syndrome in adults. Glucocorticoid monotherapy is recommended as the initial treatment. Patients with refractory minimal change disease, including steroid-dependent nephrotic syndrome (SDNS), steroid-resistant nephrotic syndrome (SRNS), and frequently relapsing nephrotic syndrome (FRNS), require long-term therapeutic strategies involving either prolonged corticosteroid maintenance therapy or combination regimens incorporating other immunosuppressive agents. Individuals often demonstrate reluctance to adhere to these immunosuppressive protocols because of these side effects. Even so, recurrences often occur, thus accelerating disease progression and relapse episodes. Rituximab can prevent some of these side effects and reduce the recurrence rate. An increasing number of studies have confirmed that RTX is a promising therapeutic option for MCD[5\u0026ndash;7, 10\u0026ndash;13].\u003c/p\u003e \u003cp\u003eThe pathogenesis of MCD is undefined. Diffuse effacement of podocyte foot processes, the absence of electron-dense deposits or negative immunofluorescence staining are the characteristics of MCD[3]. Dysregulated T cells can produce abnormally increased circulating permeability factors, thus driving the injury of podocytes in MCD. Different lines of evidence suggest a reduced function of regulatory T cells in MCD in adult patients. B lymphocytes play a crucial role in the pathogenesis of idiopathic minimal change disease[14, 15]. RTX can eliminate B cells and disrupt B-cell\u0026ndash;T-cell interactions, thus reducing the production of permeability factors. Additionally, rituximab plays a role in B-cell-independent mechanisms. Perosa et al. reported that rituximab might cross-react with sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL-3b) rather than acting directly on antibody production. Rituximab might prevent actin cytoskeleton remodeling in podocytes by preserving sphingolipid-related enzymes, SMPDL-3b and ASMase activity[16]. The podocyte cytoskeleton may be a direct target for RTX through a B lymphocyte-independent mechanism[17]. The recent discovery of nephrin autoantibodies in a subset with minimal change disease provides further support for MCD etiology, which may lead to a new molecular classification of nephrin autoantibody minimal change disease and instigate new therapeutics for MCD. Patients with anti-slit antibodies show a good response to second-line immunosuppressants and a favorable long-term outcomes. The detection of anti-slit antibodies\u003c/p\u003e \u003cp\u003ein kidney biopsies, in addition to the measurement of anti-\u003c/p\u003e \u003cp\u003enephrin antibodies in the serum of patients with steroid-resistant NS, enables the identification of patients who are more likely to respond to intense immunosuppression.\u003c/p\u003e \u003cp\u003eIn the remission maintenance period of MCD, the regimens of RTX are confusing. There is no treatment guidance for the dose or infusion interval. A few studies have provided suggestions for the induction period of MCD. It varies greatly from 500 mg, 375 mg/m\u003csup\u003e2\u003c/sup\u003e or 1000 mg at one or two time points, even once weekly for 4 weeks[14, 18\u0026ndash;22]. Takei et al. performed a prospective trial in 25 MCNS (steroid-dependent minimal-change nephrotic syndrome) patients who used a single dose of RTX (375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area) twice at an interval of 6 months[22]. Among the 13 patients with MCD who were in remission with prednisolone (PSL), immunosuppressant (IS) treatment or both, most patients received RTX two to four times at 6-month intervals with a single dose of 375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area (maximum 500 mg)[11]. In our study, RTX was initially administered at 375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area or 1000 mg, while some patients were remedicated with RTX one month after the first infusion. In the follow-up treatment, every infusion dose was 375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area or 1000 mg. The annual dose of RTX in patients who were in remission throughout our study was significantly greater than that in patients who experienced relapse. There are few studies on the infusion interval for MCD. Among relapsing ANCA-vasculitis patients, fixed-interval rituximab retreatment has been suggested or considered a more prolonged period of remission[23]. In previous short-term studies of RTX in MCD patients, the infusion intervals for remission maintenance were mostly fixed at 6-month intervals. However, depending on each patient's condition and economic factors, the infusion intervals used in our study differed. After the RTX first treatment, the second infusion was 8.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7 months after the first infusion. Among relapsed patients, the infusion intervals seemed to be longer. Some patients who received the third RTX treatment had a mean infusion interval of 12\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 months. The infusion intervals in our study were relatively long and seemingly could have increased with increasing duration of treatment. The patient with the longest follow-up duration (41 months) did not receive rituximab for the fourth time until he relapsed. The interval between infusions was 20 months for this patient. Owing to the limitations of our follow-up period, few patients who received long-term rituximab were included. Does the infusion interval lengthen as the treatment progresses? This was the first study to explore the infusion interval. We need to design trials with more patients and longer periods of time to test this conclusion in the future.\u003c/p\u003e \u003cp\u003eIn terms of reducing the relapse rate or reducing the steroid dose, RTX greatly contributes. Takei et al. confirmed that rituximab therapy was associated with a reduction in relapse frequency and in the total dose of PSL needed. Munyentwali et al. analyzed 17 patients with steroid-dependent or frequently relapsing minimal change nephrotic syndrome. Some of them stopped or had a reduction in the use of steroid and IS drugs[24]. Recently, a report verified that RTX treatment resulted in an 80.3% remission rate[6]. In another systematic review and meta-analysis, RTX treatment resulted in a 91.6% CR rate, and 27.4% of patients experienced at least one relapse after RTX treatment. RTX is associated with trivial adverse events and good tolerance[7]. RTX has the potential to maintain prolonged remission. In our study, the median relapse frequency significantly decreased from 1.87 (0.43, 2.69) to 0 (0, 1.33) times/year, which was the same as that reported in some previous studies. Five patients experienced relapse, and 11 patients stopped steroids or immunosuppressants during RTX treatment. The remaining 3 patients experienced a reduction. This finding reinforced the role of rituximab as a glucocorticoid (GC) or IS-sparing agent. Early termination of immunosuppressants could greatly reduce harm to the body. Rituximab has also been shown to be effective in treating steroid-resistant nephrotic syndrome (SRNS).\u003c/p\u003e \u003cp\u003eThe relationship between relapse and CD19-positive B-cell repletion has been reported in many studies[5, 22, 24\u0026ndash;26]. Some studies have concluded that an increase in the number of CD19-positive B cells is associated with disease relapse. However, Takei T concluded that B-cell restitution was not related to relapse[22]. In our study, relapse had no connection with B-cell reconstitution.\u003c/p\u003e \u003cp\u003eWe analyzed relapse with many possible related factors. Finally, the annual accumulative dose of RTX and the combination of multiple immunosuppressants were associated with relapse. According to logistic regression, the annual dose of RTX was significantly negatively correlated with recurrence. Neither the frequency nor the dose of rituximab was related to relapse. On the basis of experience with the infusion interval for other diseases (membranous nephropathy or ANCA-associated vasculitis), we recommend trying an infusion interval of six months or more; however, we cannot ignore the annual use of RTX in the early maintenance period. Extending the infusion period can not only reduce drug-related side effects but also relieve the financial burden on patients. Additionally, the blood concentration of RTX affects disease function. A few studies have suggested that urinary loss of RTX shortens the B-cell depletion period, which leads to relapse[24, 27]. Unfortunately, rituximab concentrations were not measured in our study. The type of disease, age, concomitant use of immunosuppressants, and dose and frequency of RTX are factors affecting the duration of B-cell depletion[28, 29].\u003c/p\u003e \u003cp\u003eThere are several limitations to our study. First, this was a retrospective study lacking comparisons and concomitant therapy. The objects of the study were limited. Second, all MCD patients included in our research were identified on the basis of initial biopsy. Whether these patients potentially progress to FSGS remains unknown.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, RTX could significantly reduce the relapse rate and facilitate earlier withdrawal of corticosteroids and immunosuppressants, which are well tolerated during the remission maintenance phase in refractory MCD. In the remission phase, we can extend the infusion interval appropriately but cannot ignore the case of an accumulated annual dose of RTX. The optimal rituximab dosage, infusion interval, subsequent treatment or more profound mechanisms associated with RTX are confusing. We hope more trials explore these questions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe gratefully acknowledge all the participants who contributed to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLi Tian, Liying Wen, Ranjie Fu, and Xuzhi Liang collected data from MCD patients. Li Tian and Lingling Xing completed the statistical calculations. Shaomei Li was the main contributor to the writing of the manuscript. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis retrospective study was approved by the Research Ethics Committee of The Second Hospital of Hebei Medical University. (ethics number: 2024-r399).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ\u003cem\u003e et al\u003c/em\u003e: Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. \u003cem\u003eKidney Int \u003c/em\u003e2021, 100(4):753-779.\u003c/li\u003e\n\u003cli\u003eNolasco F, Cameron JS, Heywood EF, Hicks J, Ogg C, Williams DG: Adult-onset minimal change nephrotic syndrome: a long-term 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Disease in Adults: Is It Time for a Change? \u003cem\u003eCureus \u003c/em\u003e2022, 14(2):e22313.\u003c/li\u003e\n\u003cli\u003eGilbert RD, Hulse E, Rigden S: Rituximab therapy for steroid-dependent minimal change nephrotic syndrome. \u003cem\u003ePediatr Nephrol \u003c/em\u003e2006, 21(11):1698-1700.\u003c/li\u003e\n\u003cli\u003eElie V, Fakhoury M, Desch\u0026ecirc;nes G, Jacqz-Aigrain E: Physiopathology of idiopathic nephrotic syndrome: lessons from glucocorticoids and epigenetic perspectives. \u003cem\u003ePediatr Nephrol \u003c/em\u003e2012, 27(8):1249-1256.\u003c/li\u003e\n\u003cli\u003ePerosa F, Favoino E, Caragnano MA, Dammacco F: Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor. \u003cem\u003eBlood \u003c/em\u003e2006, 107(3):1070-1077.\u003c/li\u003e\n\u003cli\u003eFornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, Li J, Mattiazzi A, Ciancio G, Chen L\u003cem\u003e et al\u003c/em\u003e: Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. \u003cem\u003eSci Transl Med \u003c/em\u003e2011, \u003cstrong\u003e3\u003c/strong\u003e(85):85ra46.\u003c/li\u003e\n\u003cli\u003eBagga A, Sinha A, Moudgil A: Rituximab in patients with the steroid-resistant nephrotic syndrome. \u003cem\u003eN Engl J Med \u003c/em\u003e2007, 356(26):2751-2752.\u003c/li\u003e\n\u003cli\u003eKemper MJ, Gellermann J, Habbig S, Krmar RT, Dittrich K, Jungraithmayr T, Pape L, Patzer L, Billing H, Weber L\u003cem\u003e et al\u003c/em\u003e: Long-term follow-up after rituximab for steroid-dependent idiopathic nephrotic syndrome. \u003cem\u003eNephrol Dial Transplant \u003c/em\u003e2012, 27(5):1910-1915.\u003c/li\u003e\n\u003cli\u003eFran\u0026ccedil;ois H, Daugas E, Bensman A, Ronco P: Unexpected efficacy of rituximab in multirelapsing minimal change nephrotic syndrome in the adult: first case report and pathophysiological considerations. \u003cem\u003eAm J Kidney Dis \u003c/em\u003e2007, 49(1):158-161.\u003c/li\u003e\n\u003cli\u003eHoxha E, Stahl RA, Harendza S: Rituximab in adult patients with immunosuppressive-dependent minimal change disease. \u003cem\u003eClin Nephrol \u003c/em\u003e2011, 76(2):151-158.\u003c/li\u003e\n\u003cli\u003eTakei T, Itabashi M, Moriyama T, Kojima C, Shiohira S, Shimizu A, Tsuruta Y, Ochi A, Amemiya N, Mochizuki T\u003cem\u003e et al\u003c/em\u003e: Effect of single-dose rituximab on steroid-dependent minimal-change nephrotic syndrome in adults. \u003cem\u003eNephrol Dial Transplant \u003c/em\u003e2013, 28(5):1225-1232.\u003c/li\u003e\n\u003cli\u003eSmith RM, Jones RB, Guerry MJ, Laurino S, Catapano F, Chaudhry A, Smith KG, Jayne DR: Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. \u003cem\u003eArthritis Rheum \u003c/em\u003e2012, 64(11):3760-3769.\u003c/li\u003e\n\u003cli\u003eMunyentwali H, Bouachi K, Audard V, Remy P, Lang P, Mojaat R, Desch\u0026ecirc;nes G, Ronco PM, Plaisier EM, Dahan KY: Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease. \u003cem\u003eKidney Int \u003c/em\u003e2013, 83(3):511-516.\u003c/li\u003e\n\u003cli\u003eKamei K, Ito S, Nozu K, Fujinaga S, Nakayama M, Sako M, Saito M, Yoneko M, Iijima K: Single dose of rituximab for refractory steroid-dependent nephrotic syndrome in children. \u003cem\u003ePediatr Nephrol \u003c/em\u003e2009, 24(7):1321-1328.\u003c/li\u003e\n\u003cli\u003eRuggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, Maras\u0026agrave; M, Chianca A, Rubis N, Ene-Iordache B, Rudnicki M\u003cem\u003e et al\u003c/em\u003e: Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. \u003cem\u003eJ Am Soc Nephrol \u003c/em\u003e2014, \u003cstrong\u003e25\u003c/strong\u003e(4):850-863.\u003c/li\u003e\n\u003cli\u003eGuigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, Groothoff J, Llanas B, Niaudet P, Nivet H\u003cem\u003e et al\u003c/em\u003e: Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. \u003cem\u003ePediatr Nephrol \u003c/em\u003e2008, 23(8):1269-1279.\u003c/li\u003e\n\u003cli\u003eThiel J, Rizzi M, Engesser M, Dufner AK, Troilo A, Lorenzetti R, Voll RE, Venhoff N: B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. \u003cem\u003eArthritis Res Ther \u003c/em\u003e2017, 19(1):101.\u003c/li\u003e\n\u003cli\u003eHogan J, Dossier C, Kwon T, Macher MA, Maisin A, Couderc A, Niel O, Baudouin V, Desch\u0026ecirc;nes G: Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome. \u003cem\u003ePediatr Nephrol \u003c/em\u003e2019, 34(2):253-259.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e The baseline characteristics of the study population\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003ePatients of refractory MCD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eAge years, Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eage at disease diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e18.3(10.2-47.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eage at RTX start\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e21.7(15.3-48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eSex ratio (F/M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e3/11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eComorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eDiabetes,n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e1（7.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eThromboembolic disease,n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e1（7.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003ecoronary heart disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e1（7.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eBlood-Pressure,mmHg, Mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eSystolic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e121.7\u0026plusmn;9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eDiastolic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e84.5\u0026plusmn;9.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003erenal biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eMCD,n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e14（100）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eMCD+ATN,n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e0（0）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eNS type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eSDNS , n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e8（57.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eFRNS , n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e4（28.6）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eSRNS, n (%) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e2（14.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003ePrevious IS treatments\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eSteroid, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e13（92.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003ecalcineurin inhibitor,n, (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e8（57.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003ecyclophosphamide,n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e1（7.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eleflunomide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e2（14.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003etripterygium glycosides\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e1（7.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003emycophenolate mofetil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e1（7.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003ethree or more immunosuppressants,n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e4（28.6）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003erelapse times before RTX, times/year，Mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e1.67\u0026plusmn;0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e24-hour urinary protein excretion, g,Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e0.13（0.01-2.4）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eSerum albumin, g/L, Mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e42.08\u0026plusmn;3.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eSerum creatinine,\u0026micro;mol/L, Mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e69.50\u0026plusmn;12.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eeGFR (CKD-EPI), ml/min*1.73m2,\u003cbr\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e123.01\u0026plusmn;13.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eCHOL，mmol/L，Mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e4.51\u0026plusmn;0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eCD19 positive B-cells，number/ul，Median\u003cbr\u003e\u0026nbsp;(IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e243（106-642）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003eFollow-up time, months, Mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e25.9\u0026plusmn;8.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eQuantitative data were expressed as median (minimum，maximum) or mean\u0026plusmn;standard deviation (SD)\u003c/p\u003e\n\u003cp\u003ecategorical data were presented as frequencies\u003c/p\u003e\n\u003cp\u003eeGFR, estimated glomerular filtration rate;IS, immunosupressants；SDNS, steroid-dependent NS; FRNS, frequently relapsing NS;SRNS, steriod-resistant NS\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003eThe use of previous steroids or immunosuppressants and types of refractory nephrotic syndrome\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"87%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003epatient number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eTypes of refractory nephrotic syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003ePrevious immunosuppressants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003eNumber of relapse\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSDNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSDNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，TAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eFRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，CSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eFRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，TAC，TPG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSDNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，CSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eFRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，LEF，MMF，TAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSDNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSDNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS,TAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，TAC，CSA，CTX，MMF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSDNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eTAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，CSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSDNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，CSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eFRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，TAC，CSA，LEF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eSDNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003eS，CSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp skip=\"true\"\u003eSDNS:steroid dependent nephrotic syndrome;SRNS:steroid resistaSRNSt nephrotic syndrome;FRNS:frequent relapse nephrotic syndrome;\u003c/p\u003e\n\u003cp\u003eS:steroid;CSA:cyclosporin A;TAC:tacrolimus,CTX:cyclophosphamide;LEF: leflunomide; TPG:tripterygium glycosides;MMF:mycophenolate mofetil\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e The clinical courses for RTX dose and infusion intervals\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"93%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003epatient number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eThe first dose of RTX ,mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eThe second RTX one month apart the first infusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003eRTX accumulated dose in six month,mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eRTX total dose before relapse, mg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eRTX frequency before relapse， times\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eHaving a relapse during \u0026nbsp;RTX administer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eRTX total dose\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e3000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e3000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e2600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e2600\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e4500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e4500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e3000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e4500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e3000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e3000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e1200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e3100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e3100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e3600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e4200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e1700\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e1500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e1200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e1400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e2100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4\u0026nbsp;\u003c/strong\u003eThe annual cumulative dose of RTX in all patients\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"61%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003epatient number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003emedication time,month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003eThe annual dose of RTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eHaving a relapse during \u0026nbsp;RTX administer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e3000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e2600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e4500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e4500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e3000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e1200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e3100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e4200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e1700\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e1500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e1200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 18px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17px;\"\u003e\n \u003cp\u003e2100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 37px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMedicine time: The time from the first to the last application of RTX or the time from the first RTX to relapse\u003c/p\u003e\n\u003cp\u003eAnnual dose of RTX: The total dose of rituximab divided by year of application\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5\u0026nbsp;\u003c/strong\u003eThe steroids and immunosuppresants during RTX \u0026nbsp; treatment\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"83%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003epatient number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003eIS in use at RTX initiaton \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eIS in use after RTX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003eIS stopping\u003c/p\u003e\n \u003cp\u003etime\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003eMP 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL 15 TAC 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003eCSA 100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003eMP 6 TAC 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL 5 CSA100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL 20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL 7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL 35 TAC 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003eTAC 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL 20 CSA 150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003eMP 16 CSA150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL30 TAC 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 64px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003ePSL 5 CSA 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eS,stop the use of immunosupressants;R,reduce the dose of immunosupressants;MP, methylprednisolone;PSL, prednisolone;CSA, cyclosporin A;TAC, tacrolimus\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Minimal change disease (MCD), Rituximab (RTX), Refractory nephrotic syndrome, Relapse","lastPublishedDoi":"10.21203/rs.3.rs-5858633/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5858633/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eMinimal change disease (MCD) has a high recurrence rate, with refractory MCD frequently requiring long-term corticosteroid therapy or combination regimens with other immunosuppressive agents. Rituximab has been confirmed to be an effective treatment for refractory MCD. However, in the remission maintenance phase, the effects of multiple factors remain unclear, including the dose or infusion interval of rituximab, the use of concomitant immunosuppressants, the relapse rate, the relationship between B-cell reconstruction and relapse, and relapse-related factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe reviewed 14 refractory MCD patients receiving rituximab with a mean follow-up duration of 25.9±8.9 months. Three patients were in partial remission, and 11 patients achieved complete remission before RTX treatment. RTX was administered intravenously at a dose of 375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area or 1000 mg initially. In the subsequent treatment, RTX was administered at 375 mg/m\u003csup\u003e2\u003c/sup\u003e body surface area or 1000 mg every infusion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResult:\u003c/strong\u003e Nine patients with a mean annual RTX dose of 1929±504 mg remained in remission. Five patients experience a relapse, and their mean annual RTX dose significantly decreased to 940±111 mg (P\u0026lt;0.05). Eleven patients stopped steroids or immunosuppressants, and 3 patients had a reduction in steroids or immunosuppressants. The relapse frequency significantly decreased from 1.87 (0.43, 2.69) to 0 (0, 1.33). B-cell reconstruction was not associated with relapse. The cumulative annual dose of RTX was significantly negatively correlated with relapse.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eRTX significantly reduced the relapse rate and facilitated earlier withdrawal of corticosteroids and immunosuppressants during the remission maintenance phase in refractory MCD patients. Serious side effects were not reported. During the remission phase, we can extend the infusion interval appropriately but cannot ignore the case of an accumulated annual dose of RTX.\u003c/p\u003e","manuscriptTitle":"Application of rituximab to treat minimal change disease with refractory nephrotic syndrome in the remission maintenance phase with long-term follow-up","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-27 10:27:47","doi":"10.21203/rs.3.rs-5858633/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4acfbc1d-400a-4cb1-89c5-ff81e16e8e27","owner":[],"postedDate":"March 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-12T10:08:09+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-27 10:27:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5858633","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5858633","identity":"rs-5858633","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}