Evaluation of Immunotherapy for Idiopathic Membranous Nephropathy Based on Risk Stratification and Pathological Stage

Evaluation of Immunotherapy for Idiopathic Membranous Nephropathy Based on Risk Stratification and Pathological Stage | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 26 March 2025 V1 Latest version Share on Evaluation of Immunotherapy for Idiopathic Membranous Nephropathy Based on Risk Stratification and Pathological Stage Authors : Yang Yang , Yuxin Zhang , Ran Zhang , Manna Li , Hongping Wan , Wenjun Yan , Kaiping Luo , Qipeng Huang , Daijin Ren , and Gaosi Xu 0000-0002-4001-9895 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174298888.86668266/v1 Published European Journal of Pharmacology Version of record Peer review timeline 262 views 144 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: The treatment options for idiopathic membranous nephropathy (IMN) based on risk stratification and pathological staging remains unclear. Methods: This prospective cohort study included patients over 18 years with biopsy-proven, estimated glomerular filtration rate > 50 mL/min/1.73m2 IMN patients, as well as selecting IMN patients at medium and high risk in the KDIGO guidelines, with pathological stage II and III, and treated with tacrolimus (TAC), rituximab (RTX) or cyclophosphamide (CYC). Low risk patients were divided into supportive care (SC) and non-SC (NSC) groups. Results: The incidence of complete remission (CR) was significantly higher in the TAC group than in the RTX and CYC groups in medium risk group at 12 months (P = 0.045). In high risk group, the CR rate was 48.0%, 35.6%, and 16.7% in TAC, CYC, and RTX groups, respectively (P < 0.001), and the average time to CR was the shortest in TAC group (P = 0.008). In stage II group, TAC group had a higher CR rate and shorter average time to CR (P = 0.001, P = 0.015, respectively). For low risk, the mean proteinuria in NSC group was remarkably lower than SC group at 6 months (P = 0.035), however, the overall remission rate was similar between the groups. Conclusion: Compared with RTX and CYC groups, TAC exhibited a higher rate of CR in moderate and high risk groups, and had a higher incidence of CR and a shorter average time to CR in the stage II group. Title page Evaluation of Immunotherapy for Idiopathic Membranous Nephropathy Based on Risk Stratification and Pathological Stage Yang Yang 1,2,† , Yuxin Zhang 1,3† , Ran Zhang 1,† , Manna Li 1 , Hongping Wan 4 , WenjunYan 5 , Kaiping Luo 6 , Qipeng Huang 7 , Daijin Ren 8 , Gaosi Xu 1,* 1 Department of Nephrology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, P. R. China 2 Jiangxi Key Laboratory of Molecular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, P. R. China 3 Grade 2021, the Second Clinical Medical College, Jiangxi Medical College, Nanchang University, Nanchang, P. R. China 4 Department of Pathology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, P. R. China 5 Department of Nephrology, the First Affiliated Hospital of Gannan Medical University, Ganzhou, P. R. China 6 Department of Nephrology, Ganzhou People’s Hospital, Ganzhou, P. R. China 7 Dpartment of Nephrology, The Fifth Affiliated Hospital of Jinan University, Heyuan, P. R. China 8 Dpartment of Health Management Center, Jiangxi Provincial People’s Hospital，The First Affiliated Hospital of Nanchang Medical College, Nanchang, P. R. China †These authors contributed equally to this work and share first authorship * Correspondence should be addressed to Professor Gaosi Xu (Ph.D. & M.D.); the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, China; Zip Code: 330006; Address: No. 1, Minde Road, Donghu District, Nanchang, P.R. China; E-mail: [email protected] ; Tel: +86(0)791 86312770, Fax: +86(0)791 86312770. Running heading : Risk-based treatment of IMN Availability of Data and Material All data generated or analyzed during this study are included in this published article or supplementary material. not-yet-known not-yet-known not-yet-known unknown Funding This work was supported by the National Natural Science Foundation of China (No. 82060138), the Key Project of Jiangxi Provincial Nature Science Foundation (No. 20224ACB206008), the “Thousand Talents Plan” project of introducing and training high-level talents of innovation and entrepreneurship in Jiangxi Province (No. JXSQ2023201030), and the Jiangxi Province Key Laboratory of Molecular Medicine (No. 2024SSY06231). not-yet-known not-yet-known not-yet-known unknown Conflict of interest disclosure The authors declare that they have no competing interests. Ethics approval statement This study was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University and included in the study and obtained from all individual participants(IIT-O-2021–51). not-yet-known not-yet-known not-yet-known unknown Patient consent statement Informed consent was obtained from all individual participants in verbal consent. not-yet-known not-yet-known not-yet-known unknown Permission to reproduce material from other sources Not applicable. not-yet-known not-yet-known not-yet-known unknown Clinical trial number Not applicable. not-yet-known not-yet-known not-yet-known unknown Authors’ contributions YY interpretation of data and drafting and critical revision of the manuscript. YZ and RZ enrollment of patients, collected the data and analysis the data. ML, HW, WY, KL,QH and DR collected the data. GX: critical revision of this manuscript and supervision of this study and obtained the funding. All authors contributed to the article and approved the submitted version. Principal Investigation (PI) statement The authors confirm that the PI for this paper is Gaosi Xu and that he had direct clinical responsibility for patients. not-yet-known not-yet-known not-yet-known unknown Acknowledgements Not applicable. not-yet-known not-yet-known not-yet-known unknown Abstract Background: The treatment options for idiopathic membranous nephropathy (IMN) based on risk stratification and pathological staging remains unclear. Methods: This prospective cohort study included patients over 18 years with biopsy-proven, estimated glomerular filtration rate > 50 mL/min/1.73m2 IMN patients, as well as selecting IMN patients at medium and high risk in the KDIGO guidelines, with pathological stage II and III, and treated with tacrolimus (TAC), rituximab (RTX) or cyclophosphamide (CYC). Low risk patients were divided into supportive care (SC) and non-SC (NSC) groups. Results: The incidence of complete remission (CR) was significantly higher in the TAC group than in the RTX and CYC groups in medium risk group at 12 months (P = 0.045). In high risk group, the CR rate was 48.0%, 35.6%, and 16.7% in TAC, CYC, and RTX groups, respectively (P < 0.001), and the average time to CR was the shortest in TAC group (P = 0.008). In stage II group, TAC group had a higher CR rate and shorter average time to CR (P = 0.001, P = 0.015, respectively). For low risk, the mean proteinuria in NSC group was remarkably lower than SC group at 6 months (P = 0.035), however, the overall remission rate was similar between the groups. Conclusion: Compared with RTX and CYC groups, TAC exhibited a higher rate of CR in moderate and high risk groups, and had a higher incidence of CR and a shorter average time to CR in the stage II group. Key words: idiopathic membranous nephropathy, risk stratification, pathological stage, remission Abstract word count: 245 What is known about this subject 1. IMN patients with moderate or high risk are recommended to immunotherapy therapies. 2. Low risk IMN patients may receive supportive treatment in first 6 months. not-yet-known not-yet-known not-yet-known unknown What this study adds TAC group had a higher complete remission rate in medium and high risk IMN patients. TAC group had a higher complete remission rate in IMN patients with stage II. The overall remission rate was similar between the supportive care and non-supportive care in low risk. Introduction Idiopathic membranous nephropathy (IMN) is an immune complex-mediated disease that presents with proteinuria and hypoproteinemia[1]. 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines categorized IMN patients as low, moderate, high, and very high risk of progression according to proteinuria, estimated glomerular filtration rate (eGFR), serum albumin, and antibodies against the Phospholipase A2 receptor antibody (PLA2R-Ab) level[2]. For patients above moderate risk, it recommended immunotherapy therapies such as calcineurin inhibitor ± glucocorticoids (GC), rituximab (RTX), and cyclophosphamide (CYC) + GC[2]. STARMEN and RI-CYCLO confirmed the efficacy of GC + CYC in IMN patients at high risk of progression[3,4], but no studies are comparing the efficacy of these three treatment regimens in IMN patients with different risks of progression. The natural course of IMN is variable, with about 30% of patients undergoing spontaneous remission. Patients with normal eGFR, proteinuria less than 3.5 mg/dL, and serum albumin more than 30 g/L are considered to be at low risk of progression and are advised to receive supportive care (SC)[2]. Previous study indicated that lower-grade proteinuria is associated with a higher rate of spontaneous remission[5]. But some low risk patients receiving adequate SC may also convert to moderate-to-high risk and require immunosuppressive therapy[6]. The efficacy and prognosis of different treatments for patients with a low risk of progression remain unclear. Renal biopsy is the golden standard for the diagnosis of IMN and is divided into stage I, II, III, and IV depending on the histopathologic information[7]. Zhang et al. revealed that with exacerbation of IMN from stage I to III, patients exhibited a higher positive rate of serum PLA2R-Ab, increased levels of proteinuria, and decreased levels of eGFR[8]. However, there is no evidence that PLA2R-Ab levels exhibited statistical differences across pathological stages[8,9]. Yan et al. demonstrated that CYC + GC was more effective for stage II than stage I or III patients[10]. Given that both the risk of progression and pathological stage influence the prognosis of IMN, we conducted this multicenter clinical study to provide evidence for clinical management of IMN. Materials and Methods not-yet-known not-yet-known not-yet-known unknown 2.1 Study design and patients This was a multicenter, prospective cohort study conducted at four research centers in China (the Second Affiliated Hospital of Nanchang University, the First Affiliated Hospital of Nanchang University, the First Affiliated Hospital of Gannan Medical University, Ganzhou People’s Hospital) from March 2021 to June 2023. The study was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University and written informed consent was obtained from all participants. Patients over 18 years with biopsy-proven MN, an eGFR > 50 mL/min/1.73m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration[11], treated with SC, tacrolimus (TAC), RTX, and CYC were screened. Any secondary cause of MN (hepatitis B and C, systemic lupus erythematosus, medications, malignancies) or treatment with immunosuppressive drugs before baseline, and patients who were pregnant or nursing, or had active infection, or life-threatening complications, such as heart failure or active gastrointestinal bleeding were excluded. Besides, we established a control cohort consisting of biopsy-proven non-IMN patients, who underwent PLA2R-Ab testing concurrently with renal biopsy between June 2022 to June 2023. not-yet-known not-yet-known not-yet-known unknown 2.2 Intervention TAC was administered at an initial dose of 0.05-0.1 mg/kg/day divided into two doses at intervals of 12 h. The dose was adjusted according to the target trough blood concentration of 4-8 ng/mL for the first 6 months and tapered gradually until discontinued at the end of 12 months, and also combined with oral GC (20 mg/d) therapy. Subjects received RTX at a dose of 1 g on days 1 and 15 or at a dose of 375 mg/m2 every week for a total of four doses. In the GC+CYC group, patients received GC at months 1, 3, and 5 (1 g intravenously at days 1, 2, and 3, then 0.5 mg/kg/day orally from day 4 to day 30) and received oral CYC adjusted for age and renal function (1.0-2.0 mg/kg/day for 30 days) at months 2, 4, and 6. not-yet-known not-yet-known not-yet-known unknown 2.3 Outcomes and follow-up The primary outcome of the trial was the remission rate, including complete remission (CR) and overall remission (OR). CR was defined as urinary protein (UP) ≤ 0.3 g/24 h with normal renal function, and OR was CR plus partial remission, with partial remission defined as UP < 3.5 g/24 h and reduction more than 50% of the baseline. Secondary outcome measures included changes in UP, eGFR, albumin levels, and adverse events. Study visits were conducted at baseline, 1, 3, 6, 9, and 12 months, to record the levels of clinical parameters and remission rates. not-yet-known not-yet-known not-yet-known unknown 2.4 Statistical analysis The continuous variables were expressed as mean ± standard deviation and compared with each other using t-test, Mann-Whitney U-test, or Kruskal-Wallis H-test. Categorical variables were presented as numbers and percentages, and then analyzed by performing Pearson chi-square test or Fisher’s exact test. The Kaplan-Meier curve survival analysis was performed to compare remission rates, and the log-rank test was used to evaluate the significance of differences. Treatment effects on the primary outcomes were estimated using Cox proportional hazard models with covariate adjustment. The cutoff value was optimized by receiver operating characteristic (ROC) curve analysis. Two-tailed P < 0.05 was considered as significant. Statistical analysis was performed using SPSS (version 28.0) and GraphPad (version 9.0). Results 3.1 Comparison between subgroups based on risk stratification and pathological stage Selected 352 patients with IMN who were classified as moderate or high risk according to the KDIGO guidelines and were at pathological stages II or stage III. Of these, 136 received TAC, 87 received RTX, and 129 received CYC. The general clinical characteristics of different treatments were shown in Table 1. More TAC group patients achieved CR than RTX and CYC groups during the follow-up (P < 0.001) but no difference in OR (Supplementary Table 1). Kaplan-Meier survival curves results suggested that the incidence of CR was significantly higher in the TAC than in the RTX and CYC groups in medium risk group at 12 months (P = 0.045, Figure 1A). In high risk group, the CR rate was 36/75 patients (48.0%) in the TAC group, 31/87 patients (35.6%) in CYC group, and 8/48 patients (16.7%) in RTX group (P < 0.001, Figure 1B), and the average time to CR were 9.9 ± 0.3 months, 10.8 ± 0.2 months, and 11.6 ± 0.2 months at TAC, CYC and RTX group, respectively (P = 0.008). In stage II group, 44 cases (44.0%) in TAC group, 32 (39.5%) in CYC group, and 11 (17.5%) in RTX group achieved CR (P = 0.001, Figure 1C), and the average time to CR were 9.7 ± 0.3 months, 10.6 ± 0.3 months, and 11.4 ± 0.3 months at TAC, CYC, and RTX group, respectively (P = 0.015). There was no difference in CR, OR rate and average time to CR among the three treatment groups in stage III group. (Figure 1D). Subsequently, we further analyzed the subgroups, in high risk with stage II and stage III subgroup, the rate of CR was higher in TAC group than RTX and CYC groups (P = 0.017, P = 0.031, respectively; Supplementary Figure 1A, 1C), and no differences in OR at 12 months (Supplementary Figure 1B, 1D). In moderate risk with stage II or stage III subgroup, there was no significant difference in both CR and OR (Supplementary Figure 2A-D). 24 h UP was significantly lower in the TAC group compared with the RTX and CYC groups at months 1 and 3, whereas changes in serum albumin and eGFR were not significant in high risk with stage II subgroup (Figure 2A-B). There was nonsignificant trend in 24 h UP, serum albumin, and eGFR among the 3 treatment groups in high risk with stage III subgroup (Figure 2C-D). Changes in clinical indicators in the medium risk group were shown in Supplementary Figure 3, without any statistically differences. not-yet-known not-yet-known not-yet-known unknown 3.2 Low risk of progression group Patients with low risk of progression were screened and equally assigned to SC and non-SC (NSC) groups in approximately 1: 2 ratios. Baseline characteristics in the two groups were similar (Supplementary Table 2). Compared with the baseline, both groups showed a decrease in 24 h UP during the follow-up period. At 6 months, the mean 24 h UP in the NSC groups was remarkably lower than that in the SC group (1.18 ± 0.72 vs 1.59 ± 0.91, P = 0.037, Figure 3A), while no difference between the two groups in terms of albumin and eGFR (Figure 3B-C). OR was achieved in 11 of 33 patients (33.3%) in the SC group and 32 of 70 patients (45.7%) in NSC group, with the difference being similar but not statistically significant (odds ratio: 1.7, 95% Confidence interval [CI] 0.71-3.99). Subsequently, we retrospectively divided the patients in the NSC group into two subgroups using the median PLA2R-Ab titer as the reference point. 16 patients (45.7%) in the PLA2R-Ab ≤ 41.88 RU/mL group and 11 patients (31.4%) in the PLA2R-Ab > 41.88 RU/mL group had a CR at 12 months (P = 0.017, Figure 3D). Multivariate cox regression revealed the probability of CR was significantly lower in the latter group than the former group (hazard ratio, 0.351; 95% CI, 0.132-0.934). As shown in Figure 3E, 26 patients (74.3%) in the PLA2R-Ab ≤ 41.88 RU/mL group achieved OR at 12 months, whereas 24 patients (68.6%) achieved OR in the PLA2R-Ab > 41.88 RU/mL group (odds ratio: 0.755, 95% CI 0.27-2.14), no statistical differences revealed between the groups (P = 0.265). 3.3 Optimal cutoff value of PLA2R-Ab for the diagnosis of IMN A total of 620 patients had biopsy and serum PLA2R-Ab results. Among them, 278 (44.8%) patients were in the non-IMN group, and 342 (55.2%) were in the IMN group, with 16 cases in stage I, 241 cases in stage II, and 85 cases in stage III. The median titer of PLA2R-Ab in PMN group was 36.63 (8.36, 103.70) and 0.18 (0.14, 0.52) RU/mL in non-PMN group ( P < 0.001, Figure 4A). PLA2R-Ab titers was highest in stage II, but no statistically differences compared with I and III stage ( P = 0.063, Figure 4B). Using ROC curve method to validate an optimal cutoff value of PLA2R-Ab. The results showed that 3.67 RU/mL was the cutoff with the highest Youden index (0.835), with a sensitivity of 88.9%, specificity of 94.6%, positive predictive value of 95.3%, and negative predictive value of 87.4%. The area under the ROC curve was 0.957 (95% CI, 0.940-0.974) (Figure 4C). The diagnostic efficiency of different cutoff values published in previous studies were summarized in Supplementary Table 3. 3.4 Adverse events During the follow-up, three treatments were well tolerated, with no serious adverse events and death occurring (Table 2). The major adverse reactions in the overall population included infections, gastrointestinal reactions, hepatotoxicity, cardiovascular events, hyperglycemia, osteoporosis and infusion-related reactions. Discussion This multicenter, prospective study demonstrated that, overall, the prognose of moderate and high risk patients with IMN was good, with 75% achieving remission. Using risk of progression and pathological stage as the basis for grouping, the TAC group had a higher rate of CR in moderate and high risk groups, and higher CR rate and shorter mean time to CR in stage II group. For low risk patients, the 24 h UP had a noticeable reduction in NSC group compared to SC group, but the OR rate was similar between the two groups. The current study is the first three-arm study comparison of these 3 regimens. TAC inhibits calmodulin phosphatase by forming a complex with FK-506-binding protein 12 and exerts immunosuppressive effects[12]. Zhang et al. confirmed TAC combination with low-dose GC regime improved clinical outcomes and lowered the recurrence rate in moderate risk IMN patients[13]. TAC also induced the remission more effective and rapidly compared with CYC and mycophenolate mofetil for high risk patients with IMN [14]. A meta-analysis showed that GC + TAC was significantly effective in IMN patients with both UP 8 g/d compared to other immunosuppressive agents[15]. Our conclusions also supported their viewpoints that the CR rate of TAC was higher in medium and high risk patients. GC+CYC was the first choice for patients at high risk of progression[2], and it has been proven to be more efficacious than RTX monotherapy or sequential treatment with TAC and RTX[3,4]. However, some studies also indicated that the efficacy of CYC is lower than that of the TAC regimen during the early follow-up period[16,17]. Previous study have similarly observed a lower CR rate at 12 months in the CYC group than in the TAC group[18], as the consistent with us. RTX, a CD20 antibody used for B-cell depletion, has been widely employed in the treatment of IMN[19]. However, due to its loss in urine after administration, the development of anti-RTX antibodies, and chronic and irreversible renal damage[20], RTX is ineffective in 30% of patients. This may also account for the relatively low CR rate observed in moderate or high risk patients receiving RTX in our study. Additionally, it has been reported that low-dose RTX also improved clinical outcomes and further increased the remission rate of IMN patients[21,22]. This indicated that RTX treatment is highly individualized and may be related to risk stratification. Appropriate supplementary of RTX dose based on CD19 + B cell counts may improve the remission rate, but may also increase the risk of anti-RTX antibodies production. The difference in OR rates between the three treatment regimens was not significant (79.4% vs 65.5% vs 76.7%), probably due to the well long-term efficacy of RTX and CYC. Similarly, we also observed TAC group had a higher CR rate and a shorter mean time to CR in stage II patients compared to other two groups. This may be attributed to the fact that RTX lost from the urine, CYC has a slow onset of action, whereas TAC exhibits relatively good results in inducing remission in the short term[16]. There are few studies of low risk PMN reported in the literature. In a recent clinical trial, hydroxychloroquine sulfate + SC group showed a more notable reduction in 24 h UP and PLA2R-Ab titer than SC group in low risk patients, with OR rates of 52.0% and 26.7%, respectively[6]. Rozenberg et al. indicated the remission rate in low risk patients who received SC was 90.4% during the 4 years follow-up period[23]. In the present study, we compared the efficacy of SC and NSC groups and found that the OR rates were similar in both groups. This finding provides evidence that for low risk patients, SC treatment can achieve remission rate as same as the NSC group. Next, we found PLA2R-Ab level at baseline was an independent predictive factor for achieving CR in low risk IMN patients treated with NSC, but not associated with OR, which indicated despite variations in PLA2R-Ab differ, there were no differences in baseline proteinuria, albumin, and eGFR. Under different immunotherapy regimens, the overall response rates showed little variation. In addition, we included the maximum sample size to calculate the optimal cut-off value of PLA2R-Ab for the diagnosis of IMN and found that 3.67 was more diagnostically favorable than previously published values for PLA2R-Ab, with a sensitivity of 88.9%, specificity of 94.6%. The contrasting results in this regard may be due to different time points at which PLA2R-Ab were detected, ethnicity, and the method of detection[9,24]. Our study had some limitations. Firstly, the sample size of each group was small, and the study was unblinded. Secondly, the absence of PLA2R-Ab titers in the follow-up period makes it impossible to evaluate the immune remission. Thirdly, the relatively short follow-up time may not have been sufficient to capture long-term effects of different treatments. Compared with RTX and CYC groups, TAC exhibited a higher rate of CR in moderate and high risk groups, and had a higher incidence of CR and a shorter average time to CR in the stage II group. Abbreviations: CI: confidence interval; CR: complete remission; CYC: cyclophosphamide; eGFR: estimated glomerular filtration rate; GC: glucocorticoids; IMN: Idiopathic membranous nephropathy; KDIGO: Kidney Disease: Improving Global Outcomes; NSC: non-SC: OR: overall remission; PLA2R-Ab: antibodies against the Phospholipase A2 receptor antibody; ROC: receiver operating characteristic; RTX: rituximab; SC: supportive care; TAC: tacrolimus; UP: urinary protein. not-yet-known not-yet-known not-yet-known unknown References [1] Ronco P, Beck L, Debiec H, et al. Membranous nephropathy. Nature Reviews Disease Primers. 2021;7(1).[2] Kidney Disease: Improving Global Outcomes Glomerular Diseases Work G. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.[3] Fernández-Juárez G, Rojas-Rivera J, Logt AV, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. Kidney Int. 2021;99(4):986-998.[4] Scolari F, Delbarba E, Santoro D, et al. Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial. J Am Soc Nephrol. 2021;32(4):972-982.[5] Hladunewich MA, Troyanov S, Calafati J, et al. The Natural History of the Non-Nephrotic Membranous Nephropathy Patient. Clinical Journal of the American Society of Nephrology. 2009;4(9):1417-1422.[6] Mei M, Zeng J, Liu Z, et al. A single-center, open label, randomized, controlled study of hydroxychloroquine sulfate in the treatment of low risk PLA2R-associated membranous nephropathy. BMC Nephrology. 2024;25(1).[7] Fogo AB, Lusco MA, Najafian B, et al. AJKD Atlas of Renal Pathology: Membranous Nephropathy. American Journal of Kidney Diseases. 2015;66(3):e15-e17.[8] Zhang X-d, Cui Z, Zhang M-f, et al. Clinical implications of pathological features of primary membranous nephropathy. BMC Nephrology. 2018;19(1).[9] Chen J, Jia X, Wei X, et al. Optimal Value for Serum Anti-PLA2R Antibody in Primary Membranous Nephropathy: A Multicenter Observational Study. American Journal of Nephrology. 2022;53(2-3):129-138.[10] Yan Z, Hu L, Xu G. Immunosuppressive Treatments for Idiopathic Membranous Nephropathy: A Pilot Study According to Histopathological Stages. Am J Med Sci. 2022;363(5):444-451.[11] Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.[12] Westhoff TH, van der Giet M. Tacrolimus in the treatment of idiopathic nephrotic syndrome. Expert Opin Investig Drugs. 2007;16(7):1099-110.[13] Zhang X, Dou J, Gao G, et al. Comparison of tacrolimus with or without prednisone therapy in primary membranous nephropathy: a retrospective clinical study. Scientific Reports. 2024;14(1).[14] Peng L, Wei S-Y, Li L-T, et al. Comparison of different therapies in high-risk patients with idiopathic membranous nephropathy. Journal of the Formosan Medical Association. 2016;115(1):11-18.[15] Chen M, Liu J, Xiong Y, et al. Treatment of Idiopathic Membranous Nephropathy for Moderate or Severe Proteinuria: A Systematic Review and Network Meta-Analysis. International Journal of Clinical Practice. 2022;2022:1-12.[16] Chen M, Wang H-Y, Li H, et al. Tacrolimus Combined With Corticosteroids in Treatment of Nephrotic Idiopathic Membranous Nephropathy: A Multicenter Randomized Controlled Trial. The American Journal of the Medical Sciences. 2010;339(3):233-238.[17] Cui W, Lu X, Min X, et al. Therapy of tacrolimus combined with corticosteroids in idiopathic membranous nephropathy. Brazilian Journal of Medical and Biological Research. 2017;50(4).[18] Zou H, Jiang F, Xu G. Effectiveness and safety of cyclophosphamide or tacrolimus therapy for idiopathic membranous nephropathy. Renal Failure. 2019;41(1):673-681.[19] Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. New England Journal of Medicine. 2019;381(1):36-46.[20] Yang Y, Cheng K, Xu G. Novel approaches to primary membranous nephropathy: Beyond the KDIGO guidelines. Eur J Pharmacol. 2024;982:176928.[21] Wang Y-W, Wang X-H, Wang H-X, et al. Successful treatment of patients with refractory idiopathic membranous nephropathy with low-dose Rituximab: A single-center experience. World Journal of Clinical Cases. 2023;11(3):566-575.[22] Wang S, Deng Z, Wang Y, et al. Monthly mini-dose rituximab for primary anti-PLA2R-positive membranous nephropathy: a personalized approach. BMC Nephrology. 2023;24(1).[23] Rozenberg I, Kotliroff A, Zahavi T, et al. Outcome of Idiopathic Membranous Nephropathy: A Retrospective Study. Isr Med Assoc J. 2018;20(3):186-189.[24] Chen Y, Xu Y, Chen S, et al. The application of podocyte antigen PLA2R and anti-PLA2R antibody in the diagnosis and treatment of membranous nephropathy. Renal Failure. 2023;45(2). Figure Legends Figure 1. Figure 1. Kaplan-Meier analysis of complete remission in different IMN groups not-yet-known not-yet-known not-yet-known unknown Figure 2. Evolution of proteinuria, serum albumin, and eGFR between TAC, RTX, and CYC in high-risk cohort Figure 3. Comparison of the changes of different clinical indexes in low risk patients Figure 4. The distribution of the PLA2R-Ab and the optimal cut-off value Figure 1. Kaplan-Meier analysis of complete remission in different IMN groups. (A) moderate risk group; (B) high risk group; (C) stage II group; (D) stage III group. CYC: cyclophosphamide; IMN: idiopathic membranous nephropathy; RTX: rituximab; TAC: Tacrolimus. not-yet-known not-yet-known not-yet-known unknown Figure 2. Evolution of proteinuria, serum albumin, and eGFR between TAC, RTX, and CYC in high risk cohort . (A) proteinuria and serum albumin in high risk with stage II, (B) eGFR in high risk with stage II, (C) proteinuria and serum albumin in high risk with stage III, (D) eGFR in high risk with stage III. Data are presented as mean ± standard deviation by assigned treatment. CYC: cyclophosphamide; eGFR: estimated glomerular filtration rate; RTX: rituximab; TAC: Tacrolimus. not-yet-known not-yet-known not-yet-known unknown Figure 3. Comparison of the changes of different clinical indexes in low risk patients. The changes of (A) 24 h proteinuria, (B) albumin, (C) eGFR in SC and NSC groups; (D) Kaplan-Meier estimates of complete remission and (E) overall remission in the PLA2R-Ab ≤ 41.88 RU/mL and PLA2R-Ab > 41.88 RU/mL groups. eGFR: estimated glomerular filtration rate; SC: supportive care; NSC: non supportive care. Figure 4. The distribution of the PLA2R-Ab and the optimal cut-off value (A) distribution of the PLA2R-Ab in IMN and Non-IMN; (B) distribution of the PLA2R-Ab in different pathological stage in IMN group, and (C) receiver operating characteristic curve of PLA2R-Ab for the identification of patients with IMN. IMN: idiopathic membranous nephropathy. PLA2R-Ab: antibodies against the Phospholipase A2 receptor antibody. not-yet-known not-yet-known not-yet-known unknown Table 1. Baseline characteristics according to treatment group Age (y) 48.70 ± 13.45 49.36 ± 13.75 51.78 ± 12.24 0.142 Male (%) 84 (61.8) 50 (57.5) 76 (58.9) 0.797 Systolic blood pressure (mmHg) 125.80 ± 9.51 127.39 ± 10.66 125.66 ± 9.21 0.382 Diastolic blood pressure (mmHg) 75.77 ± 9.72 74.79 ± 10.03 73.93 ± 8.56 0.281 Risk level, n (%) 0.077 Moderate risk 61 (44.9) 39 (44.8) 42 (32.6) High risk 75 (55.1) 48 (55.2) 87 (67.4) Histology grading of IMN (%) 0.128 stage II 100 (73.5) 63 (72.4) 81 (62.8) stage III 36 (26.5) 24 (27.6) 48 (37.2) Proteinuria (g/24 h) 7.05 ± 3.03 7.53 ± 3.94 7.02 ± 3.02 0.918 Serum albumin (g/L) 25.77 ± 5.16 25.61 ± 4.99 25.64 ± 5.07 0.977 Total cholesterol (mmol/L) 7.97 ± 1.40 7.72 ± 1.33 8.02 ± 1.47 0.213 Triglyceride (mmol/L) 3.02 ± 1.13 3.01 ± 1.15 3.05 ± 1.11 0.961 Alanine aminotransferase (U/L) 18.76 ± 6.40 18.85 ± 6.19 18.48 ± 5.52 0.986 Aspartate aminotransferase (U/L) 22.34 ± 7.51 21.90 ± 7.04 22.55 ± 7.81 0.828 eGFR (mL/min/1.73 m 2 ) 82.37 ± 16.44 80.90 ± 19.18 80.96 ± 15.88 0.745 CYC: cyclophosphamide; IMN: idiopathic membranous nephropathy; eGFR: estimated glomerular filtration rate; RTX: rituximab; TAC: Tacrolimus. Table 2. Summary of adverse events Infections 29 (21.3%) 17 (19.5%) 37 (28.7%) 0.219 Gastrointestinal reactions 12 (8.8%) 7 (8.0%) 15 (11.6%) 0.625 Hepatotoxicity 6 (4.4%) 4 (4.6%) 12 (9.3%) 0.198 Cardiovascular events 8 (5.9%) 6 (6.9%) 10 (7.8%) 0.833 Hyperglycemia 15 (11.0%) 2 (2.3%) 10 (7.8%) 0.057 Osteoporosis 4 (2.9%) 0 (0) 5 (3.9%) 0.198 Infusion-related reaction 0 (0) 5 (9.2%) 2 (1.6%) 0.090 not-yet-known not-yet-known not-yet-known unknown CYC: cyclophosphamide; RTX: rituximab; TAC: Tacrolimus. Electronic supplementary material not-yet-known not-yet-known not-yet-known unknown Figure 1. Kaplan-Meier analysis of CR and OR in high risk of progression IMN Figure 2. Kaplan-Meier analysis of CR and OR in moderate risk of progression IMN not-yet-known not-yet-known not-yet-known unknown Figure 3. Evolution of proteinuria, serum albumin, and eGFR between TAC, RTX, and CYC in moderate risk cohort not-yet-known not-yet-known not-yet-known unknown Table 1. Remission rates in different subgroup treated with TAC, RTX or TAC at 12 months Table 2. Baseline characteristic of IMN patients with low risk Table 3. The efficiency of PLA2R-Ab for diagnosing IMN at different cutoff values not-yet-known not-yet-known not-yet-known unknown Supplemental Figure 1. Kaplan-Meier analysis of CR and OR in high risk of progression IMN. (A) CR in high risk with stage II, (B) OR in high risk with stage II, (C) CR in high risk with stage III, (D) OR in high risk with stage III. CR: complete remission; IMN: idiopathic membranous nephropathy; eGFR: estimated glomerular filtration rate; OR: overall remission; RTX: rituximab; TAC: tacrolimus. Supplemental Figure 2. Kaplan-Meier analysis of CR and OR in moderate risk of progression IMN. (A) CR in moderate risk with stage II, (B) OR in moderate risk with stage II, (C) CR in moderate risk with stage III, (D) OR in moderate risk with stage III. CR: complete remission; IMN: idiopathic membranous nephropathy; eGFR: estimated glomerular filtration rate; OR: overall remission; RTX: rituximab; TAC: tacrolimus. Supplemental Figure 3. Evolution of proteinuria, serum albumin, and eGFR between TAC, RTX, and CYC in moderate risk cohort. (A) proteinuria and serum albumin in moderate risk with stage II, (B) eGFR in moderate risk with stage II, (C) proteinuria and serum albumin in moderate risk with stage III, (D) eGFR in moderate risk with stage III. Data are presented as mean ± standard deviation by assigned treatment. CYC: cyclophosphamide; eGFR: estimated glomerular filtration rate; RTX: rituximab; TAC: Tacrolimus. Supplementary Table 1. Remission rates in different subgroup treated with TAC, RTX or TAC at 12 months not-yet-known not-yet-known not-yet-known unknown TAC RTX CYC P TAC RTX CYC P All 60/136 (44.1) 15/87 (17.2) 50/129 (38.8) < 0.001 108/136 (79.4) 57/87 (65.5) 99/129 (76.7) 0.055 Risk class Moderate risk 24/61 (39.3) 7/39 (17.9) 19/42 (45.2) 0.025 47/61 (77.0) 25/39 (64.1) 35/42 (83.3) 0.123 High risk 36/75 (48.0) 8/48 (16.7) 31/87 (35.6) 0.002 61/75 (81.3) 32/48 (66.7) 64/87 (73.6) 0.178 Pathological stage II 44/100 (44) 11/63 (17.5) 32/81 (39.5) 0.002 79/100 (79.0) 41/63 (65.1) 62/81 (76.5) 0.123 III 16/36 (44.4) 4/24 (16.7) 18/48 (37.5) 0.079 29/36 (80.6) 16/24 (66.7) 37/48 (77.1) 0.453 Different subgroups Moderate + II 17/42 (40.5) 5/29 (17.2) 10/22 (45.5) 0.059 32/42 (76.2) 19/29 (65.5) 19/22 (86.4) 0.228 Moderate + III 7/19 (36.8) 2/10 (20) 9/20 (45) 0.408 15/19 (79.0) 6/10 (60.0) 16/20 (80.0) 0.440 High + II 28/58 (48.3) 6/34 (17.6) 22/59 (37.3) 0.021 47/58 (81.0) 22/34 (64.7) 43/59 (72.9) 0.216 High + III 9/17 (52.9) 2/14 (14.3) 9/28 (32.1) 0.075 14/17 (82.4) 10/14 (71.4) 21/28 (75.0) 0.758 CR: complete remission; CYC: cyclophosphamide; OR: overall remission; RTX: rituximab; TAC: tacrolimus. Supplementary Table 2. Baseline characteristic of IMN patients with low risk Age (y) 53.47 ± 10.82 50.04 ± 11.93 0.078 Male (%) 15 (45.5) 32 (45.7) 0.980 Proteinuria (g/24 h) 2.01 ± 0.62 2.05 ± 0.84 0.764 Serum albumin (g/L) 33.58 ± 2.14 33.85 ± 2.80 0.805 eGFR (mL/min/1.73 m 2 ) 97.84 ± 15.01 100.69 ± 13.89 0.351 PLA2R-Ab (RU/mL) 32.52 (3.71-95.60) 55.59 (8.65-114.60) 0.169 eGFR: estimated glomerular filtration rate; PLA2R-Ab: antibodies against the M-type phospholipase A2 receptor; SC: supportive care; NSC: non-supportive care. Supplementary Table 3. The efficiency of PLA2R-Ab for diagnosing IMN at different cutoff values not-yet-known not-yet-known not-yet-known unknown 2 92.40 (316/342) 89.21 (248/278) 91.32 (316/346) 90.51 (248/274) 0.813 3.67 88.89 (304/342) 94.60 (263/278) 95.30 (304/319) 87.38 (263/301) 0.835 7.06 77.49 (265/342) 97.12 (270/278) 97.07 (265/273) 77.81 (270/347) 0.746 14 63.74 (218/342) 98.20 (273/278) 97.76 (218/223) 68.77 (273/397) 0.619 20 60.23 (206/342) 98.56 (274/278) 98.10 (206/210) 66.83 (274/410) 0.588 40 48.54 (166/342) 99.28 (276/278) 98.81 (166/168) 61.06 (276/452) 0.478 not-yet-known not-yet-known not-yet-known unknown IMN: idiopathic membranous nephropathy; PLA2R-Ab: antibodies against the M-type phospholipase A2 receptor; PPV: positive predictive value; NPV: negative predictive value. Information & Authors Information Version history V1 Version 1 26 March 2025 Peer review timeline Published European Journal of Pharmacology Version of Record 1 Aug 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords chronic kidney disease clinical pharmacology clinical pharmacy nephrology therapeutics Authors Affiliations Yang Yang Nanchang University Second Affiliated Hospital View all articles by this author Yuxin Zhang Nanchang University Second Affiliated Hospital View all articles by this author Ran Zhang Nanchang University Second Affiliated Hospital View all articles by this author Manna Li Nanchang University Second Affiliated Hospital View all articles by this author Hongping Wan The First Affiliated Hospital of Nanchang University View all articles by this author Wenjun Yan First Affiliated Hospital of Gannan Medical University View all articles by this author Kaiping Luo Ganzhou People's Hospital View all articles by this author Qipeng Huang Jinan University Affiliated Heyuan Hospital View all articles by this author Daijin Ren Jiangxi Provincial People's Hospital View all articles by this author Gaosi Xu 0000-0002-4001-9895 [email protected] Nanchang University Second Affiliated Hospital View all articles by this author Metrics & Citations Metrics Article Usage 262 views 144 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yang Yang, Yuxin Zhang, Ran Zhang, et al. Evaluation of Immunotherapy for Idiopathic Membranous Nephropathy Based on Risk Stratification and Pathological Stage. Authorea . 26 March 2025. DOI: https://doi.org/10.22541/au.174298888.86668266/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.174298888.86668266/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a027629028ca1640',t:'MTc3OTkwOTcxMQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();