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  • Review
  • Open Access

25 December 2025

Membranous Nephropathy: Advances in Diagnosis and Treatment, with an Eye on PLA2R1-Negative Forms

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1
Nephrology Unit, Meyer Children’s Hospital, 50139 Florence, Italy
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Department of Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis, and Transplantation Unit, University of Bari Aldo Moro, 70124 Bari, Italy
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Nephrology and Dialysis Unit, “Santo Stefano” Hospital, 59100 Prato, Italy
4
Nephrology and Dialysis Unit, “San Giovanni di Dio” Hospital, 50143 Florence, Italy
Kidney Dial.2026, 6(1), 2;https://doi.org/10.3390/kidneydial6010002
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Abstract

Membranous nephropathy (MN) is an immune complexmediated glomerular disease defined by sub-epithelial deposits that trigger complement activation and podocyte injury. Its pathogenesis reflects loss of immune tolerance and may present as a kidney-limited autoimmune process or in association with underlying conditions (e.g., malignancy, infection, drugs, or systemic autoimmunity). Current diagnostic work-up integrates circulating antibodies—most commonly anti–phospholipase A2 receptor 1 (PLA2R1)—and kidney biopsy, which remains essential in PLA2R1-negative or atypical presentations and for antigen confirmation when serology is negative. In PLA2R1-negative MN, an expanding list of antigens is being recognized, potentially refining phenotyping and risk assessment; however, dedicated studies remain limited, and the clinical weight of many newly described antigens likely requires further validation before supporting an antigen-based classification. Uneven access to advanced diagnostics particularly affects PLA2R1-negative cases, underscoring the need for centralized testing and the development of reliable non-invasive biomarkers. Treatment has advanced with rituximab and other targeted therapies, but resistant and relapsing cases remain challenging, and the evidence base for PLA2R1-negative forms is comparatively limited. This review summarizes recent diagnostic and therapeutic advances, focusing on PLA2R1-negative MN.

1. Introduction

Membranous nephropathy (MN), despite being a rare glomerular disease, is the most common cause of nephrotic syndrome in non-diabetic adults, with a global incidence of ~1/100,000 inhabitants/year and an average age at diagnosis of 50–60 years. Male predominance is common and progression to kidney failure occurs in roughly one third of patients [1,2,3,4]. Recurrence post-transplantation has been reported in up to 10–45% of renal grafts [5]. The pathophysiology of MN likely reflects a breakdown of immune tolerance, in a multi-hit process in which several predisposing factors contribute [6], such as genetics and epigenetics [7,8,9], ectopic expression of a target antigen [10], molecular mimicry [11], and exposure to toxins or environmental factors [12]. These mechanisms ultimately promote antibody formation and chronic sub-epithelial immune deposits, leading complement activation and downstream mechanisms of podocyte injury [13,14]. Autoantibodies may target podocyte antigens, planted antigens, or sub-epithelial neo-epitopes, and some antigen–antibody complexes are linked to extra-renal diseases [6,15].
In this article, we refer to the KDIGO (Kidney Disease: Improving Global Outcomes) 2021 guidelines [16], as the KDIGO 2024 update provides no new MN-specific recommendations. The KDIGO traditionally distinguish between primary and secondary MN [17]. Primary MN is typically a kidney-specific autoimmune condition, whereas secondary MN is an immune-mediated membranous pattern linked to an underlying condition (e.g., malignancy, infection, drugs, or systemic autoimmunity), which often improves with treatment of the trigger. Antigen associations do not map neatly onto the primary/secondary distinction, since several antigens can be detected in both settings.
While MN is still globally considered a distinct entity, an evolving perspective frames it as a histological pattern of glomerular damage shared by different etiologies [18,19].
In line with this, given the expanding antigenic landscape, the Mayo Clinic consensus report on MN proposed an antigen-centered classification based on the implicated antigen and its associated conditions [20]. Phospholipase A2 receptor 1 (PLA2R1) represents the most common target antigen, accounting for 60–70% of MN cases, most of which are not associated with an underlying disorder. In PLA2R1-positive patients [20,21], serum titers of anti-PLA2R1 antibodies are employed not only to assess disease activity and guide immunosuppression, but also as a non-invasive diagnostic tool [16,22].
Although KDIGO guidelines advise that serology alone can lead to a diagnosis of MN in patients with nephrotic syndrome and a positive anti-PLA2R1 antibody test, kidney biopsy still represents a key diagnostic step [16]. While most cases show typical features under light microscopy, immunofluorescence and electron microscopy, atypical presentations can also be found, such as segmental MN (sub-epithelial deposits limited to some capillary loops), which may suggest a possible separate entity. Performing kidney biopsy is believed to be especially significant in PLA2R1-negative patients, since a low percentage of them may turn out to be PLA2R1-positive on kidney tissue [23]. Moreover, in the past five years several new antigens have been described, partially filling the knowledge gap of PLA2R1-negative MN. Nonetheless, identification of these antigens currently relies on techniques available only in selected laboratories, such as laser capture microdissection coupled with mass spectrometry (LCM/MS) on kidney specimens [24]. As a result, routine diagnostic workflows remain limited in their ability to detect these novel targets.
Therapeutic approaches will likely be affected by these advancements. Currently, all MN patients, regardless of PLA2R1 positivity/negativity, are treated with supportive care and according to MN risk stratification [16], taking into account that spontaneous remission may also occur [1]. For patients requiring immunosuppressants, approaches mainly involve anti-CD20 therapy [with rituximab (RTX) being the first choice based on its safety-efficacy profile], calcineurin inhibitors (CNIs) and cyclophosphamide (CYC). Still, a subgroup of MN patients achieves only partial remission or is resistant to the aforementioned therapies, thus necessitating the use of alternative agents. With the aim to provide an optimized and personalized therapy while minimizing side effects, some novel agents have been introduced in clinical practice, such as obinutuzumab, bortezomib [25] and, as an alternative, combinations of traditional agents have also been tested. More are currently under investigation, including B-cell/plasma cell-depleting agents and complement inhibitors [25]. The complement system has recently gained increasing attention across various fields, and its role in injury amplification is now being explored as a potential therapeutic target in MN as well [13]. In this review, we cover recent diagnostic and therapeutic advances in MN, with additional attention given to PLA2R1-negative forms in this context.

2. Diagnosis

Recent advances in the diagnosis of MN reflect a growing integration of traditional histopathology with antigen-based and molecular approaches. In the following sections, we first discuss tissue-based diagnostic strategies, including antigen identification and pathological variants, and then review emerging noninvasive and molecular tools aimed at disease monitoring and risk stratification.

2.1. New Antigens and Atypical Pathological Variants of MN

Anti-PLA2R1 antibodies are well-established markers for both diagnosis and disease monitoring [16]. However, while PLA2R1 represents the most extensively studied antigen, it alone cannot reliably distinguish between primary and secondary forms of MN [26,27]. In PLA2R1-negative MN, the role of serum antibodies remains debated. Among the best-established non-PLA2R1 targets, thrombospondin type-1 domain–containing 7A (THSD7A) and semaphorin 3B (SEMA3B) have been identified as relevant antigens, with evidence supporting their pathogenicity [20,28,29]. Nevertheless, neither of them can yet replace kidney biopsy [20]. Beyond THSD7A and SEMA3B, several new antigens have been described (Table 1), but the pathogenic relevance of their respective antibodies is often unclear [27,30]. Some of these antibodies are not detectable in the serum but only on the tissue using special techniques, which limits their applicability. Likewise, tests for their detection are not yet widely available [24]. Two points warrants emphasis: first, newly discovered antigens cannot be expected to carry the same clinical weight as PLA2R1, largely because they are identified in relatively small patient subsets, limiting robust phenotyping and outcome correlations [27,31]. Second, PLA2R1 itself has recognized caveats, underscoring the need for caution when interpreting serologic results [27]. Overall, antigen testing is a valuable adjunct to guide the diagnostic work-up and longitudinal monitoring, but a comprehensive clinical assessment integrated with histopathology remains central for both diagnosis and prognostic assessment—particularly, though not exclusively, in PLA2R1-negative MN [24].
Table 1. Reported antigens in MN.
Against this background, it is useful to briefly outline the main methodologies used to identify novel antigens, which currently fall into two board approaches, namely the conventional immunohistochemistry/immunofluorescence (IHC/IF) microscopy and the most recent LCM/MS.
IHC/IF is widely used in routine practice, but validated reagents for many recently described antigens are not yet broadly available. LCM/MS is a one-step test, more sensitive and specific than IHC/IF and less prone to interpretation errors. It represented the fundamental methodology in the discovery of the new MN-associated antigens [32] (Table 1) and clarified that MN antigens are probably mutually exclusive, warning on the fact that dual-antigen positivity is often due to technical limitations [24]. Although true double positivity is biologically plausible, most reported cases have been based on IHC/IF staining of kidney biopsies. By contrast, LCM/MS has been cited as a direct detection method in only a single, as-yet unpublished report of concurrent Neural epidermal growth factor-like 1 (NELL1) and PLA2R1 [33].
An alternative approach recently proposed is protein G–based immunoprecipitation, which isolates specific antigens from complex tissue extracts using antibody-coated beads, followed by mass spectrometry. Although still under evaluation, one study suggested that its performance may be comparable to that of LCM/MS in selected settings [34]. Additionally, advanced IF-based imaging modalities, including confocal and super-resolution microscopy have proven useful in identifying the spatial distribution of target proteins within glomerular structures [35]. While not routinely employed in MN diagnostics, they may add value in selected scenarios—such as segmental forms—where precise antigen localization is relevant.
Although these newly identified antigens appear to correlate with specific clinical and pathological profiles [24], and the Mayo Clinic Consensus introduced an antigen-centered diagnostic approach— either based on antigen frequency (“panel approach”) or on known associations with systemic conditions (“targeted approach”) [20]—an antigen-based classification of MN remains premature in clinical practice [27]. Current barriers include limited and heterogeneous evidence, variability in antibody-based assays, and restricted access to advanced tissue-based platforms. Further studies are therefore needed, and referral of biopsy material to specialized laboratories (e.g., for LCM/MS) may help both refine difficult diagnoses and accelerate validation of emerging antigen–phenotype associations.
Invasive assessment is essential in numerous cases. For instance, histological findings suggestive of a systemic autoimmune process—such as mesangial deposits or tubulo-reticular inclusions—can reveal secondary MN (e.g., due to systemic lupus erythematosus, SLE) or atypical presentations, directly informing more personalized and effective therapeutic strategies [36]. One such non-typical presentation is segmental MN (sMN), a poorly defined entity within the MN spectrum that illustrates the diagnostic challenges posed by atypical patterns. It has been described in association with both secreted and intracellular antigens, including NELL1 and high temperature requirement A serine peptidase 1 (HTRA1) [37,38] (Table 1). NELL1-associated MN, in particular, lacks a corresponding serological assay and can only be identified via kidney biopsy. sMN is typically PLA2R1-negative and may have a more benign course, even in the absence of immunosuppression [37].
Although sMN was initially considered an early or resolving phase of MN [39], longitudinal biopsy data suggest it may be a distinct entity [40]. Its segmental pattern may reflect a weaker antigenic stimulus or a more efficient immune response [39], or a different location of the target antigens, which may be more commonly intracellular. Intracellular antigens represent an emerging category in MN. Some of the new antigens are actually predominantly intracellular proteins (Table 1). In such cases, podocyte injury may expose normally hidden intracellular proteins, potentially triggering an autoimmune response.
Other atypical forms of MN include those with associated extra-capillary proliferation in the setting of SLE, anti-glomerular basement membrane (GBM) disease, or vasculitis. In patients with concurrent anti-GBM disease and MN, the presence and extent of crescents carry important prognostic implications. The pathogenic link between the two remains unclear: MN may unmask collagen epitopes that drive anti-GBM autoimmunity, or conversely, anti-GBM inflammation may lead to MN-immune complex formation and sub-epithelial deposition [41].
Finally, some forms of MN may show a ‘full-house’ pattern on immunofluorescence, without clinical evidence of a systemic disease [42]. Key features of this subtype include primary involvement of the mannose-binding lectin pathway, but its exact nosology is still unclear [43]. Taken together, these atypical presentations highlight the heterogeneity of MN and reinforce the view that, despite advances in antigen identification, kidney biopsy remains essential in unveiling underlying mechanisms and guiding appropriate management, particularly in PLA2R1-negative and non-classical forms.

2.2. Liquid Biopsy, Complement, and Molecular Characterization of MN

The search for novel noninvasive biomarkers remains a vibrant area of investigation. “Liquid biopsy”, i.e., the detection of disease-related biomarkers in blood, urine, or other body fluids, offers a non-invasive alternative to tissue biopsy. In MN, the investigation of urinary biomarkers began in the early 2000s. Initial studies suggested a potential association between urinary β2-microglobulin, α1-microglobulin levels and MN progression. However, as highlighted by Wang et al. [44], findings based on urinary protein products are difficult to standardize, and the analytes themselves are often unstable. Likewise, specificity and sensitivity issues are encountered in the assessment of urinary microRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, making miRNA a promising non-invasive biomarker for various diseases, yet inconclusive in MN [44,45].
Exosomes, small extracellular vesicles that carry organ-specific markers and contain relatively stable mRNA and miRNA [46], have also been proposed as potential biomarkers, but they come with the same limitations as miRNAs. Current research efforts are evaluating exosomal biomarkers such as Alix, CD63, TSG101, and urinary exosomal mRNA CCL2 [47,48,49,50].
Complement activation products are also detectable in the urine of patients with MN [51,52,53,54,55,56]. In some studies, high urinary levels of C3, C5b-9, C5a at baseline [57] or their persistence over time [54,55,56] have been associated with negative outcomes [58,59]. Studies have shown that, although complement activation occurs at the glomerular level in MN, urinary excretion of complement products—especially C5b-9—appears to reflect local tubular C3 activation and synthesis more closely, which may contribute to progressive renal injury [52,56]. Recently, Salant et al. demonstrated that complement activation contributes to some of the histopathologic changes typically associated with MN, through the interaction between podocyte-related complement receptors and complement itself [60,61]. This highlights the potential of complement activation products as promising biomarkers. However, it seems they are not specific to MN and so their validation is still pending [62]. Growing interest in the complement system stems from in vivo and in vitro studies demonstrating its involvement in podocyte injury and GBM alterations [57,63]. Liu et al. [14] showed that antibodies can still induce proteinuria even when complement pathways are differentially inhibited, suggesting that complement is not the sole driver of damage. Importantly, its pathogenic effects appear to involve multiple activation pathways—classical, alternative, and lectin—underscoring the relevance of complement not only as a diagnostic marker but also as a potential therapeutic target [51,64,65,66,67,68,69].
As a closing perspective, there is increasing interest in transcriptomic profiling of kidney diseases [70], based on the premise that disease-specific molecular signature may uncover both known and novel mechanisms of injury in MN. A study by Xie et al. suggests that the inappropriate activation of NFKB1- and IRF4-related pathways likely plays a critical role in the pathogenesis of MN [8]. Further validation studies are needed to draw definitive conclusions. Noninvasive diagnostic approaches are continuously evolving, with the ultimate aim of enabling comprehensive endo-phenotyping to guide personalized therapies tailored to individual treatment profiles [71]. Confidently, in the future, combination of different noninvasive diagnostic tools would avoid biopsy, especially for those who carry significant post-procedural risks. Importantly, these diagnostic advances have direct clinical implications, informing therapeutic decisions and allowing clinicians to tailor treatment strategies according to individual risk, disease activity, and potential responsiveness.

3. Therapy

The treatment of MN has evolved significantly over the past few decades, particularly due to the introduction of B-cell–targeted therapies. Management strategies are now increasingly guided by disease severity and risk stratification. However, treatment-resistant cases and frequent relapses remain major clinical challenges. Another unresolved issue is whether PLA2R1-positive and -negative forms of MN should be approached similarly or not. We will here outline treatment approaches in PLA2R1-positive MN, for which solid data from the literature are available, and subsequently deal with the therapeutic issues in patients with PLA2R1-negative forms.

3.1. Bridging What Is Known to What Is New in PLA2R1-Positive MN

KDIGO guidelines advise that all MN patients receive optimized supportive therapy, whereas immunosuppression is primarily guided by risk stratification. Patients who do not respond to RTX or CYC should be referred to expert centers, where experimental options (e.g., bortezomib, anti-CD38 therapy, and belimumab) and/or intensified conventional regimens may be considered [16]. Since this KDIGO report, many steps forward have been made.
First, standard supportive therapy, which includes ACE inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) targeting the RAAS system, combined with diet and lifestyle changes, is likely to be soon complemented by new therapeutic agents. Especially, it is increasingly conceived as a multi-target strategy, particularly in patients who achieve immunologic remission yet have persistent sub-nephrotic proteinuria [72]. Ongoing trials are evaluating additional antiproteinuric agents, including the mineral corticoid receptor antagonist (MRA) finerenone (ClinicalTrials.gov Identifier: NCT06573411) and Sodium-Glucose Co-Transporter 2 inhibitors (SGLT2i) (NCT07096986), while sulodexide has been proposed in selected settings [73]. Although the anti-proteinuric effect of SGLT2i in MN is currently considered modest [72,74] and there is no direct evidence for an effect on immunologic relapse/recurrence, their hemodynamic nephroprotective profile supports their inclusion within optimized supportive care.
Once the risk of progressive loss of kidney function has been assessed, supportive therapy started and the need for immunosuppressive therapy established, different approaches can be considered. With a nearly optimal remission rate, glucocorticoids and CYC [75] remained the mainstay of therapy in MN for several years [76], later giving way to anti-B-cell therapies [77], which, despite being apparently less effective, were significantly less toxic [78]. Through years of optimization of the RTX therapeutic regimen, this drug was eventually integrated as a primary treatment [16]. CNIs are considered alternatives, only rarely as monotherapy [19,79]. Mycophenolate mofetil (MMF) can be added to reduce CNIs dose, thereby decreasing nephrotoxicity [16]. Notably, it is a source of current debate how to treat very-high risk forms as well as RTX-resistant forms [80], which account for 20–40% of MN cases [78,81] and are typically PLA2R1-positive [82]. Resistant MN, though not formally defined [83], is generally identified by persistent proteinuria and/or anti-PLA2R1 antibody positivity despite immunosuppression [72]. Before defining a patient as resistant, misdiagnosis, secondary form, and drug-related issues [80,82,84] should be ruled out.
While some Authors recommend a combination of RTX, low-dose steroids, and CYC for high-risk forms [85] (an ongoing trial is evaluating this combination, NCT04745728), others suggest RTX as a monotherapy [86], recent evidence emphasizes the need for therapeutic alternatives, with growing support for avoiding alkylating agents in favor of multi-drug combination strategies. Some outstanding reviews highlight advancements in the therapeutic landscape [19,25,62,72,83], which will be summarized hereafter. Ongoing trials are exploring novel treatments, both as first-line options and for non-responsive cases, with some of them appearing particularly promising (Table 2).
Building on conventional and risk-stratified approaches, attention has increasingly turned to emerging therapeutic agents. These include B-cell-depleting therapies, plasma-cell directed therapies, complement inhibitors, and novel immunomodulators, which offer potential benefits in particular for patients who are refractory or at high risk of progression.

3.2. Highlights of Emerging Therapies and Clinical Trials in MN

3.2.1. B-Cell-Depleting Agents

Among B-cell-depleting therapies, obinutuzumab (anti-CD20) depletes B cells more effectively than RTX [87,88,89] and has shown efficacy in both refractory and treatment-naïve MN [90,91,92,93,94,95], with ongoing/recently completed studies furtherly investigating its efficacy (NCT06120673, NCT04629248, NCT05050214, NCT06470191, NCT07163611, NCT06781944). NCT06120673 study was deemed unfeasible due to unforeseen financial limitation. Ofatumumab (anti-CD20), with enhanced complement-mediated cytotoxicity, has shown effectiveness in refractory and relapsing MN [82,96], though no trials are currently recruiting. Zuberitimab (anti-CD20), initially studied in lymphoma [97], is currently under investigation (NCT06642909); it acts through antibody dependent cellular toxicity (ADCC) and complement-mediated cytotoxicity. MIL62 (anti-CD20), initially evaluated in hematologic neoplastic diseases, is also being investigated in MN patients (NCT05398653, NCT05862233) with promising preliminary results [see Table 2]. Lastly, budoprutug (TNT119, anti-CD19), acting through ADCC, is also currently being evaluated (NCT07096843).

3.2.2. B-Cell Modulating Agents

B-cell modulation therapies include belimumab (anti-BAFF), which is being evaluated in the NCT03949855 trial after showing promising results in an open-label trial [98]. Povetacicept and telitacicept are dual-pathway B-cell modulators targeting CD40-CD40L and BAFF pathway, and BAFF and APRIL, respectively. The efficacy of povetacicept is being assessed in the NCT05732402 trial, while telitacicept, with preliminary encouraging results from reports [99,100,101], is being investigated in the NCT06614985 trial. Lastly, a multicenter trial on atacicept, a dual BAFF-APRIL inhibitor, has recently been initiated (NCT06983028).
Bruton kinase inhibitors (BTK), like ibrutinib, are part of B-cell modulation therapies, blocking a tyrosine kinase essential for B-cell survival and function [102]. While effective in treating neoplastic disorders and potentially applicable in autoimmune diseases, BTK can cause numerous side effects. Zanubrutinib, a reversible BTK inhibitor which offers improved selectivity, potentially reducing side effects, is being investigated in few trials (NCT05800873, NCT05707377).
Table 2. Recent and ongoing Clinical Trials in MN.
Table 2. Recent and ongoing Clinical Trials in MN.
Drug ClassStudy Name and MoleculeStudy FeaturesSelection CriteriaControl and EndpointsCompletion Estimated and Status
B-cell DepletionREMIT trial (NCT06120673), obinutuzumab, anti-CD20phase 3 randomized multicenter, efficacy of obinutuzumab as initial treatment in newly diagnosed MNMN regardless PLA2R1 positivityCCS and CYC; CR, PRwithdrawn in 2025, financial limitations
MAJESTY trial (NCT04629248), obinutuzumab, anti-CD20phase 3 randomized multicenter, efficacy of obinutuzumab as initial treatment in newly diagnosed MNMN PLA2R1-positive onlyTAC; CR2025, active not recruiting. Preliminary results [103]
ORION trial (NCT05050214), obinutuzumab, anti-CD20phase 2 pilot trial, efficacy and safety of obinutuzumab in patients either RTX resistant or RTX dependentno mentionno control; CR, PR, ADR2026, active not recruiting
NCT06470191 trial, obinutuzumab, anti-CD20phase 2/3 randomized multicenter study, efficacy and safety of obinutuzumab administered by subcutaneous injectionno mentionCYA; CR, PR2026, recruiting
NCT07163611 trial, obinutuzumab, anti-CD20phase 2 pilot trial, single center, PLA2R1 reduction in MN patientsMN PLA2R1-positive onlyno control; ADR, CR, PR, PLA2R1 reduction2028, not yet recruiting
BLOSSOM trial (NCT06781944), obinutuzumab, anti-CD20phase 3, multicenter randomized trial, efficacy and safety in MN patientsMN regardless PLA2R1 positivityCYC; efficacy, safety, CR, PR2028, recruiting
NCT05398653 trial, MIL62, anti-CD20phase 1/2 multicenter randomized trial, efficacy and safety of MIL62 injectionno mentionCYA; CR, PR, ADRcompleted in 2025. Preliminary results [104]
NCT05862233 trial, MIL62, anti-CD20phase 3 clinical trial efficacy, safety, PK, PD and anti-drug antibodies of MIL62no mentionCYA; CR or PR2026, active not recruiting. Preliminary results [105]
NCT06642909 trial, zuberitimab, anti-CD20phase 2 multicenter randomized study, efficacy, safety, pharmacokinetics, and immunogenicity of zuberitamablikely MN regardless PLA2R1 positivityCYA; CR, proteinuria reduction2027, active not recruiting
PrisMN trial (NCT07096843), BUDOPRUTUG, anti-CD19phase 2, multicenter study, safety, efficacy of budoprutug (TNT119) in MN patientsPLA2R1-positive onlyNo control; ADR, CR, PR2027, recruiting
B-cell ModulationREBOOT trial (NCT03949855), belimumab, anti-BAFFphase 2, randomized multicenter study, efficacy of belimumab combined with RTXMN PLA2R1-positive onlyRTX; CR or PR2029, recruiting. Primary results [106]
RUBY-3 trial (NCT05732402), povetacicept, CD40-CD40L and BAFF pathway modulatorphase 1b/2a, safety, PK, PD of different dose levels of povetacicept in Autoantibody-Associated Glomerular DiseasesMN PLA2R1 or THSD7A positive onlyno control; safety, ADR2028, active not recruiting. Primary results [107]
OLYMPUS trial (NCT07204275), povetacicept, CD40-CD40L and BAFF pathway modulatorphase 2/3 randomized multicenter trial, safety and efficacy in patients with MNMN regardless PLA2R1 positivityno control; safety, efficacy2027, recruiting
TEST-T-PMN trial (NCT06614985), telitacicept, BAFF and APRIL modulatorphase 2, multicenter randomized clinical trial, safety and efficacy of telitaciceptlikely MN regardless PLA2R1 positivityCCS+CYC; CR2027, active not recruiting
PIONEER trial (NCT06983028), atacicept, BAFF and APRIL modulatorphase 2, randomized clinical trial, safety, efficacy of atacicept in Multiple Autoimmune Glomerular DiseasesMN PLA2R1-positive onlyno control; safety, efficacy2027, recruiting
NCT05800873 trial, zanubrutinib, reversible BTK inhibitor (rBTKi)phase 1b/2 study, safety, efficacy, PK of zanubrutinibMN PLA2R1-positive onlyno control; efficacy, safety, PK, PD2026, recruiting
ALMOND-study trial (NCT05707377), zanubrutinib, rBTKiphase 2/3 multicenter randomized study, safety, efficacy, PK of zanubrutinibMN PLA2R1-positive onlyTAC; proteinuria reduction2027, active not recruiting. Preliminary Analysis [108]
NCT05136456 trial, edralbrutinib, irreversible BTK inhibitorphase 2 randomized study, efficacy and safety of edralbrutinibMN PLA2R1-positive onlyno control; CR or PRexpected to be completed by 2024, unknown status
PCs DirectedNEWPLACE trial (NCT04733040), felzartamab, anti-CD38phase 2 multicenter, randomized, efficacy, safety and PC/PD of felzartamabMN PLA2R1-positive onlyno control; PLA2R1 level reductioncompleted in 2024, results not available yet
MONET trial (NCT04893096), felzartamab, anti-CD38phase 2, efficacy of felzartamab in RTX resistant patientsMN PLA2R1- or THSD7A-positive onlyno control; CR, PR, proteinuria reductioncompleted in 2025, results not available yet
PROMINENT trial (NCT06962800), felzartamab, anti-CD38phase 3, multicenter, randomized, efficacy and safety of felzartamab in PMNMN PLA2R1-positive or biopsy-proven MNTAC; CR,
PLA2R1 level reduction, PK		2028, recruiting
Complement InhibitorsNCT03453619 trial, pegcetacopan, C3 inhibitorphase 2 multicenter study, Safety and Biologic Activity of pegcetacopan in MN, LN, C3GPPLA2R1-positive onlyno control; proteinuria reductioncompleted in 2023. Primary results [109]
ACTHNCT05696613 trial, ACTHphase 3 randomized multicenter study, Safety and Efficacy of ACTH to RTXPLA2R1-positive onlyRTX; proteinuria reduction, CR2026, recruiting
NCT00805753 trial, ACTHphase 1, multicenter study, dose-finding of ACTHno mentionno control; proteinuria reduction, ADRcompleted in 2014, results not available yet
CAAR-T, BiAATENCT06690359 trial, IM19 CAAR-Tphase 1 study, evaluation of IM19 CAR-T in IgAN patients and MN medium-high risk patientsLikely MN regardless PLA2R1 positivityno control; safety, CR2026, not yet recruiting.
NCT06285279 trial, FKC288 CAAR-T targeting BCMA and CD19phase 1 single-center study, Safety and Efficacy of FKC288 in Participants With Autoimmune Kidney DiseasesPLA2R1-positive onlyno control; safety and ADR2028, recruiting
NCT06557265 trial, NKX019 CAAR-NKphase 1/2, non-randomized, multicenter, safety and tolerability, NKX019 (CAR NK) in LN and MNPLA2R1-positive onlyFludarabine+CYC; ADR, CR, PR2027, recruiting
NCT06982729 trial, YK012, bispecific CD19-directed CD3 T cell engagerphase 1a and phase 2b, single-center study, safety, tolerability and efficacy of YK012 in MNMN regardless PLA2R1 positivityno control; safety, tolerability, efficacy2027, recruiting
IFN ModulationALPHAGEM trial (NCT05941845), IFN-alfaphase 2 study, efficacy of personalized IFN-alpha treatment for MN patientsPLA2R1-positive onlyno control; PLA2R1 reduction2025, unknown status
nFc R InhibitorsNCT05810961 trial, efgarfitimod, autoantibodies reductionphase 2 multicenter, randomized study, efficacy and safety of efgarfitimod in Chinese MN patientsPLA2R1-positive onlyplacebo; proteinuria and PLA2R1 level reductionterminated in 2025, sponsor decision
suPAR/uPAR InhibitorsNCT06466135 trial, WAL0921, suPAR/uPAR inhibitorphase 2 multicenter randomized study, safety, efficacy, PD, PK in glomerular diseaseno mentionno control; safety, PK, PD, ADR2026, recruiting
CCS, cortico-steroid; CYA, cyclosporine; CYC, cyclophosphamide; RTX, rituximab; TAC, tacrolimus; BEL, belimumab; CR, complete remission; PR, partial remission; ADR, adverse drug reaction; PK, pharmacokinetics; PD, pharmacodynamics; PC, plasma cells. MN, membranous nephropathy; IgAN, IgA Nephropathy; LN, lupus nephritis; C3GP c3-glomerulopathies.

3.2.3. Plasma Cell-Directed Agents

These therapies include anti-CD38 antibodies and proteasome inhibitors. Monoclonal antibodies like daratumumab, felzartamab and isatuximab target CD38 especially on long-lived plasma cells, leading to plasma cell depletion [110]. Daratumumab has shown success in treating refractory PLA2R1-positive MN [111,112,113]. Felzartamab was investigated in the M-PLACE (NCT04145440).
Trial, and primary results showed its safety and efficacy in moderate to high-risk PLA2R1-positive MN [114]. Likewise, the NEWPLACE trial (NCT04733040), which shares with M-PLACE inclusion criteria and outcome measures, is currently completed, with no results available yet. There are no ongoing trials for daratumumab and isatuximab, but felzartamab continues to be investigated (NCT04893096, NCT06962800).

3.2.4. Proteasome Inhibitors Agents

Bortezomib can target antibody-producing plasma cells and has been used is a few cases to treat refractory MN with some success, despite frequent side effects [115,116,117,118]. Further research is warranted, particularly on second-generation proteasome inhibitors such as carfilzomib, ixazomib, and delanzomib, but as of December 2025, no clinical trials are ongoing.

3.2.5. Complement Inhibitors

Complement inhibitors are an emerging therapeutic class in MN. However, the clinical relevance of the different complement activation pathways in MN remains incompletely defined. Targeting C3 may be less attractive, as it would broadly inhibit complement activity and could be associated with significant adverse effects [119,120]; therefore, focusing on the lectin or alternative pathways may be more reasonable. Nevertheless, pathway-specific blockade may lead to compensatory activation of other complement routes [13]. Striking an effective balance is challenging, and recently conducted clinical trials have yielded limited evidence so far, with results pending (NCT02682407, from 2016) or inconclusive (iptacopan, NCT04154787; RENEW STUDY pelecopan, NCT05162066). A pegcetacopan trial (NCT03453619) has been completed, with primary results suggesting therapeutic benefits for C3G, but uncertainties regarding its potential effectiveness in treating MN. Meanwhile, avacopan, a C5 receptor inhibitor, has shown positive in vitro data [121], but clinical confirmation is still needed. The first trial on complement inhibition in MN, testing eculizumab, was halted due to a lack of efficacy [122], possibly also due to drug under-dosing secondary to proteinuria-related drug loss. Complement inhibitors warrant further clinical trials, with adequate amount/dosing of therapies and administration when complement-related damage is present [13].

3.2.6. Chimeric Auto-Antibody Receptor T Cells (CAAR-T)/Natural Killer Cells (CAAR-NK) and Bispecific Antibodies (BiAbs)

CAAR-T and NK technology, originally developed for cancer, has potential for treating MN by using engineered immune cells to target B cell clones expressing the autoantibody [83]. However, being CAAR technology complex and expensive technology, potentially linked to serious adverse events [83], its use should be carefully weighted. Few trials are currently ongoing in MN (NCT06690359, NCT06285279, NCT06557265; NCT07266181 not shown in Table 2).
Bispecific antibodies (BiAbs) are engineered proteins designed to bind simultaneously two different antigens, enabling targeted interactions between cells or molecules for therapeutic purposes. Bispecific AutoAntigen-T cell Engagers (BiAATEs) are a specialized subclass of BiAbs that link T cells to specific antigens on target cells (i.e., autoAb-producing B cells), thereby inducing T cell–mediated selective B-cell destruction. A recent study [123] showed that in vitro BiAATE molecules successfully induced depletion of PLA2R-specific B cells from MN patients while sparing normal B cells. They may be beneficial for all antibody-mediated autoimmune diseases with known pathogenic autoantigens, though current trials are mainly focused on cancer immunotherapy, with some exceptions (NCT06982729; NCT07234474, not shown in Table 2).

3.2.7. Adrenocorticotropic Hormone (ACTH)-Based Therapies

ACTH stabilizes the podocyte cytoskeleton and inhibits B-lymphocytes by activating podocyte melanocortin receptors. Initial studies showed that ACTH was as effective as alkylating agents in achieving remission in MN patients and was well tolerated [124,125]. A more recent study highlighted its efficacy in high-risk MN patients [126]. While two ACTH trials are registered (NCT05696613, NCT00805753), only NCT05696613 is currently active/recruiting, whereas NCT00805753 is a completed pilot study with no results posted.

3.2.8. Other Therapies

Peptide GAM immunoadsorption was recently applied to MN. It is an extra-corporeal treatment that can remove nephritogenic antibodies that, when combined with immunosuppressants, can implement their effects on antibody production [127,128]. Although it has been reported to be effective in patients with anti-THDS7A antibodies [129], a recent study showed no improvement in outcomes from removing anti-PLA2R1 antibodies [127], probably because, at a given time, immunosuppression was discontinued [83].
Sweeping antibodies are engineered IgG molecules designed to enhance the clearance of immune complexes and antigen-specific antibodies from the circulation by promoting their uptake and degradation. This concept has been proposed as a potential strategy in MN [130]; however, to our knowledge, no clinical trials are currently evaluating sweeping antibodies in this setting.
Other therapeutic approaches include efgarfitimod, an FcRn inhibitor, believed to reduce circulating autoantibody levels; a trial has recently been stopped due to sponsor decision (NCT05810961). WAL0921, a monoclonal antibody that inhibits suPAR and uPAR, which are thought to be involved in kidney diseases, is currently being studied for safety and efficacy in glomerular kidney diseases with proteinuria (NCT06466135). Interferon-related therapies, targeting Th17 cytokine production, are currently under investigation in MN (NCT05941845), since MN patients with a pro-inflammatory Th17 cytokine profile are showed to present with an increased relapse risk. T cell co-stimulatory blockade was recently suggested by Chung et al. as a new potential strategy [131], but no solid data are available.
Another intriguing new approach includes the use of nanoparticle-related technologies. In a recent study [132] nanoparticles were designed to deliver celastrol to podocytes in MN, improving its effectiveness and reducing toxicity, as celastrol has anti-inflammatory and antioxidant properties, but also poses safety concerns. Some studies are exploring even more futuristic approaches, such as those by Xie et al. [8] and Si et al. [133], aiming to identify potential therapeutic targets for MN by integrating proteome and transcriptome data.
While new therapies for MN are emerging, many patients may have limited access to them. Therefore, exploring new methods to optimize existing therapies is important to maximize efficacy while minimizing risks and costs. Zonozi et al. reported a 100% response rate in a retrospective study using a combination of CYC, rapid prednisone tapering, and two years of RTX (Cortazar Regimen) [85]. Limited trials are currently underway, for example, the recently completed NCT03804359, which compares GEMRITUX protocol and personalized RTX-based treatment approach to achieve clinical remission in MN patients (results not available yet). A newly initiated study is investigating strategies to potentiate the activity of RTX (NCT07038382).
As suggested by Yang et al. [130], combination therapies will likely become widely adopted, as new treatments—given their greater specificity, and consequently fewer side effects—will require a multi-targeted approach to achieve optimal efficacy. Combination therapies may therefore become increasingly relevant, alongside efforts to optimize and enhance the effectiveness of currently available treatments whenever feasible.

3.3. Bridging Recent Advances to Future Directions in MN, with a Focus on PLA2R1-Negative Forms

Most therapeutic evidence in MN come from PLA2R1-positive cohorts. We therefore address PLA2R1-negative forms in a dedicated section.
In the MENTOR study, 23% of patients treated with RTX were PLA2R1-negative. Among PLA2R1-negative patients, only one was anti-THSD7A-positive, and achieved complete remission at 12 months and maintained it at month 24. Although long-term outcomes remain unclear, the treatment effect during follow-up was reported to be similar regardless of PLA2R1 status. A key limitation, however, was the classification of PLA2R1 status based solely on serum testing [78]. A 2021 article showed a serum PLA2R1-negative form treated effectively with RTX [134], which, however, later turned out to be positive for IF on the renal biopsy. Lastly, a recent meta-analysis showed that PLA2R1-negative forms generally have better outcomes, but, again, their diagnosis relied only on serum PLA2R1 assessment [135]. Thus, the serum test for PLA2R1 alone may be insufficient for a definitive diagnostic and therapeutic work-up.
Available evidence has informed KDIGO guidance, indicating that, once secondary causes are excluded, a broadly similar therapeutic approach can be applied to PLA2R1-positive and -negative MN [16]. In the presence of concurrent malignancy or infection, immunosuppression may be considered if nephrotic syndrome persists after successful treatment of the underlying condition [136]. More aggressive regimens may be required in crescentic presentations according to the driving pathology (e.g., anti-GBM disease, ANCA-associated vasculitis, SLE) [16].
Evidence specifically addressing immunosuppression in PLA2R1-negative MN remains scarce. A 2023 report described heterogeneous responses in PLA2R1-negative segmental MN (PLA2R1 and THSD7A negative on kidney biopsy), often complicated by coexisting kidney diseases [137]. By contrast, in PLA2R1-positive MN, antibody kinetics can more directly support risk-based treatment tailoring: high titers often prompt more intensive therapy, and persistence after six months may guide treatment adjustment [16,138]. Antibody titers and serum albumin are among the best predictors of remission [78], and B-cell monitoring appears relevant in both PLA2R1-positive and -negative MN [139]. Ongoing studies increasingly include PLA2R1-negative cohorts (e.g., NCT06962800; Table 2), and their interpretability will critically depend on robust case definitions and harmonized endpoints.
Future studies should prioritize robust case definitions and harmonized endpoints, particularly for PLA2R1-negative cohorts (Table 2).

4. Conclusions

Despite significant progress in the workup of MN, the mechanisms driving tissue injury—and the extent of overlap with other glomerular diseases—remain incompletely defined, complicating both diagnosis and treatment. While PLA2R1 serology has become central for diagnosis and monitoring, renal biopsy remains essential, particularly for PLA2R1-negative or atypical presentations, and for confirming antigen involvement when serology is negative. Given the limited and heterogeneous evidence with newly described antigens and their rarity, a strictly antigen-based classification may be premature. Greater weight should be placed on histopathological features and the specific pattern of injury to guide treatment decisions more effectively. The emergence of therapies targeting B cells, plasma cells, and complement, as well as precision immunotherapies (e.g., CAAR-T, BiAATEs), offers promising options for refractory and high-risk disease, but their optimal use will likely rely on combination approaches guided by histopathology and immunologic profiling. If not skillfully employed, new therapies could be wrongly perceived as ineffective, in both PLA2R-negative and -positive MN. Overall, combining novel agents with optimization of established regimens is expected to further improve outcomes.

5. Future Perspectives

In the coming years, MN studies should adopt clear, reproducible enrollment criteria, and systematically collect complementary markers of disease activity (antigen status, complement activation, podocyte injury signals, and inflammatory pathways). Centralized testing and hub-and-spoke networks will be key to scale advanced tissue analyses and to validate circulating/urinary biomarkers for longitudinal monitoring. Therapeutic development is expected to increasingly rely on combined or sequential regimens, moving beyond B-cell depletion to additional targets (e.g., plasma cells, T-cell pathways, complement). Importantly, future trials should incorporate refined endpoints beyond proteinuria alone—integrating immunologic, molecular, and histopathologic readouts—to better quantify disease activity and treatment response across the MN spectrum.
Looking ahead, future guidelines will face the challenge of balancing personalized care with considerations of cost-effectiveness and feasibility in the treatment of PLA2R1-positive and -negative MN.

Author Contributions

Conceptualization, A.V., M.A.C., G.S. and F.R.; investigation, M.A.C., G.S. and F.R.; writing—original draft preparation, M.A.C., A.M., F.R. and A.J.P.; writing—review and editing, A.V., L.G., M.A.C., A.J.P. and F.D.; supervision, A.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no conflicts of interest.

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