A Single-Center, open label, Randomized, Controlled Study of Hydroxychloroquine Sulfate in the Treatment of Low Risk PLA 2 R-Associated Membranous Nephropathy

A Single-Center, open label, Randomized, Controlled Study of Hydroxychloroquine Sulfate in the Treatment of Low Risk PLA 2 R-Associated Membranous Nephropathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Single-Center, open label, Randomized, Controlled Study of Hydroxychloroquine Sulfate in the Treatment of Low Risk PLA 2 R-Associated Membranous Nephropathy Mei Mei, Jun Zeng, Zhengyang Liu, Li Gong, Li Fang, Quan Hu, Shaofen Huang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4195607/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Jul, 2024 Read the published version in BMC Nephrology → Version 1 posted 17 You are reading this latest preprint version Abstract Objective: To evaluate the efficacy and safety of hydroxychloroquine sulfate (HCQ) in the treatment of low risk phospholipase A 2 receptor (PLA 2 R)-associated membranous nephropathy (MN). Methods: A total of 110 patients with low risk PLA 2 R-associated MN were included in the study. Patients who met the inclusion and exclusion criteria were assigned randomly to two groups: the HCQ treatment group and the control group. The control group was given adequate support treatment according to the guidelines, while the HCQ treatment group was given HCQ on the basis of support treatment. The clinical data of the patients were analyzed, with comparisons made at baseline and during the six-month follow-up period. Any adverse reactions were recorded. Results: The baseline data were comparable between the HCQ treatment group and the control group. At the end of the six-month follow-up period, the reductions in urine protein excretion and serum PLA 2 R antibody titer were more notable in the HCQ treatment group than those in the control group, with these differences being statistically significant ( p <0.05). Compared to the control group, the HCQ treatment group had fewer patients who were converted from low risk to moderate-to-high risk ( p =0.084). There were also no severe adverse reactions in the HCQ treatment group. Conclusion: In patients with low risk PLA 2 R-associated MN, adequate supportive therapy combined with HCQ is superior to supportive therapy alone in terms of controlling proteinuria, reducing serum PLA 2 R antibody titers, and lowering the probability of conversion from low risk to moderate-to-high risk. In addition, our study demonstrated that the incidence of adverse reactions did not increase. Trial registration: This study was registered in the Chinese Clinical Trial Registry (Registration No.: ChiCTR1900021757，Date of registration: 2019-03-08). hydroxychloroquine sulfate low risk PLA2R-associated membranous nephropathy Figures Figure 1 1 Introduction Idiopathic membranous nephropathy (IMN) is one of the major causes of the nephrotic syndrome and end-stage renal disease, its pathogenesis remains inconclusive. While spontaneous remission may occur in some cases of IMN, the majority of patients experience a prolonged disease course, with approximately 30–40% of individuals at risk of progressing to end-stage renal disease.[1]Hou et al . [2] retrospectively analyzed the changes in the types of glomerular diseases in China, reporting a corrected incidence rate of 23.4% for MN, which exhibited a rapidly increasing trend.In recent years, the most prominent research advance on IMN was the discovery of the target antigen-M-type phospholipase A 2 receptor (PLA 2 R) on the surface of normal podocytes. [3]Although several other novel target antigens have been reported recently, PLA 2 R remains the optimal marker for diagnosing and evaluating the efficacy of IMN. [4]Based on research advances on IMN, the Kidney Disease: Improving Global Outcomes (KDIGO) reviewed almost all of the 2012 KDIGO guidelines and reassessed the diagnosis and treatment of IMN. [5]Generally, a "wait and see" strategy is used for patients with low risk IMN. However, clinical practice and outcomes indicated that there is still a possibility for some low risk IMN patients who receiving adequate supportive treatment to convert to moderate-to-high risk, and then require immunosuppressive therapy. Therefore, finding a low toxicity immunotherapy for early-stage low risk IMN patients would certainly be beneficial in the clinic. In recent years, hydroxychloroquine sulfate (HCQ) has been used to treat lupus nephritis and IgA nephropathy, [6–9]with the mechanisms of action involving repression of T and B lymphocyte activation by inhibition of the degradation of lysosomal derivatives, suppressing presentation of the major histocompatibility complex (MHC)-II-mediated autoantigen, and blocking Toll-like receptor (TLR) and cGAS-STING signals. In addition, HCQ also has effects on anticoagulation by inhibiting the PLA 2 pathway, and suppressing B cell-activating factors (BAFFs). [10]Theoretically, HCQ may exert a blocking effect on multiple aspects of the pathogenesis of PLA 2 R-associated MN. The aim of this randomized controlled study was therefore to investigate the efficacy of HCQ in the treatment of PLA 2 R-associated MN. 2 Materials and Methods 2.1 Research subjects This study was approved by the Hospital Ethics Committee (KY201994) and registered in the Chinese Clinical Trial Registry (Registration No.: ChiCTR1900021757). The study defined low-risk PLA 2 R-associated MN as: a) renal biopsy-proven MN and positive for tissue PLA 2 R and IgG4, b) serum PLA 2 R antibody titer ≤ 100RU/ml (ELISA), and c) estimated glomerular filtration rate (eGFR) > 60 mL/min/1.72 m 2 (CKD-EPI formula), urine protein excretion 25 g/L. This low risk PLA2R-MN definition made in this study in 2019 is extremely similar to the definition of the low risk group in the 2021 KDIGO guidelines for IMN.[11] Based on the criteria above,110 patients diagnosed with low risk PLA 2 R-associated MN by the serum PLA 2 R test and renal biopsy between 2019 and 2021 were included in the study. The age of the patients ranged between 18–65 years old. The exclusion criteria for the study included: 1) patients aged 65 years; 2) those with an active infection during follow-up; 3) those with other immune diseases, connective tissue diseases, amyloidosis, or requiring immunosuppressive therapy; 4) those administered with any immunosuppressive agents within 6 months before diagnosis; 5) those with complex diseases that might interfere with the study or increase its risks, such as diabetes, malignancies, blood diseases, heart or liver diseases, AIDS, or viral hepatitis. The details of the criteria for the entire study are presented in Fig. 1. 2.2 Randomization, interventions and withdrawal criteria All subjects signed written, informed consent and then received a fundus examination prior to the beginning of the research. The eligible subjects were assigned equally 1:1 to HCQ treatment group or control group using the computer random number method, with the aim of balancing the treatment groups on potential confounders. All subjects were administered adequate supportive therapy by trained investigators, including cessation of smoking and drinking, diet management, moderate exercise, and maximum tolerable RAS inhibitors (RASIs). The investigators also recorded and provided guidance for adverse reactions. The HCQ treatment group was given oral HCQ (SPH Zhongxi Pharmaceutical Co., Ltd.) based on adequate supportive therapy in the control group; 400 mg/d for patients ≥ 50 kg and 300 mg/d for those < 50 kg. Our investigators conducted weekly telephone follow-up visits with patients to ensure that they are taking their medication as prescribed. Patients who developed HCQ-related retinal toxicity (evaluated by an investigator with the assistance of an ophthalmologist) and Qtc prolongation (Electrocardiogram examination once a month)were withdrawn from the study. PLA 2 R antibody titers were re-examined at 3rd and 6th months of the follow-up period, and the levels of urine protein, plasma albumin, and serum creatinine, and coagulation function and other relevant indicators were re-examined every month. Moderate-to-high risk IMN was considered in subjects who met one of the following conditions at the 3rd month of follow-up and due to the requirement for additional immunosuppressive therapy were withdrawn from the study: 1) increase in urine protein excretion of > 50% compared to baseline or > 6 g/24 h, 2) increase in serum creatinine level by > 30% compared to baseline, and 3) an increase in PLA 2 R antibody titer by > 50% compared to baseline and an increase in the levels of urine protein or serum creatinine over those measured at baseline. 2.3 Observation indicators The percentage change in the quantity of 24-h urine protein excretion from baseline to the 6th month of follow-up was selected as the primary endpoint. A reduction of 50% or above in 24-h urine protein excretion was considered to represent effective treatment. The secondary endpoints included the percentage changes in serum PLA 2 R antibody titer, eGFR and plasma albumin level, and the number of patients converted to moderate-to-high risk. The adverse reactions were also recorded. 2.4 Statistical analysis Data with a normal distribution were expressed as mean ± standard deviation, while non-normally distributed data were expressed as medians and interquartile range (Q 25 − Q 75 ). Categorical data were expressed as count and percentage. The baseline characteristics were compared between the two groups using the paired-sample t -test, Wilcoxon rank-sum test (continuous variables) or χ 2 test (nominal variables). Univariate and multivariate logistic regression analyses was also used to determine the independent predictors for at least a 50% reduction in urine protein excretion. A p value < 0.05 was considered statistically significant. SPSS 19.0 and SAS 9.4 software were used for the statistical analyses. 3 Results 3.1 Baseline features A total of 110 PLA 2 R-associated MN patients who met the inclusion criteria were selected from October 2019 to October 2021 and categorized randomly into the HCQ treatment group and the control group. 5 patients in the treatment group and 10 patients in the control group withdrew from the study respectively (Figure 1). No significant differences were observed in the baseline clinical features between the two groups ( p >0.05) (Table 1). 3.2 Primary endpoints: Percentage change in 24-h urine protein excretion The 24-h urine protein excretion was roughly similar at baseline in the HCQ treatment group and the control group, with no statistical difference observed ( p =0.9198).Both groups of patients showed a decrease in proteinuria, but the treatment group showed a more significant decrease in proteinuria. At the 6 th month of follow-up, both groups of patients had a decrease in proteinuria compared to baseline (1.75g vs . 2.67g)(Table 2). At the 3 rd month of follow-up, excretion had declined relative to baseline levels in both groups (25.9% vs . 9.4%), with the difference being similar but not statistically significance ( p =0.0779). At the 6 th month of follow-up, the HCQ treatment group showed a more notably reduction in 24-h urine protein excretion than that in the control group (50.2% vs . 28.2%), with this difference being statistically significant ( p =0.0034) (Table 2). 3.3 Secondary endpoints 3.3.1 Percentage change in PLA 2 R antibody titers The PLA 2 R antibody titers were similar at baseline between the HCQ treatment group and the control group, with no statistically significant differences. ( p =0.4657). At the 3 rd month of follow-up, the HCQ treatment group showed statistically significant lower PLA 2 R antibody titers compared with those in the control group (-21.9% vs.-1.0%; p =0.0203). At the 6 th month of follow-up, the difference in the change of PLA2R antibody titers was also statistically significant between the HCQ treatment and control group (-50.0% vs. -25.0%, p =0.00092) (Table 2). 3.3.2 Change in eGFR There was no statistically significant difference in eGFR at baseline between the HCQ treatment group and the control group ( p =0.4753). The eGFR of both groups of patients remained stable during follow-up. At the 3 rd and 6 th months of follow-up, the change in eGFR was also not significantly different between the two groups ( p =0.4952, 0.7971) (Table 2). 3.3.3 Change in serum albumin levels Serum albumin levels showed no significant difference at baseline between the HCQ treatment group and the control group ( p =0.6359). At the 3 rd month of follow-up, the HCQ treatment group had no noticeable increase in serum albumin level than that observed in the control group (8.5% vs . 8.4%). At the 6 th month of follow-up, the increase in albumin level was significantly greater in the HCQ treatment group than that of control group (15.4% vs . 11.0%, p =0.0001) (Table 2). 3.4 Effective treatment At the 6 th month of follow-up, there were 15 cases in the HCQ treatment group where PLA2R antibody titers decreased by more than 50%, which was higher than the control group (7 cases).This difference was not statistically significant ( p =0.0956). At the 6 th month of follow-up, the number of patients with a > 50% decline in 24-h urine protein excretion was 26 cases in the HCQ treatment group and 12 cases in the control group, with this difference being statistically significant ( p =0.0118) (Table 3). 3.5 Number of patients with conversion to moderate-to-high risk After the completion of the 6-month follow-up, 5 patients in the HCQ treatment group withdrew from the study, including 4 patients with conversion to moderate-to-high risk due to an increase in urine protein excretion of >50% relative to baseline level and greater than 6 g/24 h, while 1 patient had suspected HCQ-related retinal toxicity. In the control group, 10 patients with conversion to moderate-to-high risk withdrew from the study, including 3 patients with an increase in serum creatinine level of >30% relative to baseline level, and 7 patients with an increase in urine protein excretion of >50% relative to baseline and greater than 6 g/24 h. Therefore, the probability of conversion from low risk to moderate-to-high risk was smaller in the HCQ treatment group than in the control group (4 vs . 10), although this difference was not significantly different ( p =0.086) (Table 4). 3.6 Independent predictors analysis We used univariate and multivariate logistic regression to analyze independent predictors affecting the reduction rate of effective albuminuria (by at least 50%), see Table 5. 3.7 Adverse reactions The difference in adverse reactions was not significantly different between the two groups, with no severe adverse reactions occurring in either group (Table 6). In the HCQ treatment group, one patient who presented with blurred vision withdrew from the study due to suspected HCQ-related retinal toxicity. In addition, there were 3 patients with skin pruritus, 2 patients with nausea, hepatic dysfunction, skin rashes and palpitation, and 1 patient with abdominal pain and dizziness, all of which were relieved after symptomatic treatment. In the control group, 2 patients had nausea, skin pruritus, and skin rashes and 1 patient each had either hepatic dysfunction, abdominal pain, palpitation, or dizziness. The evaluation in combination with six months of medication indicated that the safety of drugs was good in the two groups. 4 Discussion The high heterogeneity of clinical outcomes is viewed as one of the toughest problems in the treatment of IMN. Currently, spontaneous remission occurs in about one-third of IMN patients, although it is very difficult to precisely evaluate whose symptoms can be relieved spontaneously and when they will be relieved, with the optimal clinical protocol remaining inconclusive. [12–14]The newly issued KDIGO guidelines classify IMN patients into three risk groups, namely, low risk group, moderate risk group, and high risk group, with different therapies recommended in these three groups. For instance, a "wait and see" strategy is proposed for patients with low risk IMN, based on adequate supportive therapy. [15]However, in clinical practice, disease progression may also appear in low risk IMN patients who receiving adequate supportive treatment and immunosuppressive therapy has to be initiated. Therefore, it is risky to give supportive therapy alone to patients with low risk IMN. Practical evidence has confirmed that both spontaneous remission and post-treatment remission contribute to the long-term prognosis of IMN patients. [16]As such, low-toxicity and effective immunomodulatory therapy that can help low risk patients achieve a favorable immune response and remission at an early stage is of great clinical significance. HCQ possesses pharmacological effects such as immunomodulation, anti-inflammation and anti-thrombosis and has been proven to be effective in treating rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome by protecting target organs. [17–20]In recent years, HCQ has also been shown to relieve proteinuria in patients with IgA nephropathy. [21, 22]HCQ exerts immunomodulatory effects by entering lysosomes along a pH concentration gradient, thereby repressing lysosomal derivative degradation, and inhibiting presentation of MHC-II-mediated autoantigens. In addition, HCQ also suppresses antigen presentation, lymphocyte activation, the cytokine syndrome, and TLR stimulation by influencing lysosomal stability. [10]Analysis from a theoretical perspective indicates that HCQ possibly reduces the generation of IMN-specific antibodies by suppressing antigen presentation and lymphocyte activation, and it is also conducive to the treatment of IMN by protecting the kidney, inhibiting thrombosis and reducing proteinuria. Moreover, it is worth noting that HCQ has a favorable safety profile during normal use, a necessary requirement for immunotherapy in patients with low risk IMN. [23] Given that the low risk IMN patients defined at the time of inclusion in this study in 2019 satisfied the definition described in the 2021 KDIGO guidelines, the research findings can serve as a reference for clinical practice. [11]This study investigated the efficacy and safety of adequate supportive therapy combined with HCQ in the treatment of patients with low risk PLA 2 R-associated MN, with the results of the 6th month follow-up showing that the HCQ treatment group had a noticeable reduction in 24-h urine protein excretion (50.2% vs . 28.2%) and PLA 2 R antibody titers (50% vs. 25%) compared to those measured in the control group. The number of patients with a > 50% reduction in PLA 2 R antibody titers was greater in the HCQ treatment group than in the control group (15 vs. 7), although this difference was not statistically significant ( p = 0.0956). The number of patients with more than 50% decline in 24-h urine protein excretion was also significantly greater in the HCQ treatment group than that in the control group (26 vs. 12; p = 0.0118). In addition, the probability of conversion from low risk to moderate-to-high risk was smaller in the HCQ treatment group than in the control group (4 vs . 10), with this difference not being significantly different ( p = 0.086). We speculate from these findings that HCQ reduces PLA 2 R antibody titers and proteinuria and also lowers the probability of conversion from low risk to moderate-to-high risk by immunomodulatory function. This indicates that HCQ has potential as a therapeutic agent. Our data also shows that the HCQ group was comparable to the control group in terms of the incidence rate of adverse reactions. In the present study, nausea, abdominal pain, hepatic dysfunction and skin pruritus were the main adverse reactions, similar to those reported in previous studies. However, these reactions had no obvious impacts on the patients’ life, with all the reactions being relieved after symptomatic treatment. In particular, retinal toxicity, which is of more concern, [24]led to blurred vision in only one patient who subsequently withdrew from the study. However, the study was limited in that it was an open label, single-center study with a small sample size and short treatment course and follow-up period, and therefore the long-term efficacy of HCQ in the treatment of patients with low risk IMN could not be evaluated. Although this study was an early-phase exploratory trial, the potentially effective approach for treating low risk IMN patients it demonstrated should not be ignored. However, the efficacy of HCQ needs to be validated by a large-scale, long-term, multicenter clinical trial. 5 Conclusion Data from this preliminary study confirmed that adequate supportive therapy combined with HCQ reduces PLA 2 R antibody titers and proteinuria and also lowers the probability of conversion to moderate-to-high risk in patients with low risk IMN. We consider that HCQ may be a potential option for treating IMN in the future and is worthy of further investigation. Declarations Disclosures: Nothing to disclose. Conflict of interest: All authors declare that they have no conflict of interest. Funding Sources: This study was supported by the Chongqing Science and health joint medical research general program(2019MSXM082, 2019ZY023436,2021ZY023803);Chongqing University Central Hospital Scientific Research Foundation(2021KYQD1113). Author Contribution Research idea and study design: Bingbing Shen and Mei Mei. Patient follow-up and data collection:Bingbing Shen, Jun Zeng,Mei Mei, Zhengyang Liu, Li Fang, Sha Xiang, Haili Sun, Chaolin Wen. Data analysis:Jun Zeng,Liyin Chai, Xinqing Chen. Supervision or mentorship: Bingbing Shen, Mei Mei. Each author contributed important intellectual content during the manuscript drafting. Acknowledgement This study was supported by the Chongqing Science and health joint medical research general program(2019MSXM082，2019ZY023436,2021ZY023803)；Chongqing University Central Hospital Scientific Research Foundation（2021KYQD1113）.The authors would like to express their gratitude to Edit Springs (https://www.editsprings.cn ) for the expert linguistic services provided. Data Availability All data generated or analysed during this study are included in this published article. References Keri KC, Blumenthal S, Kulkarni V, Beck L, Chongkrairatanakul T: Primary membranous nephropathy: comprehensive review and historical perspective . Postgraduate Medical Journal 2019, 95 (1119):23–31. Xu X, Wang G, Chen N, Lu T, Nie S, Xu G, Zhang P, Luo Y, Wang Y, Wang X et al : Long-Term Exposure to Air Pollution and Increased Risk of Membranous Nephropathy in China . Journal of the American Society of Nephrology 2016, 27 (12):3739–3746. 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Tables Table 1: Baseline features of the two groups of patients Baseline variable HCQ treatment group (n=50) Control group (n=45) Statistic p Age (yr) 51.5±12.2 50.9±13.1 0.23 0.8177 Male ratio 28 (56.0%) 32 (71.1%) 2.32 0.1274 Mean arterial pressure (MAP, mmHg) 101.2±10.2 102.9±8.4 0.88 0.3816 Serum creatinine (Scr, µmol/L) 117.0±36.9 121.0±38.1 0.52 0.6047 eGFR (mL/min/1.73 m 2 ) 80.7±12.5 79.2±7.2 0.72 0.4753 24-h urine protein quantity (g/24 h) 3.38 (2.14, 4.24) 3.23 (2.63, 3.88) 0.10 0.9198 Serum PLA 2 R antibody titers(RU/ml) 60.0 (40.0, 80.0) 60.0 (30.0, 64.0) 0.73 0.4657 BMI 24.8±2.9 25.0±3.0 0.23 0.8219 Plasma albumin (g/L) 29.8 (27.5, 32.5) 29.1 (27.1, 32.2) 0.47 0.6359 Use of RASI Maximum tolerable ARB 20 (40.0%) 22 (48.9%) 0.76 0.3837 Maximum tolerable ACEI 10 (20.0%) 8 (17.8%) 0.08 0.7826 No significant differences were identified in the baseline features between the two groups ( p >0.05). Table 2: Primary and secondary endpoints Indicator HCQ treatment group (n=50) Control group (n=45) Statistic p Primary endpoint Percentage change in 24-h urine protein excretion at the 3 rd month -25.9% (13.0%, 46.9%) -9.4% (0.7%, 36.4%) 1.76 0.0779 Percentage change in 24-h urine protein excretion at the 6 th month -50.2% (28.4%, 65.6%) -28.2% (1.6%, 50.0%) 2.93 0.0034 24-h urine protein excretion at the 3 rd month(g/24h) 2.44（1.35,2.85) 2.98(1.47,2.97) 0.540 0.185 24-h urine protein excretion at the 6 th month(g/24h) 1.75(0.98,2.05) 2.67(1.27,2.) 6.396 0.001 Secondary endpoint PLA 2 R Percentage change in PLA 2 R antibody titers at the 3 rd month -21.9% (0%, 33.3%) -1.0% (0%, 25.0%) 2.32 0.0203 Percentage change in PLA 2 R antibody titers at the 6 th month -50.0% (20.0%, 62.5%) -25.0% (0%, 50.0%) 2.60 0.0092 PLA 2 R antibody titers at the 3 rd month(u/ml) 41.8 (31.2, 56.3) 47.4 (32.6, 58.5) 1.817 0.069 PLA 2 R antibody titers at the 6 th month(u/ml) 34.6 (28.4, 42.8) 41.3 (30.3, 54.2) 2.837 0.017 eGFR Percentage change in eGFR at the 3 rd month 0% (-1.6%, 1.6%) 0.3% (-1.2%, 1.5%) 0.68 0.4952 Percentage change in eGFR at the 6 th month -0.7% (-2.3%, 0.7%) -0.7% (-2.7%, 0.2%) 0.26 0.7971 eGFR at the 3 rd month 80.4±12.9 79.1±13.8 0.474 0.636 eGFR at the 6 th month 81.6±13.4 80.2±14.1 0.496 0.621 Albumin Percentage change in albumin at the 3 rd month 8.5% (4.5%, 18.8%) 8.4% (5.3%, 17.6%) 1.217 0.224 Percentage change in albumin at the 6 th month 15.4% (7.7%, 23.6%) 11.0% (-8.4%, 4.5%) 4.283 0.0001 albumin at the 3 rd month 32.3 (29.5, 36.4) 31.7 (29.1, 35.5) 0.487 0.626 albumin at the 6 th month 34.4 (31.2, 38.3) 32.3 (29.6, 35.9) 1.703 0.089 The percentage changes in 24-h urine protein excretion, PLA 2 R antibody titers, and albumin at the 6 th month of follow-up were statistically different ( p 0.05). Table 3: Comparison of the number of patients with reductions of more than 50% in PLA 2 R antibody titers and 24-h urine protein excretion at the 6 th month of follow-up between the two groups Variable HCQ treatment group (n=50) Control group (n=45) χ 2 p More than 50% reduction in PLA 2 R antibody titers 15 (30.0%) 7 (15.6%) 2.78 0.0956 More than 50% reduction in 24-h urine protein excretion 26 (52.0%) 12 (26.7%) 6.33 0.0118 At the 6 th month of follow-up, there was a statistically significant difference in the number of patients with more than a 50% reduction in 24-h urine protein excretion between the two groups. The number of patients with more than a 50% reduction in PLA 2 R antibody titers was similar in the two groups, with no statistically significant difference observed. Table 4: Comparison of the number of patients with conversion to Moderate-to-high risk between the two groups HCQ treatment group Control group p Number of patients at baseline 55 55 Number of patients with conversion to Moderate-to-high risk 4 (7.3%) 10 (18.2%) 0.086 The difference in the number of patients with conversion to Moderate-to-high risk between the two groups was not statistically significant ( p =0.086). Table 5. Independent predictors of univariate and multivariate logistic regression analysis. Characteristics Univariate analysis Multivariate analysis OR 95% CI P values OR 95% CI P value s Age 1.0 (0.95–1.03) 0.78 1.01 (0.96–1.04) 0.77 Gender 1.14 (0.82–1.44) 0.57 1.12 (0.85–1.37) 0.68 eGFR at baseline 1.02 (0.98–1.05) 0.62 1.0 (0.97–1.03) 0.79 proteinuria at baseline 0.84 (0.69–1.01) 0.15 0.79 (0.69–1.01) 0.09 serum PLA2R antibody titers at baseline 0.86 (0.67–0.97) 0.17 0.73 (0.61–0.88) 0.045 HCQ 1.76 (1.37–2.14) 0.029 2.15 (1.67–3.01) 0.005 Statistically significant P values are shown in bold. Table 6: Adverse reactions in the two groups Number of cases Adverse reaction HCQ treatment group Control group Severe adverse reactions 0 0 Adverse reactions Number of patients without adverse reactions 32 32 Number of patients with one adverse reaction 8 6 Number of patients with more than 2 adverse reactions 2 2 Types of adverse reactions Nausea 2 2 Abdominal pain 1 1 Hepatic dysfunction 2 1 Palpitation 2 1 Dizziness 1 1 Skin rashes 2 2 Skin pruritus 3 2 Blurred vision 1 0 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Jul, 2024 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 12 Jun, 2024 Reviews received at journal 11 Jun, 2024 Reviews received at journal 10 Jun, 2024 Reviews received at journal 09 Jun, 2024 Reviewers agreed at journal 09 Jun, 2024 Reviews received at journal 01 Jun, 2024 Reviews received at journal 31 May, 2024 Reviewers agreed at journal 19 May, 2024 Reviewers agreed at journal 19 May, 2024 Reviewers agreed at journal 19 May, 2024 Reviewers agreed at journal 17 May, 2024 Reviewers agreed at journal 15 May, 2024 Reviewers invited by journal 13 May, 2024 Editor assigned by journal 13 May, 2024 Editor invited by journal 02 Apr, 2024 Submission checks completed at journal 02 Apr, 2024 First submitted to journal 31 Mar, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Zeng","email":"","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Zeng","suffix":""},{"id":286817341,"identity":"cf5d4726-c50c-4ebc-9962-cf2ed3768c76","order_by":2,"name":"Zhengyang Liu","email":"","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Zhengyang","middleName":"","lastName":"Liu","suffix":""},{"id":286817342,"identity":"deb54031-4100-4a0b-8a23-f27165ab9aeb","order_by":3,"name":"Li Gong","email":"","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Gong","suffix":""},{"id":286817343,"identity":"a83b096f-8da3-4569-8644-b743a8a68617","order_by":4,"name":"Li Fang","email":"","orcid":"","institution":"The First Hospital Affiliated to Army Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Fang","suffix":""},{"id":286817344,"identity":"3d681b57-46bb-43fc-8057-8162b64d0903","order_by":5,"name":"Quan Hu","email":"","orcid":"","institution":"People's Hospital of Shapingba District ,Chongqing University Shapingba Hospital ,School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Quan","middleName":"","lastName":"Hu","suffix":""},{"id":286817345,"identity":"4dc0d328-f325-463e-9b04-931836d7b3c6","order_by":6,"name":"Shaofen Huang","email":"","orcid":"","institution":"People's Hospital of Shapingba District ,Chongqing University Shapingba Hospital ,School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Shaofen","middleName":"","lastName":"Huang","suffix":""},{"id":286817346,"identity":"55bc2154-540f-4c8b-bd41-2b3758e4d257","order_by":7,"name":"Liyin Chai","email":"","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Liyin","middleName":"","lastName":"Chai","suffix":""},{"id":286817347,"identity":"14fb80d7-6811-42e0-80ce-c48260c2ee9f","order_by":8,"name":"Xinqing Chen","email":"","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Xinqing","middleName":"","lastName":"Chen","suffix":""},{"id":286817348,"identity":"569606bf-e98d-4cf5-882d-c80fc98e6e80","order_by":9,"name":"Haili Sun","email":"","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Haili","middleName":"","lastName":"Sun","suffix":""},{"id":286817349,"identity":"90f49d63-f163-466c-94d7-72cd0e51552a","order_by":10,"name":"Sha Xiang","email":"","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Sha","middleName":"","lastName":"Xiang","suffix":""},{"id":286817350,"identity":"89a02c62-8e27-4f2a-ac95-d28bbf9bcda5","order_by":11,"name":"Chaolin Wen","email":"","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":false,"prefix":"","firstName":"Chaolin","middleName":"","lastName":"Wen","suffix":""},{"id":286817351,"identity":"d0431acf-6234-4a9c-ae51-54d066c47368","order_by":12,"name":"Bingbing Shen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYDACCQYGZgYDBgYDZiDnA0TMgHgtjDOI1wJVxsxDjBb52c3HHhcU3LHbzs57+LVNjXViA3vzNgmGmjs4tRjcOZZuPMPgWfLOZr4065xj6YkNPMfKJBiOPcOtRSLHTJrH4HCywWEeM+PchsOJDUARCcaGw7gdNiP/G0KLJUiL/Bv8Whhu5LCBtNgBtRg/ZgTbwoNfi8GNNDPpGQaHEyybecwYe4Aea+NJK7ZIOIbPYcnPpAv+HLY35z9j/OFHjbVsP/vhjTc+1OBxGBQkNjAwsIHjiA3ETSCogYHBHoiZP0CjdRSMglEwCkYBCgAAJtxQl95o4QQAAAAASUVORK5CYII=","orcid":"","institution":"Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University","correspondingAuthor":true,"prefix":"","firstName":"Bingbing","middleName":"","lastName":"Shen","suffix":""}],"badges":[],"createdAt":"2024-03-31 12:32:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4195607/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4195607/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-024-03670-3","type":"published","date":"2024-07-19T16:13:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":54192036,"identity":"28d8478f-73bc-4c23-88e2-b1aa736f2b9c","added_by":"auto","created_at":"2024-04-05 21:01:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":284213,"visible":true,"origin":"","legend":"\u003cp\u003eInclusion flow chart\u003c/p\u003e","description":"","filename":"F1.png","url":"https://assets-eu.researchsquare.com/files/rs-4195607/v1/1ae7808bd73b18c2abc97902.png"},{"id":61595255,"identity":"033dcbda-5c7e-4efc-a67c-c257b3b738fb","added_by":"auto","created_at":"2024-08-01 17:21:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1578555,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4195607/v1/9f8b11b5-db0e-4107-a068-515da6c7c0fd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Single-Center, open label, Randomized, Controlled Study of Hydroxychloroquine Sulfate in the Treatment of Low Risk PLA 2 R-Associated Membranous Nephropathy","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eIdiopathic membranous nephropathy (IMN) is one of the major causes of the nephrotic syndrome and end-stage renal disease, its pathogenesis remains inconclusive. While spontaneous remission may occur in some cases of IMN, the majority of patients experience a prolonged disease course, with approximately 30\u0026ndash;40% of individuals at risk of progressing to end-stage renal disease.[1]Hou \u003cem\u003eet al\u003c/em\u003e. [2] retrospectively analyzed the changes in the types of glomerular diseases in China, reporting a corrected incidence rate of 23.4% for MN, which exhibited a rapidly increasing trend.In recent years, the most prominent research advance on IMN was the discovery of the target antigen-M-type phospholipase A\u003csub\u003e2\u003c/sub\u003e receptor (PLA\u003csub\u003e2\u003c/sub\u003eR) on the surface of normal podocytes. [3]Although several other novel target antigens have been reported recently, PLA\u003csub\u003e2\u003c/sub\u003eR remains the optimal marker for diagnosing and evaluating the efficacy of IMN. [4]Based on research advances on IMN, the Kidney Disease: Improving Global Outcomes (KDIGO) reviewed almost all of the 2012 KDIGO guidelines and reassessed the diagnosis and treatment of IMN. [5]Generally, a \"wait and see\" strategy is used for patients with low risk IMN. However, clinical practice and outcomes indicated that there is still a possibility for some low risk IMN patients who receiving adequate supportive treatment to convert to moderate-to-high risk, and then require immunosuppressive therapy. Therefore, finding a low toxicity immunotherapy for early-stage low risk IMN patients would certainly be beneficial in the clinic. In recent years, hydroxychloroquine sulfate (HCQ) has been used to treat lupus nephritis and IgA nephropathy, [6\u0026ndash;9]with the mechanisms of action involving repression of T and B lymphocyte activation by inhibition of the degradation of lysosomal derivatives, suppressing presentation of the major histocompatibility complex (MHC)-II-mediated autoantigen, and blocking Toll-like receptor (TLR) and cGAS-STING signals. In addition, HCQ also has effects on anticoagulation by inhibiting the PLA\u003csub\u003e2\u003c/sub\u003e pathway, and suppressing B cell-activating factors (BAFFs). [10]Theoretically, HCQ may exert a blocking effect on multiple aspects of the pathogenesis of PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN. The aim of this randomized controlled study was therefore to investigate the efficacy of HCQ in the treatment of PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Research subjects\u003c/h2\u003e \u003cp\u003eThis study was approved by the Hospital Ethics Committee (KY201994) and registered in the Chinese Clinical Trial Registry (Registration No.: ChiCTR1900021757). The study defined low-risk PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN as: a) renal biopsy-proven MN and positive for tissue PLA\u003csub\u003e2\u003c/sub\u003eR and IgG4, b) serum PLA\u003csub\u003e2\u003c/sub\u003eR antibody titer\u0026thinsp;\u0026le;\u0026thinsp;100RU/ml (ELISA), and c) estimated glomerular filtration rate (eGFR)\u0026thinsp;\u0026gt;\u0026thinsp;60 mL/min/1.72 m\u003csup\u003e2\u003c/sup\u003e (CKD-EPI formula), urine protein excretion\u0026thinsp;\u0026lt;\u0026thinsp;4 g/d, and plasma albumin level\u0026thinsp;\u0026gt;\u0026thinsp;25 g/L. This low risk PLA2R-MN definition made in this study in 2019 is extremely similar to the definition of the low risk group in the 2021 KDIGO guidelines for IMN.[11]\u003c/p\u003e \u003cp\u003eBased on the criteria above,110 patients diagnosed with low risk PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN by the serum PLA\u003csub\u003e2\u003c/sub\u003eR test and renal biopsy between 2019 and 2021 were included in the study. The age of the patients ranged between 18\u0026ndash;65 years old. The exclusion criteria for the study included:\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003e1) patients aged \u003c 18 years or \u003e 65 years;\u003c/h3\u003e\n\n\u003ch3\u003e2) those with an active infection during follow-up;\u003c/h3\u003e\n\n\u003ch3\u003e3) those with other immune diseases, connective tissue diseases, amyloidosis, or requiring immunosuppressive therapy;\u003c/h3\u003e\n\n\u003ch3\u003e4) those administered with any immunosuppressive agents within 6 months before diagnosis;\u003c/h3\u003e\n\u003cp\u003e5) those with complex diseases that might interfere with the study or increase its risks, such as diabetes, malignancies, blood diseases, heart or liver diseases, AIDS, or viral hepatitis.\u003c/p\u003e \u003cp\u003eThe details of the criteria for the entire study are presented in Fig.\u0026nbsp;1.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Randomization, interventions and withdrawal criteria\u003c/h2\u003e \u003cp\u003e All subjects signed written, informed consent and then received a fundus examination prior to the beginning of the research. The eligible subjects were assigned equally 1:1 to HCQ treatment group or control group using the computer random number method, with the aim of balancing the treatment groups on potential confounders.\u003c/p\u003e \u003cp\u003eAll subjects were administered adequate supportive therapy by trained investigators, including cessation of smoking and drinking, diet management, moderate exercise, and maximum tolerable RAS inhibitors (RASIs). The investigators also recorded and provided guidance for adverse reactions. The HCQ treatment group was given oral HCQ (SPH Zhongxi Pharmaceutical Co., Ltd.) based on adequate supportive therapy in the control group; 400 mg/d for patients\u0026thinsp;\u0026ge;\u0026thinsp;50 kg and 300 mg/d for those\u0026thinsp;\u0026lt;\u0026thinsp;50 kg. Our investigators conducted weekly telephone follow-up visits with patients to ensure that they are taking their medication as prescribed. Patients who developed HCQ-related retinal toxicity (evaluated by an investigator with the assistance of an ophthalmologist) and Qtc prolongation (Electrocardiogram examination once a month)were withdrawn from the study. PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers were re-examined at 3rd and 6th months of the follow-up period, and the levels of urine protein, plasma albumin, and serum creatinine, and coagulation function and other relevant indicators were re-examined every month.\u003c/p\u003e \u003cp\u003eModerate-to-high risk IMN was considered in subjects who met one of the following conditions at the 3rd month of follow-up and due to the requirement for additional immunosuppressive therapy were withdrawn from the study: 1) increase in urine protein excretion of \u0026gt;\u0026thinsp;50% compared to baseline or \u0026gt;\u0026thinsp;6 g/24 h, 2) increase in serum creatinine level by \u0026gt;\u0026thinsp;30% compared to baseline, and 3) an increase in PLA\u003csub\u003e2\u003c/sub\u003eR antibody titer by \u0026gt;\u0026thinsp;50% compared to baseline and an increase in the levels of urine protein or serum creatinine over those measured at baseline.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Observation indicators\u003c/h2\u003e \u003cp\u003eThe percentage change in the quantity of 24-h urine protein excretion from baseline to the 6th month of follow-up was selected as the primary endpoint. A reduction of 50% or above in 24-h urine protein excretion was considered to represent effective treatment.\u003c/p\u003e \u003cp\u003eThe secondary endpoints included the percentage changes in serum PLA\u003csub\u003e2\u003c/sub\u003eR antibody titer, eGFR and plasma albumin level, and the number of patients converted to moderate-to-high risk. The adverse reactions were also recorded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eData with a normal distribution were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, while non-normally distributed data were expressed as medians and interquartile range (Q\u003csub\u003e25 \u0026minus;\u003c/sub\u003e Q\u003csub\u003e75\u003c/sub\u003e). Categorical data were expressed as count and percentage. The baseline characteristics were compared between the two groups using the paired-sample \u003cem\u003et\u003c/em\u003e-test, Wilcoxon rank-sum test (continuous variables) or χ\u003csup\u003e2\u003c/sup\u003e test (nominal variables). Univariate and multivariate logistic regression analyses was also used to determine the independent predictors for at least a 50% reduction in urine protein excretion. A \u003cem\u003ep\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. SPSS 19.0 and SAS 9.4 software were used for the statistical analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cp\u003e3.1 Baseline features\u003c/p\u003e\n\u003cp\u003eA total of 110 PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN patients who met the inclusion criteria were selected from October 2019 to October 2021 and categorized randomly into the HCQ treatment group and the control group. 5 patients in the treatment group and 10 patients in the control group withdrew from the study respectively (Figure 1). No significant differences were observed in the baseline clinical features between the two groups (\u003cem\u003ep\u003c/em\u003e\u0026gt;0.05) (Table 1).\u003c/p\u003e\n\u003cp\u003e3.2 Primary endpoints: Percentage change in 24-h urine protein excretion\u003c/p\u003e\n\u003cp\u003eThe 24-h urine protein excretion was roughly similar at baseline in the HCQ treatment group and the control group, with no statistical difference observed (\u003cem\u003ep\u003c/em\u003e=0.9198).Both groups of patients showed a decrease in proteinuria, but the treatment group showed a more significant decrease in proteinuria. At the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up, both groups of patients had a decrease in proteinuria compared to baseline (1.75g \u003cem\u003evs\u003c/em\u003e. 2.67g)(Table 2). At the 3\u003csup\u003erd\u003c/sup\u003e month of follow-up, excretion had declined relative to baseline levels in both groups (25.9% \u003cem\u003evs\u003c/em\u003e. 9.4%), with the difference being similar but not statistically significance (\u003cem\u003ep\u003c/em\u003e=0.0779). At the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up, the HCQ treatment group showed a more notably reduction in 24-h urine protein excretion than that in the control group (50.2% \u003cem\u003evs\u003c/em\u003e. 28.2%), with this difference being statistically significant (\u003cem\u003ep\u003c/em\u003e=0.0034) (Table 2).\u003c/p\u003e\n\u003cp\u003e3.3 Secondary endpoints\u003c/p\u003e\n\u003cp\u003e3.3.1 Percentage change in PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers\u003c/p\u003e\n\u003cp\u003eThe PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers were similar at baseline between the HCQ treatment group and the control group, with no statistically significant differences. (\u003cem\u003ep\u003c/em\u003e=0.4657). At the 3\u003csup\u003erd\u003c/sup\u003e month of follow-up, the HCQ treatment group showed statistically significant lower PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers compared with those in the control group (-21.9% vs.-1.0%; \u003cem\u003ep\u003c/em\u003e=0.0203). At the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up, the difference in the change of PLA2R antibody titers was also statistically significant between the HCQ treatment and control group (-50.0% \u003cem\u003evs.\u003c/em\u003e -25.0%, \u003cem\u003ep\u003c/em\u003e=0.00092) (Table 2).\u003c/p\u003e\n\u003cp\u003e3.3.2 Change in eGFR\u003c/p\u003e\n\u003cp\u003eThere was no statistically significant difference in eGFR at baseline between the HCQ treatment group and the control group (\u003cem\u003ep\u003c/em\u003e=0.4753). The eGFR of both groups of patients remained stable during follow-up. At the 3\u003csup\u003erd\u003c/sup\u003e and 6\u003csup\u003eth\u003c/sup\u003e months of follow-up, the change in eGFR was also not significantly different between the two groups (\u003cem\u003ep\u003c/em\u003e=0.4952, 0.7971) (Table 2).\u003c/p\u003e\n\u003cp\u003e3.3.3 Change in serum albumin levels\u003c/p\u003e\n\u003cp\u003eSerum albumin levels showed no significant difference at baseline between the HCQ treatment group and the control group (\u003cem\u003ep\u003c/em\u003e=0.6359). At the 3\u003csup\u003erd\u003c/sup\u003e month of follow-up, the HCQ treatment group had no noticeable increase in serum albumin level than that observed in the control group (8.5% \u003cem\u003evs\u003c/em\u003e. 8.4%). At the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up, the increase in albumin level was significantly greater in the HCQ treatment group than that of control group (15.4% \u003cem\u003evs\u003c/em\u003e. 11.0%, \u003cem\u003ep\u003c/em\u003e=0.0001) (Table 2).\u003c/p\u003e\n\u003cp\u003e3.4 Effective treatment\u003c/p\u003e\n\u003cp\u003eAt the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up, there were 15 cases in the HCQ treatment group where PLA2R antibody titers decreased by more than 50%, which was higher than the control group (7 cases).This difference was not statistically significant (\u003cem\u003ep\u003c/em\u003e=0.0956). At the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up, the number of patients with a \u0026gt; 50% decline in 24-h urine protein excretion was 26 cases in the HCQ treatment group and 12 cases in the control group, with this difference being statistically significant (\u003cem\u003ep\u003c/em\u003e=0.0118) (Table 3).\u003c/p\u003e\n\u003cp\u003e3.5 Number of patients with conversion to moderate-to-high risk\u003c/p\u003e\n\u003cp\u003eAfter the completion of the 6-month follow-up, 5 patients in the HCQ treatment group withdrew from the study, including 4 patients with conversion to moderate-to-high risk due to an increase in urine protein excretion of \u0026gt;50% relative to baseline level and greater than 6 g/24 h, while 1 patient had suspected HCQ-related retinal toxicity. In the control group, 10 patients with conversion to moderate-to-high risk withdrew from the study, including 3 patients with an increase in serum creatinine level of \u0026gt;30% relative to baseline level, and 7 patients with an increase in urine protein excretion of \u0026gt;50% relative to baseline and greater than 6 g/24 h. Therefore, the probability of conversion from low risk to moderate-to-high risk was smaller in the HCQ treatment group than in the control group (4 \u003cem\u003evs\u003c/em\u003e. 10), although this difference was not significantly different (\u003cem\u003ep\u003c/em\u003e=0.086) (Table 4).\u003c/p\u003e\n\u003cp\u003e3.6 Independent predictors analysis\u003c/p\u003e\n\u003cp\u003eWe used univariate and multivariate logistic regression to analyze independent predictors affecting the reduction rate of effective albuminuria (by at least 50%), see Table 5.\u003c/p\u003e\n\u003cp\u003e3.7 Adverse reactions\u003c/p\u003e\n\u003cp\u003eThe difference in adverse reactions was not significantly different between the two groups, with no severe adverse reactions occurring in either group (Table 6). In the HCQ treatment group, one patient who presented with blurred vision withdrew from the study due to suspected HCQ-related retinal toxicity. In addition, there were 3 patients with skin pruritus, 2 patients with nausea, hepatic dysfunction, skin rashes and palpitation, and 1 patient with abdominal pain and dizziness, all of which were relieved after symptomatic treatment. In the control group, 2 patients had nausea, skin pruritus, and skin rashes and 1 patient each had either hepatic dysfunction, abdominal pain, palpitation, or dizziness. The evaluation in combination with six months of medication indicated that the safety of drugs was good in the two groups.\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe high heterogeneity of clinical outcomes is viewed as one of the toughest problems in the treatment of IMN. Currently, spontaneous remission occurs in about one-third of IMN patients, although it is very difficult to precisely evaluate whose symptoms can be relieved spontaneously and when they will be relieved, with the optimal clinical protocol remaining inconclusive. [12\u0026ndash;14]The newly issued KDIGO guidelines classify IMN patients into three risk groups, namely, low risk group, moderate risk group, and high risk group, with different therapies recommended in these three groups. For instance, a \"wait and see\" strategy is proposed for patients with low risk IMN, based on adequate supportive therapy. [15]However, in clinical practice, disease progression may also appear in low risk IMN patients who receiving adequate supportive treatment and immunosuppressive therapy has to be initiated. Therefore, it is risky to give supportive therapy alone to patients with low risk IMN. Practical evidence has confirmed that both spontaneous remission and post-treatment remission contribute to the long-term prognosis of IMN patients. [16]As such, low-toxicity and effective immunomodulatory therapy that can help low risk patients achieve a favorable immune response and remission at an early stage is of great clinical significance.\u003c/p\u003e \u003cp\u003eHCQ possesses pharmacological effects such as immunomodulation, anti-inflammation and anti-thrombosis and has been proven to be effective in treating rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome by protecting target organs. [17\u0026ndash;20]In recent years, HCQ has also been shown to relieve proteinuria in patients with IgA nephropathy. [21, 22]HCQ exerts immunomodulatory effects by entering lysosomes along a pH concentration gradient, thereby repressing lysosomal derivative degradation, and inhibiting presentation of MHC-II-mediated autoantigens. In addition, HCQ also suppresses antigen presentation, lymphocyte activation, the cytokine syndrome, and TLR stimulation by influencing lysosomal stability. [10]Analysis from a theoretical perspective indicates that HCQ possibly reduces the generation of IMN-specific antibodies by suppressing antigen presentation and lymphocyte activation, and it is also conducive to the treatment of IMN by protecting the kidney, inhibiting thrombosis and reducing proteinuria. Moreover, it is worth noting that HCQ has a favorable safety profile during normal use, a necessary requirement for immunotherapy in patients with low risk IMN. [23]\u003c/p\u003e \u003cp\u003e Given that the low risk IMN patients defined at the time of inclusion in this study in 2019 satisfied the definition described in the 2021 KDIGO guidelines, the research findings can serve as a reference for clinical practice. [11]This study investigated the efficacy and safety of adequate supportive therapy combined with HCQ in the treatment of patients with low risk PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN, with the results of the 6th month follow-up showing that the HCQ treatment group had a noticeable reduction in 24-h urine protein excretion (50.2% \u003cem\u003evs\u003c/em\u003e. 28.2%) and PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers (50% \u003cem\u003evs.\u003c/em\u003e 25%) compared to those measured in the control group. The number of patients with a\u0026thinsp;\u0026gt;\u0026thinsp;50% reduction in PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers was greater in the HCQ treatment group than in the control group (15 \u003cem\u003evs.\u003c/em\u003e 7), although this difference was not statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0956). The number of patients with more than 50% decline in 24-h urine protein excretion was also significantly greater in the HCQ treatment group than that in the control group (26 \u003cem\u003evs.\u003c/em\u003e 12; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0118). In addition, the probability of conversion from low risk to moderate-to-high risk was smaller in the HCQ treatment group than in the control group (4 \u003cem\u003evs\u003c/em\u003e. 10), with this difference not being significantly different (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.086). We speculate from these findings that HCQ reduces PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers and proteinuria and also lowers the probability of conversion from low risk to moderate-to-high risk by immunomodulatory function. This indicates that HCQ has potential as a therapeutic agent. Our data also shows that the HCQ group was comparable to the control group in terms of the incidence rate of adverse reactions. In the present study, nausea, abdominal pain, hepatic dysfunction and skin pruritus were the main adverse reactions, similar to those reported in previous studies. However, these reactions had no obvious impacts on the patients\u0026rsquo; life, with all the reactions being relieved after symptomatic treatment. In particular, retinal toxicity, which is of more concern, [24]led to blurred vision in only one patient who subsequently withdrew from the study. However, the study was limited in that it was an open label, single-center study with a small sample size and short treatment course and follow-up period, and therefore the long-term efficacy of HCQ in the treatment of patients with low risk IMN could not be evaluated. Although this study was an early-phase exploratory trial, the potentially effective approach for treating low risk IMN patients it demonstrated should not be ignored. However, the efficacy of HCQ needs to be validated by a large-scale, long-term, multicenter clinical trial.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eData from this preliminary study confirmed that adequate supportive therapy combined with HCQ reduces PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers and proteinuria and also lowers the probability of conversion to moderate-to-high risk in patients with low risk IMN. We consider that HCQ may be a potential option for treating IMN in the future and is worthy of further investigation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDisclosures:\u003c/h2\u003e \u003cp\u003eNothing to disclose.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConflict of interest:\u003c/h2\u003e \u003cp\u003eAll authors declare that they have no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding Sources:\u003c/h2\u003e \u003cp\u003eThis study was supported by the Chongqing Science and health joint medical research general program(2019MSXM082, 2019ZY023436,2021ZY023803);Chongqing University Central Hospital Scientific Research Foundation(2021KYQD1113).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eResearch idea and study design: Bingbing Shen and Mei Mei. Patient follow-up and data collection:Bingbing Shen, Jun Zeng,Mei Mei, Zhengyang Liu, Li Fang, Sha Xiang, Haili Sun, Chaolin Wen. Data analysis:Jun Zeng,Liyin Chai, Xinqing Chen. Supervision or mentorship: Bingbing Shen, Mei Mei. Each author contributed important intellectual content during the manuscript drafting.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThis study was supported by the Chongqing Science and health joint medical research general program(2019MSXM082，2019ZY023436,2021ZY023803)；Chongqing University Central Hospital Scientific Research Foundation（2021KYQD1113）.The authors would like to express their gratitude to Edit Springs (https://www.editsprings.cn ) for the expert linguistic services provided.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKeri KC, Blumenthal S, Kulkarni V, Beck L, Chongkrairatanakul T: \u003cstrong\u003ePrimary membranous nephropathy: comprehensive review and historical perspective\u003c/strong\u003e. \u003cem\u003ePostgraduate Medical 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\u003cstrong\u003e100\u003c/strong\u003e(4):S1-S276.\u003c/li\u003e\n\u003cli\u003eSalant DJ: \u003cstrong\u003eUnmet challenges in membranous nephropathy\u003c/strong\u003e. \u003cem\u003eCurrent Opinion in Nephrology and Hypertension\u003c/em\u003e 2019, \u003cstrong\u003e28\u003c/strong\u003e(1):70\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003eWu C-L, Chang C-C, Kor C-T, Yang T-H, Chiu P-F, Tarng D-C, Hsu C-C: \u003cstrong\u003eHydroxychloroquine Use and Risk of CKD in Patients with Rheumatoid Arthritis\u003c/strong\u003e. \u003cem\u003eClinical Journal of the American Society of Nephrology\u003c/em\u003e 2018, \u003cstrong\u003e13\u003c/strong\u003e(5):702\u0026ndash;709.\u003c/li\u003e\n\u003cli\u003eAn N, Yang C, Wu H-L, Guo Y, Huang X-J, Huang T-S, Wu Z-H, Xue J, Chen R-H, Li Z-H \u003cem\u003eet al\u003c/em\u003e: \u003cstrong\u003eHydroxychloroquine administration exacerbates acute kidney injury complicated by lupus nephritis\u003c/strong\u003e. \u003cem\u003eArthritis Research 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review\u003c/strong\u003e. \u003cem\u003eRenal Failure\u003c/em\u003e 2021, \u003cstrong\u003e43\u003c/strong\u003e(1):1520\u0026ndash;1527.\u003c/li\u003e\n\u003cli\u003eTang C, Lv J-C, Shi S-F, Chen Y-Q, Liu L-J, Zhang H: \u003cstrong\u003eEffect of hydroxychloroquine in patients with IgA nephropathy with insufficient responses to immunosuppressive therapy: a retrospective case-control study\u003c/strong\u003e. \u003cem\u003eBMC Nephrology\u003c/em\u003e 2020, \u003cstrong\u003e21\u003c/strong\u003e(1).\u003c/li\u003e\n\u003cli\u003eRen L, Xu W, Overton JL, Yu S, Chiamvimonvat N, Thai PN: \u003cstrong\u003eAssessment of Chloroquine and Hydroxychloroquine Safety Profiles: A Systematic Review and Meta-Analysis\u003c/strong\u003e. \u003cem\u003eFront Pharmacol\u003c/em\u003e 2020, \u003cstrong\u003e11\u003c/strong\u003e:562777.\u003c/li\u003e\n\u003cli\u003eDaftarian N, Lima A, Marozoff S, Ojo D, Levasseur SD, Maberley DAL, Hoens A, Esdaile J, Dawes M, Avi\u0026ntilde;a-Zubieta JA \u003cem\u003eet al\u003c/em\u003e: \u003cstrong\u003eRetINal Toxicity And HydroxyChloroquine Therapy (INTACT): protocol for a prospective population-based cohort study\u003c/strong\u003e. \u003cem\u003eBMJ Open\u003c/em\u003e 2022, \u003cstrong\u003e12\u003c/strong\u003e(2).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Baseline features of the two groups of patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eBaseline variable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003eHCQ treatment group (n=50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003eControl group (n=45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eStatistic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eAge (yr)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e51.5\u0026plusmn;12.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e50.9\u0026plusmn;13.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.8177\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eMale ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e28 (56.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e32 (71.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e2.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.1274\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eMean arterial pressure (MAP, mmHg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e101.2\u0026plusmn;10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e102.9\u0026plusmn;8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.3816\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eSerum creatinine (Scr, \u0026micro;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e117.0\u0026plusmn;36.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e121.0\u0026plusmn;38.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.6047\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eeGFR (mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e80.7\u0026plusmn;12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e79.2\u0026plusmn;7.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.4753\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003e24-h urine protein quantity (g/24 h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e3.38 (2.14, 4.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e3.23 (2.63, 3.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.9198\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eSerum PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers(RU/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e60.0 (40.0, 80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e60.0 (30.0, 64.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.4657\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e24.8\u0026plusmn;2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e25.0\u0026plusmn;3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.8219\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003ePlasma albumin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e29.8 (27.5, 32.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e29.1 (27.1, 32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.6359\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eUse of RASI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eMaximum tolerable ARB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e20 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e22 (48.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.3837\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.927835051546392%\" valign=\"top\"\u003e\n \u003cp\u003eMaximum tolerable ACEI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.8659793814433%\" valign=\"top\"\u003e\n \u003cp\u003e10 (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.61855670103093%\" valign=\"top\"\u003e\n \u003cp\u003e8 (17.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24742268041237%\" valign=\"top\"\u003e\n \u003cp\u003e0.7826\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eNo significant differences were identified in the baseline features between the two groups (\u003cem\u003ep\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003eTable 2: Primary and secondary endpoints\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003eIndicator\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003eHCQ treatment group (n=50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003eControl group\u003c/p\u003e\n \u003cp\u003e(n=45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003eStatistic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eendpoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage change in 24-h urine protein excretion at the 3\u003csup\u003erd\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e-25.9% (13.0%, 46.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e-9.4% (0.7%, 36.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e1.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.0779\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage change in 24-h urine protein excretion at the 6\u003csup\u003eth\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e-50.2% (28.4%, 65.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e-28.2% (1.6%, 50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e2.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.0034\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003e24-h urine protein excretion at the 3\u003csup\u003erd\u003c/sup\u003e month(g/24h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e2.44（1.35,2.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e2.98(1.47,2.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.540\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.185\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003e24-h urine protein excretion at the 6\u003csup\u003eth\u003c/sup\u003e month(g/24h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e1.75(0.98,2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e2.67(1.27,2.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e6.396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary endpoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePLA\u003csub\u003e2\u003c/sub\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage change in PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers at the 3\u003csup\u003erd\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e-21.9% (0%, 33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e-1.0% (0%, 25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e2.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.0203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage change in PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers at the 6\u003csup\u003eth\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e-50.0% (20.0%, 62.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e-25.0% (0%, 50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e2.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.0092\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePLA\u003csub\u003e2\u003c/sub\u003eR antibody titers at the 3\u003csup\u003erd\u003c/sup\u003e month(u/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e41.8 (31.2, 56.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e47.4 (32.6, 58.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e1.817\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePLA\u003csub\u003e2\u003c/sub\u003eR antibody titers at the 6\u003csup\u003eth\u003c/sup\u003e month(u/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e34.6 (28.4, 42.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e41.3 (30.3, 54.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e2.837\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003eeGFR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage change in eGFR at the 3\u003csup\u003erd\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e0% (-1.6%, 1.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e0.3% (-1.2%, 1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.4952\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage change in eGFR at the 6\u003csup\u003eth\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e-0.7% (-2.3%, 0.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e-0.7% (-2.7%, 0.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.7971\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003eeGFR at the 3\u003csup\u003erd\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e80.4\u0026plusmn;12.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e79.1\u0026plusmn;13.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.474\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.636\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003eeGFR at the 6\u003csup\u003eth\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e81.6\u0026plusmn;13.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e80.2\u0026plusmn;14.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.496\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.621\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003eAlbumin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage change in albumin at the 3\u003csup\u003erd\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e8.5% (4.5%, 18.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e8.4% (5.3%, 17.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e1.217\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.224\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ePercentage change in albumin at the 6\u003csup\u003eth\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e15.4% (7.7%, 23.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e11.0% (-8.4%, 4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e4.283\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ealbumin at the 3\u003csup\u003erd\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e32.3 (29.5, 36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e31.7 (29.1, 35.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e0.487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.626\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.835051546391753%\" valign=\"top\"\u003e\n \u003cp\u003ealbumin at the 6\u003csup\u003eth\u003c/sup\u003e month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.804123711340207%\" valign=\"top\"\u003e\n \u003cp\u003e34.4 (31.2, 38.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.711340206185568%\" valign=\"top\"\u003e\n \u003cp\u003e32.3 (29.6, 35.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.34020618556701%\" valign=\"top\"\u003e\n \u003cp\u003e1.703\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.309278350515465%\" valign=\"top\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe percentage changes in 24-h urine protein excretion, PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers, and albumin at the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up were statistically different (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05), while that of eGFR showed no statistical difference (\u003cem\u003ep\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003eTable 3: Comparison of the number of patients with reductions of more than 50% in PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers and 24-h urine protein excretion at the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up between the two groups\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.632653061224488%\" valign=\"top\"\u003e\n \u003cp\u003eHCQ treatment group (n=50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003eControl group\u0026nbsp;(n=45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eMore than 50% reduction in PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.632653061224488%\" valign=\"top\"\u003e\n \u003cp\u003e15 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e7 (15.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"top\"\u003e\n \u003cp\u003e2.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"top\"\u003e\n \u003cp\u003e0.0956\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.571428571428573%\" valign=\"top\"\u003e\n \u003cp\u003eMore than 50% reduction in 24-h urine protein excretion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.632653061224488%\" valign=\"top\"\u003e\n \u003cp\u003e26 (52.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" valign=\"top\"\u003e\n \u003cp\u003e12 (26.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"top\"\u003e\n \u003cp\u003e6.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" valign=\"top\"\u003e\n \u003cp\u003e0.0118\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAt the 6\u003csup\u003eth\u003c/sup\u003e month of follow-up, there was a statistically significant difference in the number of patients with more than a 50% reduction in 24-h urine protein excretion between the two groups. The number of patients with more than a 50% reduction in PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers was similar in the two groups, with no statistically significant difference observed.\u003c/p\u003e\n\u003cp\u003eTable 4: Comparison of the number of patients with conversion to Moderate-to-high risk between the two groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eHCQ treatment group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eControl group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients at baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients with conversion to Moderate-to-high risk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e4 (7.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e10 (18.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25%\" valign=\"top\"\u003e\n \u003cp\u003e0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe difference in the number of patients with conversion to Moderate-to-high risk between the two groups was not statistically significant (\u003cem\u003ep\u003c/em\u003e=0.086).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e5.\u003c/strong\u003e Independent predictors of univariate and multivariate logistic regression analysis.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"602\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.398009950248756%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"36.15257048092869%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.449419568822556%\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariate analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.625%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.291666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.5%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;values\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.958333333333332%\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.958333333333332%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003es\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.398009950248756%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.457711442786069%\" valign=\"top\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.764510779436153%\" valign=\"top\"\u003e\n \u003cp\u003e(0.95\u0026ndash;1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\" valign=\"top\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.266998341625207%\" valign=\"top\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e(0.96\u0026ndash;1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.398009950248756%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.457711442786069%\" valign=\"top\"\u003e\n \u003cp\u003e1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.764510779436153%\" valign=\"top\"\u003e\n \u003cp\u003e(0.82\u0026ndash;1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\" valign=\"top\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.266998341625207%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; 1.12\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e(0.85\u0026ndash;1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.398009950248756%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eeGFR at baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.457711442786069%\" valign=\"top\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.764510779436153%\" valign=\"top\"\u003e\n \u003cp\u003e(0.98\u0026ndash;1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\" valign=\"top\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.266998341625207%\" valign=\"top\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e(0.97\u0026ndash;1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.398009950248756%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eproteinuria at baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.457711442786069%\" valign=\"top\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.764510779436153%\" valign=\"top\"\u003e\n \u003cp\u003e(0.69\u0026ndash;1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\" valign=\"top\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.266998341625207%\" valign=\"top\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e(0.69\u0026ndash;1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.398009950248756%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eserum PLA2R antibody titers at baseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.457711442786069%\" valign=\"top\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.764510779436153%\" valign=\"top\"\u003e\n \u003cp\u003e(0.67\u0026ndash;0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\" valign=\"top\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.266998341625207%\" valign=\"top\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e(0.61\u0026ndash;0.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.045\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.398009950248756%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHCQ\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.457711442786069%\" valign=\"top\"\u003e\n \u003cp\u003e1.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.764510779436153%\" valign=\"top\"\u003e\n \u003cp\u003e(1.37\u0026ndash;2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.029\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.266998341625207%\" valign=\"top\"\u003e\n \u003cp\u003e2.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e(1.67\u0026ndash;3.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.091210613598673%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eStatistically significant P values are shown in bold.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 6: Adverse reactions in the two groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.65656565656566%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNumber of cases\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eAdverse reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003eHCQ treatment group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eControl group\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eSevere adverse reactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eAdverse reactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients without adverse reactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients with one adverse reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients with more than 2 adverse reactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eTypes of adverse reactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eHepatic\u0026nbsp;dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003ePalpitation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003eDizziness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd 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\u003c/td\u003e\n \u003ctd width=\"31.31313131313131%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.343434343434346%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"hydroxychloroquine sulfate, low risk, PLA2R-associated membranous nephropathy","lastPublishedDoi":"10.21203/rs.3.rs-4195607/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4195607/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To evaluate the efficacy and safety of hydroxychloroquine sulfate (HCQ) in the treatment of low risk phospholipase A\u003csub\u003e2\u003c/sub\u003e receptor (PLA\u003csub\u003e2\u003c/sub\u003eR)-associated membranous nephropathy (MN).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A total of 110 patients with low risk PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN were included in the study. Patients who met the inclusion and exclusion criteria were assigned randomly to two groups: the HCQ treatment group and the control group. The control group was given adequate support treatment according to the guidelines, while the HCQ treatment group was given HCQ on the basis of support treatment. The clinical data of the patients were analyzed, with comparisons made at baseline and during the six-month follow-up period. Any adverse reactions were recorded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The baseline data were comparable between the HCQ treatment group and the control group. At the end of the six-month follow-up period, the reductions in urine protein excretion and serum PLA\u003csub\u003e2\u003c/sub\u003eR antibody titer were more notable in the HCQ treatment group than those in the control group, with these differences being statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05). Compared to the control group, the HCQ treatment group had fewer patients who were converted from low risk to moderate-to-high risk (\u003cem\u003ep\u003c/em\u003e=0.084). There were also no severe adverse reactions in the HCQ treatment group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e In patients with low risk PLA\u003csub\u003e2\u003c/sub\u003eR-associated MN, adequate supportive therapy combined with HCQ is superior to supportive therapy alone in terms of controlling proteinuria, reducing serum PLA\u003csub\u003e2\u003c/sub\u003eR antibody titers, and lowering the probability of conversion from low risk to moderate-to-high risk. In addition, our study demonstrated that the incidence of adverse reactions did not increase.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e This study was registered in the Chinese Clinical Trial Registry (Registration No.: ChiCTR1900021757，Date of registration:\u0026nbsp;\u0026nbsp; 2019-03-08).\u003c/p\u003e","manuscriptTitle":"A Single-Center, open label, Randomized, Controlled Study of Hydroxychloroquine Sulfate in the Treatment of Low Risk PLA 2 R-Associated Membranous Nephropathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-05 21:01:48","doi":"10.21203/rs.3.rs-4195607/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-06-12T06:45:44+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-11T12:45:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-10T08:58:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-09T14:06:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"30669248338173988874000533386927251520","date":"2024-06-09T13:51:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-02T01:39:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-31T14:03:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"331834261119130964165372384200135686096","date":"2024-05-20T02:31:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18129684464793485179822440657791645773","date":"2024-05-19T13:16:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"176912775155696108907037522169072838899","date":"2024-05-19T06:06:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"52309974544206994322067185129332522569","date":"2024-05-17T12:42:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"201041620980233844565301705524545399008","date":"2024-05-15T13:11:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-13T13:03:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-13T12:55:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-04-02T11:19:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-02T05:56:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2024-03-31T12:31:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c769597d-7745-4554-bdb9-b49ab19b2eff","owner":[],"postedDate":"April 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-01T16:19:10+00:00","versionOfRecord":{"articleIdentity":"rs-4195607","link":"https://doi.org/10.1186/s12882-024-03670-3","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2024-07-19 16:13:04","publishedOnDateReadable":"July 19th, 2024"},"versionCreatedAt":"2024-04-05 21:01:48","video":"","vorDoi":"10.1186/s12882-024-03670-3","vorDoiUrl":"https://doi.org/10.1186/s12882-024-03670-3","workflowStages":[]},"version":"v1","identity":"rs-4195607","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4195607","identity":"rs-4195607","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}