Background: Idiopathic membranous nephropathy (IMN) is the most common form of primary nephrotic syndrome in adults. Antibodies against the M-type phospholipase A2 receptor (PLA2R-ab) are considered as diagnostic biomarkers of IMN. Objective: Here, we performed an updated meta-analysis to assess the diagnostic value of PLA2R-ab for clinical remission in IMN patients. Method: PubMed, Embase, and Cochrane databases were searched for relevant studies published before September 2022. Odds ratios and corresponding 95% confidence intervals were determined using a fixed or random effects model. The heterogeneity among studies was explored by subgroup analysis. Results: Sixteen studies involving 1,761 IMN participants were included. There were significant differences between PLA2R-ab (+) and PLA2R-ab (−) patients in terms of complete remission (CR) and spontaneous remission. The rates of partial remission (PR) and relapse were similar between the two groups. Patients with PLA2R-ab (−) were at a higher CR rate when treated with a calcineurin inhibitor or a treatment course for 3 months and 6 months, while the spontaneous remission rate was higher in PLA2R-ab seronegative patients from Asia. However, the CR and spontaneous remission rate only significantly declined in IMN patients with the highest titer, but not a middle titer, when compared to those with the lowest titer. Conclusion: In contrast with previous meta-analyses, our results verified that PLA2R-ab can likely predict CR and spontaneous remission in IMN patients, instead of PR and relapse. Race, immunosuppressive agents, and duration of treatment may affect the prognostic value of PLA2R-ab. Considering that the remission rate of IMN patients with a middle level of PLA2R-ab was not different from that of patients with the lowest level, a proper cut-off value of PLA2R-ab for prognosis should be clarified.

Membranous nephropathy, an organ-specific autoimmune disease, is a major cause of nephrotic syndrome in nondiabetic adults and one of the leading causes of end-stage renal disease in patients with primary glomerulonephritis [1, 2]. The most prominent manifestation is nephrotic syndrome, which manifests as proteinuria, edema, hypoalbuminemia, and hyperlipidemia. Specifically, approximately 80% of cases are idiopathic membranous nephropathy (IMN), while 20% of cases are secondary membranous nephropathy [3]. IMN patients are at an increased risk of venous thromboembolism [4], cardiovascular events [5], and cancer [6].

Most IMNs are mediated by antibodies to the M-type phospholipase A2 receptor (PLA2R-ab) (85%), and 3–5% of patients are detected by anti-thrombospondin type 1 domain containing 7A (THSD7A) antibodies [3]. The discovery of other disease antigens, such as neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, and netrin G1, was also previously reported [7]. The effect of PLA2R-ab on prognosis is under investigation. Evidence has confirmed an association between high levels of anti-PLA2R and proteinuria [8] and poor clinical outcomes [9]. Bech, A. P. showed that PLA2R-ab levels at baseline did not predict initial response, but antibody status at the end of therapy predicted remission [10]. A meta-analysis with only 5 articles confirmed that patients with PLAR2-ab (−) have a high spontaneous remission rate with conservative treatment [11]. Patients with positive PLA2R-ab experienced clinical remission [12] but not relapse [13]. However, the definite association between PLA2R-ab and complete remission (CR) or partial remission (PR) is still unknown. The interaction effect of PLA2R-ab and other factors, such as immunosuppressive agents and duration of treatment, still warrants exploration. We conducted this updated meta-analysis to further address the prognostic value of PLA2R-ab among patients with IMN.

We conducted this systematic review in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The study protocol was registered in PROSPERO (CRD42022360460) prior to data extraction.

Data Sources and Searches

Electronic searches of PubMed, Embase, and the Cochrane Library prior to September 2022 were conducted with the search strategy described in the online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529415). In addition, relevant references were searched manually to identify eligible studies.

Study Selection

Two reviewers independently evaluated the title and abstract of all retrieved search records to determine potential eligibility, while discrepancies were further discussed and resolved ultimately by the third author, if necessary. The inclusion criteria were as follows: (1) patients were diagnosed with MN by renal biopsy and designated idiopathic after exclusion of known secondary etiologies, (2) patients were divided into groups with or without detectable PLA2R-ab by immunofluorescence test, enzyme-linked immunosorbent assay, or Western blotting, and (3) a specific definition of CR, PR, and relapse was defined, as shown in Table 1. Studies were excluded for the following reasons: (1) insufficient data on diagnostic criteria or primary or secondary outcomes, (2) case reports, commentaries, and systematic reviews, and (3) lack of relevant outcome data. We excluded studies that were not in the English language.

Table 1.

Definition of CR, PR, and relapse

StudyCRPRRelapse
Zhang et al. 2019 [16] Proteinuria <0.3 g/day, and normal serum albumin and creatinine levels Proteinuria <3.5 g/day and a 50% reduction in baseline levels, with improving serum albumin and creatinine  
Sun et al. 2022 [17] Urinary protein excretion <0.5 g/day (UPCR <500 mg/g) 50% or greater reduction from peak values of urinary protein and urinary protein excretion <3.5 g/day  
Song et al. 2018 [18] UPCR <0.3 g/g UPCR <3.5 g/g with at leasta 50% reduction from baseline and stable renal function  
Kim et al. 2015 [19] UPCR <0.3 g/g and normal range of serum albumin and creatinine UPCR <3.5 g/g, reduction from 50% of baseline value, and improvement of serum albumin and creatinine  
Jullien et al. 2017 [20] Proteinuria <0.5 g/24 h observed on at least two consecutive consultations   
Hofstra et al. 2012 [21] Protein excretion was <0.2 g/day with stable renal function Proteinuria <3.5 g/day with a decrease of proteinuria >50% from baseline and stable renal function  
Ruggenenti et al. 2015 [22] 24-h urinary protein excretion <0.3 g 24-h urinary protein excretion <3.0 g (with at least 50% reduction vs. baseline) 24-h proteinuria increase to >3.5 g in subjects with previous CR or PR 
Timmermans et al. 2015 [23] Proteinuria of <0.2 g/day Proteinuria of <2.0 g/day but ≥0.2 g/day  
Oh et al. 2013 [24]   UPCR>3.5 g/g after some period of remission 
Jatem Escalante et al. 2015 [25] Proteinuria <0.3 g/day in two consecutive controls Proteinuria <3.5 g/day, and>0.3 g/day in two consecutive controls Proteinuria >3.5 g/day associated with hypoalbuminemia in two consecutive controls following treatment suppression 
Jurubiță et al. 2021 [26] Proteinuria of no more than 0.3 g/day and a serum albumin of at least 3.5 g/dL A reduction in proteinuria of at least 50% from baseline to a level between 0.3 and 3.5 g/day  
Deng et al. 2021 [27] Urinary protein is < 0.3 g/24 h, accompanied by normal serum albumin and serum creatinine Urinary protein <3.5 g/24 h and a 50% or greater reduction from peak values, accompanied by an improvement or normalization of the serum albumin and stable serum creatinine New nephrotic syndrome after an achievement of CR or PR, urinary protein >3.5 g/24 h or >50% of the peak values, and with areduction in serum albumin 
Yin et al. 2020 [28] 24-h urinary protein <0.3 g or urinary albumin/creatinine <0.3 g/g and serum albumin >40 g/L 24-h urinary protein of 0.3–3.5 g or urinary albumin/creatinine of 0.3–3.5 g/g and serum albumin >30 g/L  
Ramachandran et al. 2016 [29] Urine protein excretion decreased to <500 mg/day with normal serum albumin and serum creatinine Proteinuria was 0.5–2 g/day or <50% of baseline with normal serum albumin (≥3.5 g/dL) and serum creatinine  
Wang et al. 2017 [30] Urinary protein excretion <0.3 g/24 h, with a normal serum albumin concentration and a normal serum creatinine Urinary protein excretion <3.5 g/24 h or a ≥50% reduction from peak value, accompanied by an improving or normalization serum albumin concentration and stable serum creatinine Urinary protein excretion >3.5 g/24 h or >50% of the peak value, with a reduction in serum albumin concentration after CR or PR 
Bech et al. 2014 [10] Proteinuria <0.2 g/day with stable kidney function Proteinuria <3.5 g/day with a reduction in >50% from baseline and stable kidney function Proteinuria>3.5 g/day and an increase of >50% compared with the lowest value during remission 
StudyCRPRRelapse
Zhang et al. 2019 [16] Proteinuria <0.3 g/day, and normal serum albumin and creatinine levels Proteinuria <3.5 g/day and a 50% reduction in baseline levels, with improving serum albumin and creatinine  
Sun et al. 2022 [17] Urinary protein excretion <0.5 g/day (UPCR <500 mg/g) 50% or greater reduction from peak values of urinary protein and urinary protein excretion <3.5 g/day  
Song et al. 2018 [18] UPCR <0.3 g/g UPCR <3.5 g/g with at leasta 50% reduction from baseline and stable renal function  
Kim et al. 2015 [19] UPCR <0.3 g/g and normal range of serum albumin and creatinine UPCR <3.5 g/g, reduction from 50% of baseline value, and improvement of serum albumin and creatinine  
Jullien et al. 2017 [20] Proteinuria <0.5 g/24 h observed on at least two consecutive consultations   
Hofstra et al. 2012 [21] Protein excretion was <0.2 g/day with stable renal function Proteinuria <3.5 g/day with a decrease of proteinuria >50% from baseline and stable renal function  
Ruggenenti et al. 2015 [22] 24-h urinary protein excretion <0.3 g 24-h urinary protein excretion <3.0 g (with at least 50% reduction vs. baseline) 24-h proteinuria increase to >3.5 g in subjects with previous CR or PR 
Timmermans et al. 2015 [23] Proteinuria of <0.2 g/day Proteinuria of <2.0 g/day but ≥0.2 g/day  
Oh et al. 2013 [24]   UPCR>3.5 g/g after some period of remission 
Jatem Escalante et al. 2015 [25] Proteinuria <0.3 g/day in two consecutive controls Proteinuria <3.5 g/day, and>0.3 g/day in two consecutive controls Proteinuria >3.5 g/day associated with hypoalbuminemia in two consecutive controls following treatment suppression 
Jurubiță et al. 2021 [26] Proteinuria of no more than 0.3 g/day and a serum albumin of at least 3.5 g/dL A reduction in proteinuria of at least 50% from baseline to a level between 0.3 and 3.5 g/day  
Deng et al. 2021 [27] Urinary protein is < 0.3 g/24 h, accompanied by normal serum albumin and serum creatinine Urinary protein <3.5 g/24 h and a 50% or greater reduction from peak values, accompanied by an improvement or normalization of the serum albumin and stable serum creatinine New nephrotic syndrome after an achievement of CR or PR, urinary protein >3.5 g/24 h or >50% of the peak values, and with areduction in serum albumin 
Yin et al. 2020 [28] 24-h urinary protein <0.3 g or urinary albumin/creatinine <0.3 g/g and serum albumin >40 g/L 24-h urinary protein of 0.3–3.5 g or urinary albumin/creatinine of 0.3–3.5 g/g and serum albumin >30 g/L  
Ramachandran et al. 2016 [29] Urine protein excretion decreased to <500 mg/day with normal serum albumin and serum creatinine Proteinuria was 0.5–2 g/day or <50% of baseline with normal serum albumin (≥3.5 g/dL) and serum creatinine  
Wang et al. 2017 [30] Urinary protein excretion <0.3 g/24 h, with a normal serum albumin concentration and a normal serum creatinine Urinary protein excretion <3.5 g/24 h or a ≥50% reduction from peak value, accompanied by an improving or normalization serum albumin concentration and stable serum creatinine Urinary protein excretion >3.5 g/24 h or >50% of the peak value, with a reduction in serum albumin concentration after CR or PR 
Bech et al. 2014 [10] Proteinuria <0.2 g/day with stable kidney function Proteinuria <3.5 g/day with a reduction in >50% from baseline and stable kidney function Proteinuria>3.5 g/day and an increase of >50% compared with the lowest value during remission 

UPCR, urine protein to creatinine ratio; CR, complete remission; PR, partial remission.

Data Extraction and Data Synthesis

Extracted data included first author, year of publication, study design, sample size, follow-up duration, and outcome measures. The primary review outcomes were CR, PR, spontaneous remission, and relapse. Secondary outcomes were baseline characteristics, estimated glomerular filtration rate (eGFR), serum creatinine, serum albumin, cholesterol, and proteinuria.

The meta-analysis was carried out using Review Manager 5.3 software. Dichotomous data were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Statistical heterogeneity between studies was estimated using the I2 test, with I2 values >50% indicating high heterogeneity [14]. A randomized-effect model was adopted with significant heterogeneity; otherwise, a fixed effect model was used. The methodological quality of each included study was evaluated using the Newcastle-Ottawa scale (NOS) [15]. Subgroup analysis was performed to account for the potential source of heterogeneity. A funnel plot was applied to evaluate the potential publication bias (shown in online suppl. Fig. 6).

Study Characteristics

According to the selection criteria, 16 studies were included [10, 16‒30]. The literature selection process is presented in Figure 1, and the characteristics of the included studies are shown in Table 2. The sixteen studies included a total of 1,761 participants, of which 812 participants were PLA2R-ab (+).

Fig. 1.

Flow diagram for this meta-analysis.

Fig. 1.

Flow diagram for this meta-analysis.

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Table 2.

Characteristics and quality of included studies

StudyCountryDesignSample sizeAnti-PLA2R (+/−)Definition of anti-PLA2R (+)Testing methodAge, yearsMale (%)Immunology treatmentFollow-upNOS
Zhang et al. 2019 [16] China Retrospective 89 71/18 >0.91 mg/L Time-resolved fluoroimmunoassay Anti-PLA2R (+): 54.31±14.03 Anti-PLA2R (−): 46.67±13.30 52 Cyclophosphamide, glucocorticoids, tacrolimus At least 1 year 
Sun et al. 2022 [17] China Retrospective 155 96/59 20 RU/mL ELISA 54.1±11.8 117 Calcineurin inhibitor, glucocorticoid  
Song et al. 2018 [18] Korea Retrospective 48 25/23 20 RU/mL ELISA Anti-PLA2R (+): 56.6±12.7Anti-PLA2R (−): 54.0±14.0 29 Steroid, cyclosporin, mycophenolate mofetil, tacrolimus 65 (3–133) months 
Kim et al. 2015 [19] Korea  93 41/52 14 RU/mL ELISA Anti-PLA2R (+): 58.20±1.86Anti-PLA2R (−): 55.19±2.13 53   
Jullien et al. 2017 [20] France Retrospective 68  128 RU/mL ELISA  45 Rituximab, alkylating agents, corticosteroids, calcineurin inhibitor Median: 81 months 
Hofstra et al. 2012 [21] The Netherlands  110 82/28 40 U/mL IIFT and ELISA Anti-PLA2R (+): 50±16Anti-PLA2R (−): 51±17 85 Cyclophosphamide, mycophenolate mofetil, rituximab, adrenocorticotrophic hormone 54 (2–277) months 
Ruggenenti et al. 2015 [22] Italy Prospective 81  14 RU/mL ELISA 55.4±13.8 62 Rituximab 30.84 (6.00–145.36) months 
Timmermans et al. 2015 [23] The Netherlands Retrospective 73 65/8 20 RU/mL ELISA 52.4±14.0 44 Cyclophosphamide, cyclosporine, prednisolone monotherapy, chlorambucil, mycophenolate mofetil and rituximab 11.3 (5.4–16.9) years 
Oh et al. 2013 [24] Korea Retrospective 77 56/21  Western blot 55±13.9 40 Steroid, cyclosporine, tacrolimus, cyclophosphamide, mycophenolate mofetil  
Jatem Escalante et al. 2015 [25] Spain Retrospective 85 55/30 20 RU/mL ELISA Anti-PLA2R (+): 49±16.4Anti-PLA2R (−): 57.8±15.7 61 Corticosteroids, alkylating agents, calcineurin inhibitors 62 (39–105) months 
Jurubițăet al. 2021 [26] Romania Prospective 65 52/13 20 RU/mL ELISA   Cyclophosphamide, calcineurin inhibitors, rituximab  
Deng et al. 2021 [27] China Retrospective 447  20 RU/mL ELISA  317 Cyclophosphamide, glucocorticoids, tacrolimus 11.70±1.22 months 
Yin et al. 2020 [28] China Retrospective 114 81/33  Direct immunofluorescence   Cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, tripterygium wilfordii  
Ramachandran et al. 2016 [29] UK Prospective 114 76/38 20 RU/mL IIFT and ELISA 41.39±13.32 67 Corticosteroid, calcineurin inhibitors and cyclophosphamide 10.55±4.37 months 
Wang et al. 2017 [30] China Retrospective 91 78/13  Indirectimmunofluorescence Anti-PLA2R (+): 53.81±14.64Anti-PLA2R (−): 53.54±17.52 57 Tacrolimus, cyclosporine, cyclophosphamide, prednisone  
Beck et al. 2014 [10] UK Prospective 48 34/14 40 RU/mL ELISA 55 (34–75) 37 MycophenolateMofetil, cyclophosphamide, corticosteroids 52 (0–60) months 
StudyCountryDesignSample sizeAnti-PLA2R (+/−)Definition of anti-PLA2R (+)Testing methodAge, yearsMale (%)Immunology treatmentFollow-upNOS
Zhang et al. 2019 [16] China Retrospective 89 71/18 >0.91 mg/L Time-resolved fluoroimmunoassay Anti-PLA2R (+): 54.31±14.03 Anti-PLA2R (−): 46.67±13.30 52 Cyclophosphamide, glucocorticoids, tacrolimus At least 1 year 
Sun et al. 2022 [17] China Retrospective 155 96/59 20 RU/mL ELISA 54.1±11.8 117 Calcineurin inhibitor, glucocorticoid  
Song et al. 2018 [18] Korea Retrospective 48 25/23 20 RU/mL ELISA Anti-PLA2R (+): 56.6±12.7Anti-PLA2R (−): 54.0±14.0 29 Steroid, cyclosporin, mycophenolate mofetil, tacrolimus 65 (3–133) months 
Kim et al. 2015 [19] Korea  93 41/52 14 RU/mL ELISA Anti-PLA2R (+): 58.20±1.86Anti-PLA2R (−): 55.19±2.13 53   
Jullien et al. 2017 [20] France Retrospective 68  128 RU/mL ELISA  45 Rituximab, alkylating agents, corticosteroids, calcineurin inhibitor Median: 81 months 
Hofstra et al. 2012 [21] The Netherlands  110 82/28 40 U/mL IIFT and ELISA Anti-PLA2R (+): 50±16Anti-PLA2R (−): 51±17 85 Cyclophosphamide, mycophenolate mofetil, rituximab, adrenocorticotrophic hormone 54 (2–277) months 
Ruggenenti et al. 2015 [22] Italy Prospective 81  14 RU/mL ELISA 55.4±13.8 62 Rituximab 30.84 (6.00–145.36) months 
Timmermans et al. 2015 [23] The Netherlands Retrospective 73 65/8 20 RU/mL ELISA 52.4±14.0 44 Cyclophosphamide, cyclosporine, prednisolone monotherapy, chlorambucil, mycophenolate mofetil and rituximab 11.3 (5.4–16.9) years 
Oh et al. 2013 [24] Korea Retrospective 77 56/21  Western blot 55±13.9 40 Steroid, cyclosporine, tacrolimus, cyclophosphamide, mycophenolate mofetil  
Jatem Escalante et al. 2015 [25] Spain Retrospective 85 55/30 20 RU/mL ELISA Anti-PLA2R (+): 49±16.4Anti-PLA2R (−): 57.8±15.7 61 Corticosteroids, alkylating agents, calcineurin inhibitors 62 (39–105) months 
Jurubițăet al. 2021 [26] Romania Prospective 65 52/13 20 RU/mL ELISA   Cyclophosphamide, calcineurin inhibitors, rituximab  
Deng et al. 2021 [27] China Retrospective 447  20 RU/mL ELISA  317 Cyclophosphamide, glucocorticoids, tacrolimus 11.70±1.22 months 
Yin et al. 2020 [28] China Retrospective 114 81/33  Direct immunofluorescence   Cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, tripterygium wilfordii  
Ramachandran et al. 2016 [29] UK Prospective 114 76/38 20 RU/mL IIFT and ELISA 41.39±13.32 67 Corticosteroid, calcineurin inhibitors and cyclophosphamide 10.55±4.37 months 
Wang et al. 2017 [30] China Retrospective 91 78/13  Indirectimmunofluorescence Anti-PLA2R (+): 53.81±14.64Anti-PLA2R (−): 53.54±17.52 57 Tacrolimus, cyclosporine, cyclophosphamide, prednisone  
Beck et al. 2014 [10] UK Prospective 48 34/14 40 RU/mL ELISA 55 (34–75) 37 MycophenolateMofetil, cyclophosphamide, corticosteroids 52 (0–60) months 

PLA2R, phospholipase A2 receptor; ELISA, enzyme-linked immunosorbent assay; IIFT, indirect immunofluorescence assay.

Comparison of Baseline Characteristics between PLA2R-ab-Positive and PLA2R-ab-Negative Groups

Eight studies reported the age of IMN patients, disaggregated by PLA2R-ab positive (n = 484) and negative (n = 223). The results showed no significant relationship between the two groups (MD = 0.35, 95% CI [−2.82, 3.53], p = 0.83). Eight studies reported no significant difference in males between the PLA2R-ab-positive (n = 484) and PLA2R-ab-negative (n = 223) groups (OR = 0.99, 95% CI [0.7, 1.39], p = 0.94) (shown in Fig. 2).

Fig. 2.

Meta-analysis of baseline characteristics between PLA2R-ab (+) and PLA2R-ab patients (−) (a. age; b. male).

Fig. 2.

Meta-analysis of baseline characteristics between PLA2R-ab (+) and PLA2R-ab patients (−) (a. age; b. male).

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Comparison of Clinical Parameters between PLA2R-ab-Positive and PLA2R-ab-Negative Groups

Five studies reported serum albumin of IMN patients, disaggregated by PLA2R-ab positive and negative. The albumin level of patients in the serum PLA2R-ab (+) group was significantly lower than that in the PLA2R-ab (−) group (MD = −0.31, 95% CI [−0.48, −0.14], p = 0.0005). By meta-analysis, we found that the level of 24-h proteinuria was significantly higher in patients with PLA2R-ab (+) without heterogeneity (MD = 0.75, 95% CI [0.28, 1.22], p = 0.002). Four studies also reported total cholesterol levels in the PLA2R-ab (+) and PLA2R-ab (−) groups. Owing to significant heterogeneity (I2 = 60%), a random effect model was used, and cholesterol was significantly higher in patients with PLA2R-ab (+). However, no significant difference was observed in terms of creatinine (MD = −0.02, 95% CI [−0.12, 0.09], p = 0.76) or eGFR (MD = 4.87, 95% CI [−1.52, 11.26], p = 0.14) (shown in Fig. 3).

Fig. 3.

Meta-analysis of laboratory indices between PLA2R-ab (+) and PLA2R-ab (−) patients (a. albumin; b. 24-h proteinuria; c. cholesterol; d. creatinine; e. estimated glomeruli filtration rate).

Fig. 3.

Meta-analysis of laboratory indices between PLA2R-ab (+) and PLA2R-ab (−) patients (a. albumin; b. 24-h proteinuria; c. cholesterol; d. creatinine; e. estimated glomeruli filtration rate).

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Comparison of Immunosuppressive Treatment between PLA2R-ab-Positive and PLA2R-ab-Negative Groups

Meta-analysis of seven studies showed that the prevalence of tacrolimus was significantly higher in patients with PLA2R-ab (+). A fixed effect model was employed with nonsignificant heterogeneity. However, the application of other immunosuppressive therapies, such as cyclosporine, cyclophosphamide, and mycophenolate mofetil, was not different between the two groups (shown in Fig. 4).

Fig. 4.

Meta-analysis of immunology treatment between PLA2R-ab (+) and PLA2R-ab (−) patients (a. tacrolimus; b. cyclosporine; c. cyclophosphamide; d. mycophenolate mofetil).

Fig. 4.

Meta-analysis of immunology treatment between PLA2R-ab (+) and PLA2R-ab (−) patients (a. tacrolimus; b. cyclosporine; c. cyclophosphamide; d. mycophenolate mofetil).

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Effect of PLA2R-ab on the Rate of Clinical Prognosis

As shown in Figure 5, the rates of CR (OR = 0.5, 95% CI, 0.37–0.67; p < 0.00001) and spontaneous remission (OR = 0.3, 95% CI, 0.11–0.87; p = 0.03) were significantly lower in PLA2R-ab-positive patients. However, the rate was relatively similar considering the rate of PR and relapse. The funnel plot was roughly symmetric, as shown in online supplementary Figure 6.

Fig. 5.

Forest plot for the correlation between PLA2R-ab and the rate of clinical remission in patients with IMN (a. CR; b. PR; c. spontaneous remission; d. relapse).

Fig. 5.

Forest plot for the correlation between PLA2R-ab and the rate of clinical remission in patients with IMN (a. CR; b. PR; c. spontaneous remission; d. relapse).

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Effect of PLA2R-ab Titer on the Rate of Clinical Prognosis

To further explore the association between PLA2R-ab titer and clinical remission, patients were divided into low, middle, or high groups according to the original research. The rates for CR (OR = 0.37, 95% CI, 0.27–0.51; p < 0.00001) and spontaneous remission (OR = 0.19, 95% CI, 0.08–0.46; p = 0.0002) were significantly decreased at higher levels of PLA2R-ab. The PR rate was similar between patients with lower and higher PLA2R-ab titers. In addition, we found that the prognostic value of a middle level of PLA2R-ab for both CR and spontaneous remission was not clearly different compared to a lower level (shown in Fig. 6). In terms of the progression of kidney function, we compared the incidence of progression to end-stage renal disease between patients with higher and lower titers of PLA2R-ab, although no significant difference was observed (shown in online suppl. Fig. 1).

Fig. 6.

Forest plot for the correlation between PLA2R-ab titer and the rate of clinical remission in patients with IMN (a. high vs. low for CR; b. middle vs. low for CR; c. high vs. low for spontaneous remission; d. middle vs. low for spontaneous remission; e. high vs. low for PR).

Fig. 6.

Forest plot for the correlation between PLA2R-ab titer and the rate of clinical remission in patients with IMN (a. high vs. low for CR; b. middle vs. low for CR; c. high vs. low for spontaneous remission; d. middle vs. low for spontaneous remission; e. high vs. low for PR).

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Subgroup Analysis

For CR, subgroup analysis was applied by follow-up, immunosuppressive regimen, and test method for PLA2R-ab. PLA2R-ab (−) patients had a higher CR rate than seropositive patients within 3 months and 6 months of follow-up (shown in online suppl. Fig. 2). IMN patients without PLA2R-ab were at a higher CR rate when treated with a calcineurin inhibitor (OR = 0.45, 95% CI, 0.22–0.92; p = 0.03) but not cyclophosphamide and rituximab (shown in online suppl. Fig. 3). In addition, different assay methods for PLA2R-ab did not affect its prognostic value (shown in online suppl. Fig. 4). Considering spontaneous remission, a subgroup analysis was also performed based on race. Remarkably, the subgroup analysis showed that the spontaneous remission rate was higher in PLA2R-ab-seronegative patients from Asia (OR = 0.13, 95% CI, 0.05–0.35; p < 0.0001) but not in non-Asian patients, which might account for the heterogeneity (shown in online suppl. Fig. 5).

In this study, we analyzed the association between PLA2R-ab and various clinical prognoses in IMN patients using an updated meta-analysis, including CR, PR, spontaneous remission, and relapse. As a result, we found that the clinical manifestation of nephrotic syndrome was more significant in PLA2R-ab (+) patients. Positive PLA2R-ab and a higher titer of PLA2R-ab are associated with a lower rate of CR and spontaneous remission but not PR or relapse. Patients with PLA2R-ab (+) have a lower likelihood of remission versus PLA2R (−) when treated with calcineurin inhibitor. Quantitative measures of PLA2R-ab levels for risk stratification appear to be essential according to the guidelines, although there are insufficient data to determine antibody cut-off values [31]. The diagnostic effect of a relatively medium level of PLA2R-ab was weak in our analysis, and a proper cut-off point of PLA2R-ab associated with an increased risk of disease activity should be determined.

IMN is an autoimmune disease, and the identification of podocyte target antigens has been a major diagnostic advance. PLA2R is a transmembrane glycoprotein member of the mannose receptor family. Beck, L. H., Jr. identified circulating autoantibodies against PLA2R in patients with IMN [32], and the diagnostic value of PLA2R-ab was presented, with 68% sensitivity and 97% specificity [33], which are better than those for proteinuria [34]. Anti-PLA2R reactive epitopes are conformation dependent and have been identified in three domains: cysteine rich, C-type lectin-like domain (CTLD) 1, and CTLD7 [35, 36]. In clinical practice, enzyme-linked immunosorbent assay is the most suitable for PLA2R-ab measurements, whereas indirect immunofluorescence is more sensitive for the detection of very low antibody levels [37]. Various studies have suggested an association between PLA2R-ab and clinical course, including CR and spontaneous remission, with a limited sample size [18, 26, 27]. However, whether PLA2R-ab can predict prognosis remains unknown [24, 25]. Although previous studies explored the effect of PLA2R-ab in IMN patients, the number of included studies in a meta-analysis for spontaneous remission was small [11], leading to an unreliable conclusion. In our meta-analysis, we updated the search from the database and included more recently published studies. We found that both CR and spontaneous remission rates were significantly higher in PLA2R-ab (−) patients, consistent with previous studies [12, 13]. Conversely, there was no difference in the PR or relapse rate between the PLA2R-ab (+) and PLA2R-ab (−) groups in our study.

In our meta-analysis, we found that IMN patients with PLA2R-ab (+) had higher disease activity, presenting with lower serum albumin, higher 24-h proteinuria and serum cholesterol. Serum PLA2R-ab was correlated with albumin, creatinine, eGFR, and proteinuria [19, 38]. However, the residual renal function, manifested as creatinine and eGFR, was relatively similar between the two groups in our study. In addition, we found no significant differences between patients with a higher and lower titer of PLA2R-ab considering the progression to renal failure. Jullien, P. also reported no significant association between different PLA2R-ab titers and the activity of IMN [20]. Our meta-analysis showed that the highest PLA2R titer could predict poor prognosis when compared to the lowest level. The rate of clinical remission between the middle and lowest titer of PLA2R-ab was relatively similar. PLA2R-ab seemed to be an independent predictor of the development of nephrotic proteinuria [39]. Emerging data point to the prognostic value of quantitatively measuring PLA2R-ab levels. A predictive value of 40 RU/mL was previously noted to predict the disease course [40]. Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases has included PLA2R-ab >50 RU/mL in the criteria for assessing high risk; however, the cut-off values have not been validated [41]. Three articles included in this meta-analysis reported a cut-off value for the middle titer disaggregated by 87 RU/mL [21], 149.23 RU/mL [29], and 176 RU/mL [20], and the middle level of antibody showed no significant effect on poor clinical remission. Since few studies have explored a middle level of PLA2R-ab, we could not perform a subgroup analysis according to the different titers. Our results indicate that a proper cut-off value for PLA2R-ab titer for risk stratification and clinical remission should be explored in the future.

All patients with IMN and proteinuria should receive optimal supportive care, including blood pressure control, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy to minimize proteinuria, statins for hyperlipidemia, and a low-salt and low-protein diet, while immunosuppressive therapy should be restricted to patients at risk for progression of kidney function [41]. Measurement of PLA2R-ab might aid in predicting treatment response and follow-up. In this meta-analysis, we found that tacrolimus was initiated more frequently in PLA2R-ab-positive patients. There was no difference between the two groups in terms of other agents, including cyclosporine, cyclophosphamide, and mycophenolate mofetil. In addition, we explored the association between the CR rate and PLA2R-ab in different immunosuppressive regimens. The CR rate was higher in serum PLA2R-ab (−) patients than in PLA2R-ab (+) patients treated with a calcineurin inhibitor, but the difference was not statistically significant in the cyclophosphamide and rituximab regimens. The guidelines recommend starting immunosuppressive treatment with cyclophosphamide associated with steroids, rituximab, or calcineurin inhibitors with rituximab [42]. The optimal immunosuppressive regimen for IMN remains controversial. The effect of tacrolimus [43] and cyclosporine A [44] on remission was relatively better than that of cyclophosphamide, rituximab, and mycophenolate mofetil. Although rituximab was superior in the decline of proteinuria and PLA2R-ab [45], the result was not consistent, and more randomized trials are needed.

Furthermore, through our subgroup analysis, we found that the induced CR rate was significantly higher in IMN patients without PLA2R-ab after a 3-month and 6-month follow-up. However, no similar result was noted after a regimen for 12 months, perhaps owing to severe adverse events and complications associated with nephrotic syndrome. In other previous studies, the merits of calcineurin inhibitors for clinical remission were also similar after 12 months of treatment [42, 46]. Further studies are needed to evaluate the efficacy and necessity of long-term immunosuppressive agents. For spontaneous remission, we found that the predictive value of PLA2R-ab was significant in Asian patients but not in non-Asian patients. A combination of tacrolimus with prednisone could relieve IMN even at a low dose in Chinese populations [47]. Consequently, a personalized therapeutic option should be applied due to ethnic, environmental, lifestyle, economic, and other social differences.

The CR rate was significantly higher in IMN patients without PLA2R-ab than in patients with PLA2R-ab, regardless of the different assay methods, which contrasts with another meta-analysis [48]. Interestingly, our study first explored the association between the presence of PLA2R-ab and induced PR, and no difference was noted. This study suggests that immunosuppressive agents can effectively induce PR in IMN patients, regardless of the presence or different titers of PLA2R-ab.

Our study has some limitations. First, we did not consider the PLA2R antigens in glomerular deposits or their clinical significance. Second, the number of studies exploring different immunosuppressive agents and duration of treatment was relatively small, which may have affected our results. Third, the source of heterogeneity among our studies could not be assessed completely by other factors, such as residual renal function and subclass of antibody.

The disease activity was relatively higher in IMN patients with PLA2R-ab. Compared with the negative group, the serum PLA2R-ab-positive group had a lower rate of CR and spontaneous remission instead of PR and relapse. This study provides the first demonstration that a specific PLA2R-ab titer for risk stratification and a choice of first-line therapy should be indicated in clinical studies with large samples.

Ethical approval and consent were not required as this study was based on publicly available data.

The authors have no conflicts of interest to declare.

This study was supported by the Ministry of Education & National Natural Science Foundation of Beijing [No. KZ 202110025038] and National Natural science Foundation of China [No. 81570663].

Conceptualization: Aihua Zhang; data curation and methodology: Jialing Zhang and Aihua Zhang; formal analysis: Jialing Zhang, Zhengjia Fan, and Peixin Wang; and writing – original draft: Jialing Zhang.

All data generated or analyzed during this study are included in this article and its online supplementary materials. Further inquiries can be directed to the corresponding author.

1.
Ronco
P
,
Debiec
H
.
Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care
.
Lancet
.
2015
;
385
(
9981
):
1983
92
.
2.
Storrar
J
,
Gill-Taylor
T
,
Chinnadurai
R
,
Chrysochou
C
,
Poulikakos
D
,
Rainone
F
.
A low rate of end-stage kidney disease in membranous nephropathy: a single centre study over 2 decades
.
PLoS One
.
2022
;
17
(
10
):
e0276053
.
3.
Couser
WG
.
Primary membranous nephropathy
.
Clin J Am Soc Nephrol
.
2017
;
12
(
6
):
983
97
.
4.
Rankin
AJ
,
McQuarrie
EP
,
Fox
JG
,
Geddes
CC
,
MacKinnon
B
Scottish Renal Biopsy Registry
.
Venous thromboembolism in primary nephrotic syndrome: is the risk high enough to justify prophylactic anticoagulation
.
Nephron
.
2017
;
135
(
1
):
39
45
.
5.
Lee
T
,
Derebail
VK
,
Kshirsagar
AV
,
Chung
Y
,
Fine
JP
,
Mahoney
S
.
Patients with primary membranous nephropathy are at high risk of cardiovascular events
.
Kidney Int
.
2016
;
89
(
5
):
1111
8
.
6.
Leeaphorn
N
,
Kue-A-Pai
P
,
Thamcharoen
N
,
Ungprasert
P
,
Stokes
MB
,
Knight
EL
.
Prevalence of cancer in membranous nephropathy: a systematic review and meta-analysis of observational studies
.
Am J Nephrol
.
2014
;
40
(
1
):
29
35
.
7.
Chung
EYM
,
Wang
YM
,
Keung
K
,
Hu
M
,
McCarthy
H
,
Wong
G
.
Membranous nephropathy: clearer pathology and mechanisms identify potential strategies for treatment
.
Front Immunol
.
2022
;
13
:
1036249
.
8.
Hofstra
JM
,
Beck
LH
Jr.
,
Beck
DM
,
Wetzels
JF
,
Salant
DJ
.
Anti-phospholipase A- receptor antibodies correlate with clinical status in idiopathic membranous nephropathy
.
Clin J Am Soc Nephrol
.
2011
;
6
(
6
):
1286
91
.
9.
Hoxha
E
,
Thiele
I
,
Zahner
G
,
Panzer
U
,
Harendza
S
,
Stahl
RAK
.
Phospholipase A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy
.
J Am Soc Nephrol
.
2014
;
25
(
6
):
1357
66
.
10.
Bech
AP
,
Hofstra
JM
,
Brenchley
PE
,
Wetzels
JFM
.
Association of anti-PLA-R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy
.
Clin J Am Soc Nephrol
.
2014
;
9
(
8
):
1386
92
.
11.
Wu
W
,
Shang
J
,
Tao
C
,
Wang
S
,
Hu
X
,
Zhang
S
.
The prognostic value of phospholipase A2 receptor autoantibodies on spontaneous remission for patients with idiopathic membranous nephropathy: a meta-analysis
.
Medicine
.
2018
;
97
(
23
):
e11018
.
12.
Dong
D
,
Fan
TT
,
Wang
YY
,
Zhang
L
,
Song
L
,
Zhang
L
.
Relationship between renal tissues phospholipase A2 receptor and its serum antibody and clinical condition and prognosis of idiopathic membranous nephropathy: a meta-analysis
.
BMC Nephrol
.
2019
;
20
(
1
):
444
.
13.
Liang
Y
,
Wan
J
,
Chen
Y
,
Pan
Y
.
Serum anti-phospholipase A2 receptor (PLA2R) antibody detected at diagnosis as a predictor for clinical remission in patients with primary membranous nephropathy: a meta-analysis
.
BMC Nephrol
.
2019
;
20
(
1
):
360
.
14.
Higgins
JPT
,
Thompson
SG
,
Deeks
JJ
,
Altman
DG
.
Measuring inconsistency in meta-analyses
.
Bmj
.
2003
;
327
(
7414
):
557
60
.
15.
Stang
A
.
Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses
.
Eur J Epidemiol
.
2010
;
25
(
9
):
603
5
.
16.
Zhang
Q
,
Liu
X
,
Zhang
Z
,
Wu
M
,
Huang
B
,
Zhang
Y
.
A comparison of clinical features between idiopathic membranous nephropathy patients with and without serum antibody against phospholipase A2 receptor
.
Medicine
.
2019
;
98
(
45
):
e17658
.
17.
Sun
Y
,
Lan
P
,
Feng
J
,
Wang
Z
,
Liu
C
,
Xie
L
.
Analysis of glomerular PLA2R efficacy in evaluating the prognosis of idiopathic membranous nephropathy in the background of different serum anti-PLA2R levels
.
Ren Fail
.
2022
;
44
(
1
):
731
40
.
18.
Song
EJ
,
Jeong
KH
,
Yang
YA
,
Lim
JH
,
Jung
HY
,
Choi
JY
.
Anti-phospholipase A2 receptor antibody as a prognostic marker in patients with primary membranous nephropathy
.
Kidney Res Clin Pract
.
2018
;
37
(
3
):
248
56
.
19.
Kim
YG
,
Choi
YW
,
Kim
SY
,
Moon
JY
,
Ihm
CG
,
Lee
TW
.
Anti-phospholipase A2 receptor antibody as prognostic indicator in idiopathic membranous nephropathy
.
Am J Nephrol
.
2015
;
42
(
3
):
250
7
.
20.
Jullien
P
,
Seitz Polski
B
,
Maillard
N
,
Thibaudin
D
,
Laurent
B
,
Ollier
E
.
Anti-phospholipase A2 receptor antibody levels at diagnosis predicts spontaneous remission of idiopathic membranous nephropathy
.
Clin Kidney J
.
2017
;
10
(
2
):
209
14
.
21.
Hofstra
JM
,
Debiec
H
,
Short
CD
,
Pellé
T
,
Kleta
R
,
Mathieson
PW
.
Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy
.
J Am Soc Nephrol
.
2012
;
23
(
10
):
1735
43
.
22.
Ruggenenti
P
,
Debiec
H
,
Ruggiero
B
,
Chianca
A
,
Pellé
T
,
Gaspari
F
.
Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy
.
J Am Soc Nephrol
.
2015
;
26
(
10
):
2545
58
.
23.
Timmermans
SAMEG
,
Abdul Hamid
MA
,
Cohen Tervaert
JW
,
Damoiseaux
JGMC
,
van Paassen
P
Limburg Renal Registry
.
Anti-PLA2R antibodies as a prognostic factor in pla2r-related membranous nephropathy
.
Am J Nephrol
.
2015
;
42
(
1
):
70
7
.
24.
Oh
YJ
,
Yang
SH
,
Kim
DK
,
Kang
SW
,
Kim
YS
.
Autoantibodies against phospholipase A2 receptor in Korean patients with membranous nephropathy
.
PLoS One
.
2013
;
8
(
4
):
e62151
.
25.
Jatem Escalante
E
,
Segarra Medrano
A
,
Carnicer Cáceres
C
,
Martín-Gómez
MA
,
Salcedo Allende
MT
,
Ostos Roldan
H
.
Clinical features, course and prognosis of idiopathic membranous nephropathy depending on the presence of antibodies against M-type phospholipase A2 receptor
.
Nefrologia
.
2015
;
35
(
5
):
479
86
.
26.
Jurubiță
R
,
Obrișcă
B
,
Sorohan
B
,
Achim
C
,
Micu
GE
,
Mircescu
G
.
Clinical phenotypes and predictors of remission in primary membranous nephropathy
.
J Clin Med
.
2021
;
10
(
12
):
2624
.
27.
Deng
L
,
Huang
Q
,
Wang
J
,
Luo
K
,
Liu
J
,
Yan
W
.
Efficacy and safety of different immunosuppressive therapies in patients with membranous nephropathy and high PLA2R antibody titer
.
Front Pharmacol
.
2021
;
12
:
786334
.
28.
Yin
P
,
Wang
J
,
Liang
W
,
Zhan
L
,
Liu
Y
,
Lin
J
.
Outcomes of primary membranous nephropathy based on serum anti-phospholipase A2 receptor antibodies and glomerular phospholipase A2 receptor antigen status: a retrospective cohort study
.
Ren Fail
.
2020
;
42
(
1
):
675
83
.
29.
Ramachandran
R
,
Kumar
V
,
Kumar
A
,
Yadav
AK
,
Nada
R
,
Kumar
H
.
PLA2R antibodies, glomerular PLA2R deposits and variations in PLA2R1 and HLA-DQA1 genes in primary membranous nephropathy in South Asians
.
Nephrol Dial Transplant
.
2016
;
31
(
9
):
1486
93
.
30.
Wang
J
,
Xie
Q
,
Sun
Z
,
Xu
N
,
Li
Y
,
Wang
L
.
Response to immunosuppressive therapy in PLA(2)R- associated and non-PLA(2)R- associated idiopathic membranous nephropathy: a retrospective, multicenter cohort study
.
BMC Nephrol
.
2017
;
18
(
1
):
227
.
31.
Floege
J
,
Barbour
SJ
,
Cattran
DC
,
Hogan
JJ
,
Nachman
PH
,
Tang
SCW
.
Management and treatment of glomerular diseases (part 1): conclusions from a kidney disease: improving global outcomes (KDIGO) controversies conference
.
Kidney Int
.
2019
;
95
(
2
):
268
80
.
32.
Beck
LH
Jr.
,
Bonegio
RGB
,
Lambeau
G
,
Beck
DM
,
Powell
DW
,
Cummins
TD
.
M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy
.
N Engl J Med
.
2009
;
361
(
1
):
11
21
.
33.
Dai
H
,
Zhang
H
,
He
Y
.
Diagnostic accuracy of PLA2R autoantibodies and glomerular staining for the differentiation of idiopathic and secondary membranous nephropathy: an updated meta-analysis
.
Sci Rep
.
2015
;
5
:
8803
.
34.
Wei
SY
,
Wang
YX
,
Li
JS
,
Zhao
SL
,
Diao
TT
,
Wang
Y
.
Serum anti-pla2r antibody predicts treatment outcome in idiopathic membranous nephropathy
.
Am J Nephrol
.
2016
;
43
(
2
):
129
40
.
35.
Kao
L
,
Lam
V
,
Waldman
M
,
Glassock
RJ
,
Zhu
Q
.
Identification of the immunodominant epitope region in phospholipase A2 receptor-mediating autoantibody binding in idiopathic membranous nephropathy
.
J Am Soc Nephrol
.
2015
;
26
(
2
):
291
301
.
36.
Fresquet
M
,
Jowitt
TA
,
Gummadova
J
,
Collins
R
,
O’Cualain
R
,
McKenzie
EA
.
Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy
.
J Am Soc Nephrol
.
2015
;
26
(
2
):
302
13
.
37.
Timmermans
SAMEG
,
Damoiseaux
JGMC
,
Heerings-Rewinkel
PTJ
,
Ayalon
R
,
Beck
LH
Jr.
,
Schlumberger
W
.
Evaluation of anti-PLA2R1 as measured by a novel ELISA in patients with idiopathic membranous nephropathy: a cohort study
.
Am J Clin Pathol
.
2014
;
142
(
1
):
29
34
.
38.
Pang
L
,
Zhang
AM
,
Li
HX
,
Du
JL
,
Jiao
LL
,
Duan
N
.
Serum anti-PLA2R antibody and glomerular PLA2R deposition in Chinese patients with membranous nephropathy: a cross-sectional study
.
Medicine
.
2017
;
96
(
24
):
e7218
.
39.
Hoxha
E
,
Harendza
S
,
Pinnschmidt
H
,
Panzer
U
,
Stahl
RAK
.
PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system
.
PLoS One
.
2014
;
9
(
10
):
e110681
.
40.
Rodas
LM
,
Matas-García
A
,
Barros
X
,
Blasco
M
,
Viñas
O
,
Llobell
A
.
Antiphospholipase 2 receptor antibody levels to predict complete spontaneous remission in primary membranous nephropathy
.
Clin Kidney J
.
2019
;
12
(
1
):
36
41
.
41.
Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group
.
KDIGO 2021 clinical practice guideline for the management of glomerular diseases
.
Kidney Int
.
2021
100
4s
S1
276
.
42.
Chapter 7: idiopathic membranous nephropathy
.
Kidney Int Suppl
.
2012
;
2
(
2
):
186
97
.
43.
Chen
M
,
Liu
J
,
Xiong
Y
,
Xu
G
.
Treatment of idiopathic membranous nephropathy for moderate or severe proteinuria: a systematic review and network meta-analysis
.
Int J Clin Pract
.
2022
;
2022
:
4996239
.
44.
Lin
S
,
Li
HY
,
Zhou
T
,
Lin
W
.
Efficacy and safety of cyclosporine A in the treatment of idiopathic membranous nephropathy in an Asian population
.
Drug Des Devel Ther
.
2019
;
13
:
2305
30
.
45.
Fervenza
FC
,
Appel
GB
,
Barbour
SJ
,
Rovin
BH
,
Lafayette
RA
,
Aslam
N
.
Rituximab or cyclosporine in the treatment of membranous nephropathy
.
N Engl J Med
.
2019
;
381
(
1
):
36
46
.
46.
Qiu
TT
,
Zhang
C
,
Zhao
HW
,
Zhou
JW
.
Calcineurin inhibitors versus cyclophosphamide for idiopathic membranous nephropathy: a systematic review and meta-analysis of 21 clinical trials
.
Autoimmun Rev
.
2017
;
16
(
2
):
136
45
.
47.
Yuan
H
,
Liu
N
,
Sun
GD
,
Jia
Y
,
Luo
P
,
Miao
LN
.
Effect of prolonged tacrolimus treatment in idiopathic membranous nephropathy with nephrotic syndrome
.
Pharmacology
.
2013
91
5–6
259
66
.
48.
Li
W
,
Zhao
Y
.
Prognostic value of phospholipase A2 receptor in primary membranous nephropathy: a systematic review and meta-analysis
.
Int Urol Nephrol
.
2019
;
51
(
9
):
1581
96
.