Therapy of Rituximab in Idiopathic Membranous Nephropathy with Nephrotic Syndrome: A Systematic Review and Meta-analysis

IDIOPATHIC membranous nephropathy (IMN)is one of the most common cause of adult nephrotic syndrome (NS), accounting for about 75% of membranous nephropathy (MN) cases.About 20%-30% IMN patients (often with non-nephrotic proteinuria) entered spontaneous remission,1 and 30%-40% of patients progress to end-stage renal disease (ESRD) within 5 to 15 years.2 M-type phospholipase A2 receptor (PLA2R) , which can be detected on glomerular podocytes and in subepithelial immune deposits, presented in 70%-80% IMN patients.3

小学阶段的学生处在成长发展的关键阶段，是审美价值观形成的关键时期。因此时的学生对教师有着较大的信服感，所以教师在小学语文中进行审美教育的渗透对学生有着重要的影响。为了达到事半功倍的效果，在实际操作的时候，需要我们教师切合实际地采用一定的方式方法。

Immunosuppressive treatment including corticosteroid, alkylating agents, calcineurin inhibitors (CNIs),mycophenolate mofetil (MMF) and azathioprine, is advised to high-risk patients (proteinuria ＞ 8 g/d with or without renal insufficiency) and medium-risk patients(normal renal function, proteinuria ＞ 4 to ＜ 8 g/d)when nephrotic proteinuria persisted more than 6 months.4-5 However, these immunosuppressive agents bring along with adverse events such as infection,myelosuppression and nephrotoxicity. Novel drugs are needed to improve the situation.

由于学生会同时使用两种或两种以上的词典，因此百分比相加的总和会大于100。表4说明两组都有大约三分之二的学生选择使用在线词典(使用手机上网)，譬如，有道、谷歌、金山词霸，约五分之一的学生选择使用电子词典，如：步步高、文曲星。在纸质词典的选择方面，两组有很大的差别，英语四级分数大于等于500分的学生中有47%使用纸质词典，而另一组却只有21%使用，不过，这21%的份额中，有将近50%的学生填写的所使用的纸质词典为汉英词典，使用目的主要是完成汉译英学习任务时方便进行查询。

利用DNASTAR软件分析JEV P3株C基因编码127个氨基酸(如表2)，分子量大小13 KDa；从氨基酸组成上，25个强酸性氨基酸 (K,R)，5个强碱性氨基酸 (D, E)，53个疏水性氨基酸(A, I, L, F, W, V)，18个两性氨基酸 (N, C, Q, S, T, Y)，等电点为11. 89，在中性环境中带正电。C蛋白的二级结构分析 (图4) 发现C蛋白主要由β片层结构和α螺旋结构构成，中间有少量的β转角相连接。整个蛋白亲水性一般，有较强的抗原性。

Seven studies involving 120 patients (73% were men) were included in our systematic review and meta-analysis. RTX was used as first-line therapy or second-line therapy. Our results demonstrated that RTX was efficient in the treatment of IMN. The reduction in proteinuria was gradual and obvious, paralleled with serum albumin increasing and serum cholesterol decreasing. Renal functions were stable. Relapse was rare. Adverse events about RTX therapy were mostly infusion-related reactions and generally were not serious.

MATERIALS AND METHODS

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol.8

Eligibility and exclusion criteria

Prospective cohort studies that reported the use of RTX in biopsy-proven IMN adult patients with NS were included for review. Publications on secondary MN,other pathological types of glomerular diseases, and recurrence of disease after renal transplantation were excluded. Studies with follow-up period less than 12 months were excluded. Pediatric patients were excluded. We also excluded retrospective studies and two ongoing multicenter randomized controlled trials (RCTs).9-10

三是聚焦打仗导向。战斗力是军队建设唯一的根本的标准。军民融合发展的质效如何，最终落脚点要看在军地资源双向互动互促的过程中，军队战斗力建设能否得到显著提升。为此，必须始终坚持一切为战的根本指向，牢固树立战争观念、备战意识，真正以能打仗打胜仗这个指挥棒来统筹谋划军民融合、协调推动军民融合。通过促进经济发展方式转变和经济结构调整，找准生产力和战斗力的最佳契合点，使国防和军队建设深度融入经济社会大体系，依托整个国家力量全面提升我军备战打仗能力。

Literature search

A systematic literature search of the PubMed (2002 to December 2016), Embase (2002 to December 2016),Cochrane Library (2007 to December 2016) and Clinical Trials (2007 to December 2016) was conducted, using the key words “Rituximab”, “anti-CD20 monoclonal antibodies”, “membranous nephropathy”, “membranous glomerulonephritis”, “primary”, “idiopathic”, “nephrotic syndrome”, and “adults”. We also manually identified additional relevant studies. The search was limited to articles published in English language.

Study selection and data extraction

The eligible references obtained by literature search were assessed by two independent reviewers (Zou PM and Chen ZJ) according to a predetermined protocol.Data extracted by two independent reviewers (Zou PM and Chen ZJ) included: study characteristics (design,country, publication year), follow-up period, baseline data of patients (age, gender, course of disease, histopathologic features, baseline proteinuria, baseline renal function, previous treatment), RTX administration regime, and treatment response (remission situation and the definition, renal function, relapse, adverse events).Differences over inclusion of studies and interpretation of data were resolved by consensus discussion.

Quality assessment

“妈妈，我知道您是怕我难过，今天您才从深圳赶过来参加家长会，您晚上还要赶回去，真是太辛苦了。昨天我和弟弟给您准备了一份惊喜，放在桌洞里。”舟舟真是个极懂事的孩子。

Statistical and bias analysis

The mechanism of RTX to MN is unknown. It was supposed that RTX develops its role of reducing urinary proteins and protects renal function by specifically interferes with B lymphocytes and disturbs B cell differentiation. The treatment response may be related to the remaining B cells counts. Unfortunately, different outcomes in patients could not be explained, since all studies recorded circulating B lymphocytes in all patients depleted and maintained below normal range during whole studies after RTX first administration,CD19+ B cells followed an identical trend as well. Most studies reported serum hemoglobin levels, total white blood cells, platelet counts and levels of IgG, IgA, and IgM had no significant difference. However, data from studies of Fervenza et al17-18 showed the not very consistent results of CD19+ B cells recovery and the IgG level, making these conclusions controversial.

RESULTS

Literature search

通过提出现实生活中的具体问题来调动学生积极性，培养学生独立思考能力[4]。如讲解脂肪水解时，可以提问为什么吃了油腻的东西会感觉口渴；讲解蛋白质沉淀时，提问为什么重金属中毒后以服用蛋清或牛奶来解毒；讲解蛋白质变性时，提问为什么吃肉要炒熟，以及用酒精对皮肤消毒、高温高压对手术器械灭菌的机理，帮助学生理解蛋白质变性，让学生能够将书本上的知识联系到实际生活中，通过贴近生活的例子明白生物化学与医学关系密切，与我们的生活息息相关，进而产生浓厚的兴趣。

Study characteristics

Basic characteristics of 7 included studies are summarized in Table 1. All patients were renal biopsy-proven IMN with creatinine clearance ＞ 20 ml/(min·1.73 m2), and persistent proteinuria ＞ 3.5 g/d for at least 6 months with previous treatment ［44 (36.7%) had immunosuppressive treatment］. Quality assessment by the Newcastle-Ottawa Scale is shown in Table 2. Among the 7 included studies, Ruggenenti et al21 organized their research in two steps—first came the retrospective analysis of 14 IMN patients treated with RTX in their Nephrology Unit (the outcome of 8 of these patients was reported previously20) and finally concluded that tubulointerstitial (TI) scores ＜ 1.7 predicted better response to RTX. Then they did a prospective study including 9 IMN patients of TI scores ＜ 1.7. We only assessed the prospective part. Cravedi et al15 carried out a matched cohort study that compared the B cell-driven and the four-dose protocol of RTX, data of the 24 IMN patients of the four-dose protocol group came from their previous studies. To avoid inclusion of repeated data,we only evaluated the experimental group-12 patients accepted the B cell-driven protocol. All included studies defined CR as proteinuria≤0.3 g/24 h or≤0.5 g/24 h,and PR as proteinuria≤3.5 g/24 h or≤3.0 g/24 h. One study did not mention the definitions of CR and PR,21 so we regarded the authors used the generally accepted definitions (CR as proteinuria≤0.3 g/24 h with normal serum creatinine, PR as proteinuria ＜ 3.5 g/24 h and a≥ 50% reduction from peak values with improvement of serum albumin22).

Figure 1. Flowchart of studies included in the meta-analysis.

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Table 2. Quality assessment of the included studies by the Newcastle-Ottawa Scale (score)

Items Moroni et al19 Selection Representativeness of the exposed cohort　1　1　1　1　1　1　1 Selection of the non-exposed cohort　1　1　1　1　1　1　1 Ascertainment of exposure　1　1　1　1　1　1　1 Demonstration that outcome of interest was not present at Start of study Ruggenenti et al20 Ruggenenti et al21 Cravedi et al15 Fervenza et al18 Fervenza et al17 Cravedi et al16 1 1 1 1 1　1　1 Comparability　1　2　1　2　2　2　2 Outcome Assessment of outcome　1　1　1　1　1　1　1 Was follow-up long enough for outcomes to occur?　1　1　1　1　1　1　1 Adequacy of follow-up of cohort　1　1　1　1　1　1　1 Total score　8　9　8　9　9　9　9

Efficiency of RTX therapy in severe IMN patients

The pooled CR rate and cumulate remission (CR + PR)rate at 12-month were 15% (95%CI, 0.09-0.23) and 56% (95%CI, 0.47-0.65) (Fig. 2). Only 3 studies16-17,19 had a follow-up period of 24 months, the pooled CR rate and cumulate remission rate at 24-month were 20% (95%CI, 0.12-0.32) and 68% (95%CI, 0.41-0.87). Heterogeneity was revealed at 24-month remission rate with I2 of 73% (Fig. 3). Sensitivity analysis suggested that the 24-month pooled remission rate was stable and omitting a single study did not change the significance of the pooled survival rates (95%CI,0.49-0.74) (Fig. 4).

The Newcastle-Ottawa Scale (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp), which graded studies according to the quality of selection,comparability and outcome of cohort, was performed to make quality assessments of the eligible references. Discrepancies were addressed by consensus discussion.

Totally, 639 articles were identified via database search.And 255 duplicate studies were removed by Endnote Software. After exclusion based on title and abstract,37 full-text articles were reviewed. Five studies were excluded for the following reasons: three studies used the same series of patients7,11-12 and two studies did not reach our inclusion criteria.13-14 Finally, 7 studies were included.15-21 A flowchart of article screening for the meta-analysis has been illustrated in Fig. 1.

Renal function was stable and did not change significantly in most studies. But, Fervenza et al17 reported creatinine clearance increased from 72.4±33 ml/(min·1.73 m2) at baseline to 88.4 ± 31.5 ml/(min/1.73 m2) at 24 months (P = 0.02) in their study published in 2010. Quite the opposite, in Moroni et al’s study,19 the mean serum creatinine of the 24 patients who were followed for at least 18 months after RTX therapy was significantly higher than that at 12 months (141.4 ± 70.7 versus 114.9 ± 44.2 μmol/L;P = 0.02), however we cannot rule out the confounding factors brought by 6 non-responders. In Fervenza et al’s study,18 2 patients who had the lowest creatinine clearance at entry ［40 and 59 ml/(min·1.73 m2)］ and proteinuria remained unchanged in the whole study,progressed to ESRD at 18-month and 19-month after RTX treatment.

Four studies16-17,19,21 reported relapse cases,mostly happened in the second year. Pooled data of the relapse rate in 24-month after RTX treatment was 8% (95%CI, 0.03-0.16) (Fig. 5).

Other parameters

The reduction in proteinuria was paralleled to a significant increase in serum albumin and decrease in total serum cholesterol.

Two studies reported that serum concentrations of IgG, IgA, and IgM did not change significantly throughout its whole study period;20-21 but Fervenza et al in their two studies recorded significantly increase of baseline IgG level and decrease of IgM level, while serum IgA remained relatively stable at 12 months and later. Subsequent quantification of IgG subclasses proved total IgG increase was due to an increase in IgG1, IgG2, and IgG3 isotypes, whereas IgG4 levels remained unchanged.17-18

After the first administration of RTX infusion,most included studies15-17,19-21 recorded that circulating CD19+, CD20+ B cells depletion were achieved and remained below normal ranges by study end. Only one study found that the majority of patients had CD19+B cells recovered to the normal range (mean 110 ± 97 cells/ml, range: 28-317) at 6-month.18 No significant changes in total white blood cell, hemoglobin, platelet,and lymphocyte counts and in lymphocyte subpopulations including CD3+, CD4+, CD8+, natural killer cells,and CD4+/CD8+ ratios.

Figure 2. Pooled CR rate and remission (CR + PR) rate at 12 months. A. pooled 12-month CR rate; B. pooled 12-month CR+PR rate. CR: complete remission; PR: partial remission; W: weight. *In the 15 enrolled patients, 14 patients completed 12 months of follow-up; †In the 20 enrolled patients, 1 patient who was immunosuppression naive before entry was removed from the study at 6 months because of worsening proteinuria and rapidly declining kidney function.

Figure 3. Pooled CR rate and remission (CR + PR) rate at 24 months. A. pooled 24-month CR rate; B. pooled 24-month CR+PR rate.

Figure 4. Sensitivity analysis of pooled 24-month CR+PR rate.

Figure 5. Pooled relapse rate at 24 months.

3.中央政府对贫困地区健康扶贫财政支持由模糊到清晰。除承担国家免疫，重大传染病防治等投入责任外，还需在基本医疗卫生制度筹资方面承担起更多责任，使更多的卫生资源转移到贫困地区，以缩小地区之间医疗卫生服务和健康差距，促进基本医疗卫生服务均等化的有效实现。为此，借鉴国外经验，需要在以下三方面加以明确，一是明确中央财政针对收入较低贫困居民而设立的专门医疗救助投入比例；二是明确中央财政针对落后地区的财政投入比例；三是明确医疗救助支出占GDP的合理比重。

Safety

Adverse events observed in RTX treatment were mainly infusion-related reactions, including itchy throat,skin rash, chills, flu-like symptoms, et al. Symptoms were varied but generally not serious. Infections were uncommon, three studies17-19 reported infectious complications: 3 patients experienced community-acquired pneumonia and 2 patients experienced herpes zoster,relieved with oral-medications. Myocardial infarction,happened in 2 patients from two studies,17,19 respectively occurred 3 months and 5 months after RTX infusion. Another patient was diagnosed with adenocarcinoma in the lung 3 months after the first infusion.18

Publication bias

As shown in Fig. 6, the shape of funnel plots did not reveal any obvious asymmetry. Begger’s and Egger’s test confirmed that there was no publication bias(P＞0.05).

DISCUSSION

Rituximab (RTX), a monoclonal antibody targeting CD20, applied in chronic lymphocytic leukaemia,non-Hodgkin lym phoma, vasculitis and rheumatoid arthritis, recently emerged to be an option for the treatment of NS.6 Animal experiments suggested that B cells were involved in the pathological process of MN.B cells mediate typical subepithelial immune deposits in glomeruli, accelerate injury of the glomerular filtering barrier and result in proteinuria. Although IMN autoantigens remain elusive and the role of B cells has not been fully understood in humans, agents that specifically interfere with B cells would ideally represent the first step toward selective therapy in humans.7 Lots of studies reported successful use of RTX in the treatment of both IMN and secondary MN, as first-line and second-line therapy. However, these studies were small sample prospective observation studies or case reports, further investigation is required. Thus, combing the current evidences of RTX therapy in IMN from eligible studies, we carried out this systematic review and meta-analysis, to systematically evaluate the efficacy and safety of RTX in IMN.

Spontaneous remission is a special characteristic of MN, occurred in about 30% patients, and generally happens in the first 2 years. Although spontaneous remission was more often seen in patients with lower baseline proteinuria levels, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8-12 g/24 h and 22%among those with proteinuria ＞ 12 g/24 h.23 Important independent predictors for spontaneous remission include: baseline serum creatinine and proteinuria,treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs), and a ＞ 50% decline of proteinuria from baseline during the first year of follow-up.23 Patients in all included studies had massive proteinuria, supportive treatment consisted of ACEi, and/or ARB at maximal tolerated dose was conducted with RTX administration. However,most patients selected had a prolonged disease course,proteinuria maintained unchanged despite conservative treatment and even immunosuppressive therapy added for enough time previously. Hence spontaneous remission was unlikely to occur.

Figure 6. Funnel plots of the meta-analysis. A: 12-month CR rate; B: 12-month CR+PR rate; C: 24-month CR rate; D:24-month CR+PR rate; E: relapse rate at 24 months.

Traditional RTX protocol is 375 mg/m2 RTX once weekly for 4 weeks, or 1 g RTX on day 1 and day 15.Some nephrologists give a second course routinely or according to the B cell counts (when B cells≥5/mm3)after 6 months. It’s confusing whether clinical efficacy is different in different protocols. Limited to the very few study and detail data unavailable, we failed to make a relative meta-analysis. Remuzzi et al7 firstly demonstrated RTX was efficient in the treatment of IMN, used the four-dose protocol. Segarra et al13 successfully used the four-dose protocol in 13 IMN patients with long-term calcineurin inhibitors (CNIs)dependence to overcome dependence of CNIs. Studies of Fervenza et al17-18 suggested that four doses of RTX resulted in more effective B cell depletion, but proteinuria reduction was similar to RTX at 1 g every 2 weeks. In addition, there was no difference in proteinuria response between patients who were immunosuppression naive versus those who had been previously treated.17-18 In 2007, Cravedi et al15 conducted a matched-cohort study, concluded that B cell titrated RTX protocol was as effective as standard fourdose RTX treatment in achieving B cell depletion and IMN remission, but cost only a quarter of the standard regimen. Based on their previous finding, these investigators further demonstrated that second-line RTX therapy was equally efficient to first-line RTX therapy in IMN as well.16 Contrary to Cravedi’s opinion, recently in 2016, results from a multi-centric study involving 34 IMN patients (15 patients had been treated with glucocorticoids and immunosuppressive agents) suggested that low-dose RTX was poorly effective, obtained remission in ＜50% of IMN patients.19

There was no significant difference between RTX applied as the first-line therapy and the second-line therapy. No conclusion was drawn on which RTX protocol is preferred. Lack of rigorous RCTs, we cannot assert RTX is superior to other treatments commonly applied in clinic. Whether to use RTX combined or continued with other medications include supportive regimes and immunosuppressive agents can induce more remission remain uncertain and needs further study. Luckily there are 2 ongoing multicenter RCTs:the MENTOR study (rituximab versus cyclosporine) and the STARMEN study (sequential treatment with tacrolimus-tituximab versus steroids plus cyclophosphamide), and we are looking forward to the publication of their results.

Complete remission (CR) or partial remission (PR) was regarded as effective therapy, and the cumulate rate(CR + PR) was calculated. We evaluated the 12-month and the 24-month pooled remission rates. Pooled relapse rate in 24-month was also assessed. Cochrane Q test and the inconsistency index (I2) statistic were applied to analyze the heterogeneity of the included studies. We used a random effects model for the data analysis when a significant heterogeneity was observed(P＜0.1 or I2＞50%), otherwise we used a fixed effect model. Sensitivity analysis was used by sequential omission of individual studies. Funnel plots were used to estimate the publication bias of the meta-analysis.All analyses were performed using R software and the meta/metaphor package (www.r-project.org). P value less than 0.05 was considered statistically significant.

Pharmacokinetics and pharmacodynamics analyses showed serum RTX levels in IMN patients were lower than patients with rheumatoid arthritis, and half-life of RTX was also shorter. However, there were no differences in serum RTX levels at any point between responders and non-responders.18

Human antichimeric antibodies (HACAs) can be induced by repeated or prolonged exposure to RTX.24 The production of HACAs may limit the effect of treatment and increase the risk for hypersensitivity reactions of the immediate type upon drug re-exposure.Six and two patients in two studies of Fervenza17-18 were detected to have HACAs, but the titers were low and the presence of HACAs was not associated with treatment respond.24

Nephrologists never stop looking for factors that can efficiently predict response to RTX in IMN patients.In 2006, a pilot study of Ruggenenti suggested that TI score was the only significant predictor, patients with a TI score of ＜ 1.7 showed better response to RTX.21 However, it was not consolidated demonstrated by Cravedi,15 since average proteinuria reduction on follow-up versus baseline tended to correlate with TI score, but the correlation did not reach statistical significance (P=0.10). It was reported the CD4+/CD8+T cell ratio predict response to RTX therapy by Zucchelli et al,25 but Fervenza’s study18 failed to certify it.In addition they found there was no relation between the total number of CD20+ or CD3+ cells, the ratio of CD20+/CD3+ cells, or the number of CD20+ cells/mm2 present in the diagnostic renal biopsies and the response to rituximab treatment.17-18 Irazabal et al12 suggested low- and high-molecular-weight urinary proteins predict response to RTX in IMN patients. Anti-PLA2R lever measuring were commonly developed in clinical works nowadays, levels of anti-PLA2R correlate with the immunological activity of MN and can well predict response to treatment with RTX.26 One study reported that patients with lower serum creatinine,higher estimated glomerular filtration rate, lower proteinuria, lower titer of anti-PLA2R antibodies at baseline showed better outcome to RTX therapy.19 However,relationship between response and initial proteinuria remains controversial.

RTX is well tolerated and safe in IMN patients.Adverse events were mainly infusion-related reaction and mostly were not serious. Infections were uncommon since RTX targeted on B cells, and caused no significant changes in total white blood cell, lymphocyte counts and in lymphocyte subpopulations, even some studies recorded serum IgG levels increased. Two researches reported one patient happen myocardial infarction 5 and 3 months after RTX administration respectively;17,19 one study reported a patient diagnosed with adenocarcinoma of the lung 3 months after the first RTX infusion.18 Previous research verified that patients with NS and IMN were at high risk of cardiovascular events.27-28 Approximately 10% MN patients had a malignancy (predominantly solid organ cancers,mainly in the lung, colon, or breast) at the time of renal biopsy or within a year thereafter, and the incidence increased up to 20%-25% after age 60.29-30 Thus, we should be cautious to conclude that these severe events were due to the RTX administration. Compared to immunosuppressive agents, side effects of RTX are fewer and milder. Most obvious disadvantage of RTX may be its experience cost. Perhaps it’s better accepted by wealthy patients who care more about adverse events of glucocorticoid and immunosuppressive drugs. However, the safety of RTX still needs more observation.

There are several limitations in our study. All included researches were small sample prospective observation cohort studies or matched-cohort studies,mainly came from two common centers, one study was multi-centric (4 nephrology units in northern Italy). Only three studies followed up for 24 months,which may weaken the role of meta-analysis of pooled 24-month remission rate. Limited to the very few study and detail data unavailable, we failed to make a relative meta-analysis of clinical efficacy in different RTX protocols. Prognostic factors specifically to RTX treatment are controversial since each publication came to different conclusions, making a meta-analysis on the prognostic factors unrealistic. More investigations are needed in the future.

（2）第三方评价情况。注重提升绩效评价质量和深度，聚焦转移支付项目、民生项目、产业资金等重点领域，开展第三方评价。

In conclusion, RTX provides a new approach for the treatment of IMN, and it can be seemed as a narrow, disease-specific treatment to IMN. Rigorous and large multicenter RCTs still need to be well performed.It is also necessary to further evaluate the long-term outcome, safety, and factors predict treatment efficacy.

Acknowledgements

The authors appreciate Dandan Hu, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College for her kind support in language editing.

3.3造成各项调查数据偏低的原因:1)农民居住分散、大多地处偏僻、交通不便、经济收入低的地区,难以接触到无偿献血的宣传,因此对无偿献血没有正确认识。有部分农民对献血存在错误认识,甚至恐惧心理,认为献血会影响身体健康,传染疾病。2)因为农民文化程度普遍较低 ,大多只有小学文化程度,对血液生理知识、献血意义的理解有一定的难度 。3)受传统思想的束缚 ,农民普遍担心献血会损害自己的身体健康和影响生产劳动。

Conflicts of interest statement

The authors have no conflicts of interest to disclose.

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