small molecules

2026-09-27 | Model-Informed Precision Dosing of Tacrolimus Initial Dosage Optimization in Membranous Nephropathy Patients.

Due to the therapeutic window of tacrolimus is narrow and there are significant individual differences in metabolism, a uniform dosage is prone to result in poor efficacy or increased toxic side effects. This study aimed to explore tacrolimus initial dosage optimization in membranous nephropathy (MN) patients based on model-informed precision dosing (MIPD). Population pharmacokinetic model, an effective tool of MIPD, was constructed using the non-linear mixed effect modeling approach implemented in NONMEM software, which encompassed a range of patient-related data, including demographic characteristics, physiological and biochemical test results, as well as details regarding concurrent medications. From the aspect of individualized drug administration, in adult MN patients, the initial dosages of tacrolimus were 0.06 mg/kg, 0.04 mg/kg for patients weighted 50-53 kg, 53-100 kg, respectively. In pediatric MN patients, the initial dosages of tacrolimus were 0.12 mg/kg, 0.10 mg/kg, 0.08 mg/kg, 0.06 mg/kg for patients weighted 10-12.7 kg, 12.7-16.4 kg, 16.4-26.7 kg, 26.7-40 kg, respectively. This study was the first time to simultaneously recommend the optimal initial dosage of tacrolimus for both adult and pediatric MN patients based on MIPD. Moreover, the dosage required for pediatric MN patients was higher than that for adult MN patients.

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2026-09-25 | A case of membranous nephropathy during asymptomatic syphilis.

We experienced membrane nephropathy associated with syphilis infection. A 51-year-old woman had an increase in body weight with leg edema. Blood and urine examination showed low serum protein and heavy proteinuria. She was diagnosed with nephrotic syndrome. The light microscope showed normal glomeruli with no bubbling appearance or spike lesions. Immunofluorescence analysis on the renal biopsy sample showed granular deposition of IgG, C3, C1q, κ and λ on capillary walls. The electron microscope showed a hump-like subepithelial and mesangial electron-dense deposit. Her pathologic diagnosis was Ehrenreich-Churg stage I membrane nephropathy. Negative staining of IgG4 on glomerular walls indicates secondary membrane nephropathy. The immunology test indicated active syphilis infection despite the lack of any skin lesions or constitutional symptoms related to syphilis. NDNF, which was recently identified as an antigen of syphilis-associated MN, was positive on capillary walls. The antibiotic treatment led to rapid, complete remission without using immunosuppressive treatment.

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2026-08-05 | Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy.

Membranous nephropathy (MN) is the leading cause of adult nephrotic syndrome with rising global incidence. A substantial proportion of patients progress to end-stage renal disease. Multiple programmed cell death (PCD) pathways-including apoptosis, pyroptosis, ferroptosis, and autophagy-are activated by complement-dependent and -independent pathogenic factors, collectively driving podocyte injury and MN progression. Current immunosuppressive therapies are limited by adverse reactions and variable responses. Traditional Chinese medicine (TCM), characterized by multi-component, multi-target, and multi-pathway regulation, shows therapeutic advantages in MN. To systematically review the regulatory mechanisms of PCD in MN, summarize the molecular basis of TCM interventions targeting PCD, and identify current research limitations and future directions. This narrative review systematically elaborates the regulatory association between PCD and podocyte injury in MN. Literatures were systematically retrieved from PubMed, Embase and China National Knowledge Infrastructure (CNKI) from the establishment of each database to May 2026, and 41 preclinical studies exploring TCM modulation of PCD in MN were included after strict screening. Complement-dependent and complement-independent pathways in MN can synergistically initiate podocyte apoptosis, pyroptosis, ferroptosis, and autophagy dysfunction. TCM can regulate PCD through core signaling pathways such as phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1), mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase/forkhead box O1 (JNK/FoxO1), and PTEN-induced kinase 1/Parkin (PINK1/Parkin), while simultaneously intervening in non-PCD pathological processes including inflammation, oxidative stress, and renal fibrosis. Clinical evidence further indicates that TCM or combined with conventional therapy can elevate MN remission rates and decrease adverse reactions. PCD represents a core mechanism mediating podocyte injury and MN progression. TCM effectively modulates PCD imbalance through multi-target regulation, demonstrating prominent clinical efficacy and safety. These findings provide a theoretical basis and translational direction for developing high-efficacy, low-toxicity therapeutic strategies for MN.

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2026-07-09 | Calcineurin Inhibitor–Based versus Cyclophosphamide-Based Immunosuppression for Primary Membranous Nephropathy: A Meta-Analysis of Remission and Relapse

Introduction. Primary membranous nephropathy (MN) is a leading cause of the nephrotic syndrome in adults. Calcineurin inhibitor (CNI)-based and cyclophosphamide-based regimens are both endorsed as first-line therapy, but their comparative efficacy and the durability of the remission they induce remain uncertain. This study was aimed to compare CNI-based versus cyclophosphamide-based regimens for total remission, complete remission and relapse in adults with primary MN. Methods. PubMed/MEDLINE, with Scopus and Web of Science indexing checks and manual reference screening, was searched for randomised controlled trials (RCTs) comparing a CNI-based regimen (tacrolimus or cyclosporine) with a cyclophosphamide-based regimen. Risk ratios (RRs) were pooled with a DerSimonian–Laird random-effects model; heterogeneity was quantified with I2. Risk of bias used the Cochrane RoB 2 tool. The review was not registered. Results. Nine RCTs (eleven articles; 599 participants) were included. Total remission did not differ between strategies (RR 1.02, 95% CI 0.86-1.20; I2=67%; 95% prediction interval 0.61-1.72; CNI 222/297 versus cyclophosphamide 215/302). Complete remission did not differ (RR 0.84, 95% CI 0.34-2.04). Relapse tended to be more frequent after CNI-based therapy (RR 1.76, 95% CI 0.95-3.24; I2=0%) without reaching significance. Estimates were stable across all sensitivity analyses (RR 0.91-1.11) and no small-study effect was detected (Egger p=0.87). Conclusion. CNI-based and cyclophosphamide-based regimens produced comparable remission in primary MN; a non-significant signal towards more frequent relapse after CNI therapy supports individualised, durability- and toxicity-aware treatment selection.

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2026-07-07 | Acetate ameliorates membranous nephropathy by modulating the immune response and podocyte function.

Membranous nephropathy (MN) is an antibody-mediated podocytopathy in which subepithelial immune deposits and complement activation lead to podocyte injury and proteinuria. Short-chain fatty acids (SCFAs) are microbiota-derived metabolites with immunomodulatory properties, but their therapeutic potential and mechanisms in MN remain incompletely defined. We evaluated acetate, propionate, and butyrate in a passive Heymann nephritis (PHN) rat model (n = 6/group). Rats received 150 mM sodium acetate, propionate, or butyrate in drinking water from day 0 to day 42. Proteinuria and biochemical indices were monitored; glomerular immune deposition and ultrastructure were assessed by immunofluorescence and transmission electron microscopy. Antigen-specific antibodies were quantified by ELISA. Glomerular expression of synaptopodin and WT1 was detected by immunohistochemistry. Splenic CD4+ T-cell subsets were analyzed by flow cytometry. In vitro, conditionally immortalized human podocytes were exposed to plasma from patients with primary MN, with or without acetate and the GPR43 antagonist GLPG0974, migration, synaptopodin expression, reactive oxygen species (ROS), apoptosis, and viability were assessed, and SCFA receptor expression was examined. All three SCFAs significantly reduced proteinuria in PHN rats compared with disease controls and ameliorated ultrastructural injury, including GBM thickening and podocyte foot-process effacement. Acetate and propionate reduced subepithelial immune-complex deposits. Acetate selectively decreased antigen-specific anti-sheep IgG responses without altering total IgG. PHN was associated with decreased Tregs and increased Th1/Th17 polarization; acetate increased the Treg proportion in splenocytes. Acetate protected podocyte cytoskeletal integrity and viability in vivo. Acetate acted through GPR43, as the GPR43 antagonist GLPG0974 partially or completely blocked acetate's effects on ROS reduction, migration improvement, and synaptopodin mRNA upregulation. Acetate treatment reduced HDAC activity in both renal cortex and podocytes while increasing HAT activity. Acetate mitigated primary MN plasma-induced dysfunction by improving migration and synaptopodin signal, reducing ROS, limiting apoptosis, and restoring cell viability. Acetate ameliorates experimental MN through coordinated immunomodulatory effects and amelioration of podocyte foot process effacement. These findings support targeting acetate pathways as a mechanistically plausible adjunct strategy with low potential toxicity for MN.

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antibodies

2026-09-26 | Rituximab Outcomes and Predictors of Treatment Failure in Primary Membranous Nephropathy: A Retrospective Cohort Study.

Background/Objectives: Rituximab (RTX) is an established treatment for primary membranous nephropathy (PMN); however, real-world data on predictors of response and the influence of previous treatment status remain limited. We evaluated outcomes and predictors of treatment failure in PMN patients treated with RTX. Methods: This retrospective cohort study included 58 adults with biopsy-proven PMN who received RTX between 2013 and 2023. Clinical remission at 6 and 9 months, treatment failure (persistent non-response or relapse after remission), and failure-free survival were evaluated. Outcomes were compared according to baseline anti-phospholipase A2 receptor (anti-PLA2R) antibody levels and previous treatment status. Results: Clinical remission increased significantly from 60.3% at 6 months to 72.4% (42/58) at 9 months (p < 0.001). Patients with baseline anti-PLA2R levels ≤ 150 RU/mL achieved significantly higher remission rates at both time points. The pattern of treatment failure also differed, with persistent refractory disease predominating at higher antibody levels and relapse after remission at lower levels. Baseline serum albumin was the only variable independently associated with treatment failure (odds ratio 0.18, 95% confidence interval 0.04-0.61; p = 0.010). Outcomes were comparable among treatment-naive, relapsing, and treatment-refractory patients at the predefined 9-month assessment. Infections occurred in 7 patients (12.1%). Conclusions: RTX achieved favorable clinical outcomes in PMN, with remission continuing to improve beyond 6 months. Baseline anti-PLA2R antibody levels and serum albumin provided complementary prognostic information. Previous treatment status was not associated with remission or treatment failure at the predefined 9-month assessment and was not independently associated with failure-free survival after adjustment for baseline serum albumin, although this finding should be interpreted cautiously given the limited sample size and unequal follow-up.

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2026-09-24 | Does baseline proteinuria affect the efficacy of obinutuzumab in patients with primary membranous nephropathy and minimal change disease? a single-center retrospective study.

Primary membranous nephropathy (PMN) and minimal change disease (MCD) are common causes of nephrotic syndrome in adults and represent the two diseases in which anti-CD20 monoclonal antibodies are most widely used. Previous studies have demonstrated that the clinical efficacy of rituximab (RTX) is influenced by the baseline level of proteinuria. Obinutuzumab is a novel anti-CD20 monoclonal antibody with superior efficacy and safety to RTX. However, whether its therapeutic efficacy in PMN and MCD is similarly influenced by baseline proteinuria remains unclear. We recruited 40 patients with PMN and 42 patients with MCD confirmed by renal biopsy. All patients received obinutuzumab. All patients with PMN were divided into two groups based on baseline proteinuria: ≤8 g/d group and >8 g/d group. MCD patients were divided into two groups: the GC + obinutuzumab group and the Obinutuzumab group. Compared the clinical outcomes and side-effects of patients in different groups after a 12-month follow-up. Among patients with PMN and MCD, no statistically significant differences were observed between the two groups in complete remission (CR) rates, partial remission (PR) rates, or composite remission rates at the first, third, sixth, ninth, and 12th months. Kaplan-Meier analysis showed that there is no significant difference in cumulative CR rates and composite remission rates between two groups in patients with PMN and patients with MCD. At the end of follow-up, all patients exhibited a significant reduction in proteinuria, an increase in serum albumin, and no deterioration in kidney function. Furthermore, the safety profile of obinutuzumab was favorable in this study. Our findings suggest that the efficacy of obinutuzumab in PMN and MCD is not affected by the baseline level of proteinuria. Besides, obinutuzumab monotherapy has shown satisfactory therapeutic effects in both PMN and MCD.

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2026-09-03 | Obinutuzumab Compared to Cyclosporine with Steroids for the Treatment of Primary Membranous Nephropathy: A Propensity Score-Matched Analysis.

To compare the efficacy and safety profiles of obinutuzumab or cyclosporine combined with steroid in treating primary membranous nephropathy. This retrospective study included patients with primary membranous nephropathy treated at Shanghai Ruijin Hospital between January 2020 and June 2023. Patients received either obinutuzumab or cyclosporine combined with corticosteroid and were followed for at least 24 months unless relapse or treatment failure occurred. Propensity score matching (PSM, ratio: 1:1) based on age, sex, degree of proteinuria, eGFR, serum albumin and PLA2R antibody was applied to pair patients receiving Obinutuzumab with those receiving cyclosporine combined with corticosteroid. The primary outcome was defined as the combination of partial remission and complete remission at 24 months. Logistic regression model and Kaplan-Meier curves were applied to compare the efficacy of two treatments. After PSM, 30 patients receiving obinutuzumab and 30 patients receiving cyclosporine with corticosteroid were included in the study. By 24 months, a higher proportion of patients in the obinutuzumab group reached the primary endpoints compared to those treated with cyclosporine combined with corticosteroid. (Obinutuzumab vs. Cyclosporine: 86 % vs. 54 %, P=0.01; HR:5.42, 95%CI:1.49-19.69, P=0.01). Relapses of nephrotic syndrome were less frequent in the obinutuzumab group than in the cyclosporine group (Obinutuzumab vs. Cyclosporine: 15% vs. 52%, P=0.01; HR:0.16, 95%CI: 0.04-0.60, P=0.01). Obinutuzumab induced a faster immunologic remission at 6 months (Obinutuzumab vs. Cyclosporine: 91% vs. 59%, P<0.01; HR: 7.22, 95% CI: 1.40-37.25, P=0.02) and maintained a better persistent immunologic remission at 24 months [Obinutuzumab vs. Cyclosporine: 95% vs. 45%, P<0.01; HR: 24.44, 95%CI: 2.73-219.09, P<0.01]. Both treatment regimens were generally well-tolerated. The incidence of infection was lower in the obinutuzumab group than in the cyclosporine combined with corticosteroid group (Obinutuzumab vs. Cyclosporine: 23% vs. 50%, P=0.03). Our study demonstrated that obinutuzumab is associated with higher remission rates at 24 months, faster immunological remission and less infections than cyclosporine combined with corticosteroids in the treatment of PMN.

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2026-09-03 | Comparison of efficacy and safety among four therapeutic regimens in primary membranous nephropathy with high anti-PLA2R antibody titers: a single-center retrospective cohort study.

Patients with primary membranous nephropathy (PMN) and high anti-PLA2R antibody titers (> 150 RU/mL) often respond poorly to conventional treatments, and the optimal immunosuppressive regimen remains unclear. We conducted a retrospective study to compare the efficacy and safety of four regimens in this high-risk population: rituximab monotherapy (RTX regimen), tacrolimus plus glucocorticoids (TAC regimen), rituximab plus cyclosporine (RTX plus CsA regimen), and cyclophosphamide plus glucocorticoids (CTX regimen). We retrospectively enrolled 185 patients with biopsy-proven PMN and anti-PLA2R titers > 150 RU/mL. All patients completed the full treatment course and the 24-month follow-up period. The primary outcome was total remission (TR) at 24 months, and the secondary outcomes included complete remission (CR), partial remission (PR), immunological remission (IR), relapse rate, time to remission, and adverse events. At 24 months, the TR rates were 54.5% (24/44) for the RTX regimen, 52.2% (24/46) for the TAC regimen, 76% (38/50) for the RTX plus CsA regimen, and 73.3% (33/45) for the CTX regimen. Kaplan-Meier analysis revealed significant differences in cumulative IR rate (log-rank P = 0.0009), cumulative CR rate (log-rank P = 0.0072), and cumulative TR rate (log-rank P = 0.0005) among the four regimens. The TAC regimen had a significantly higher relapse rate (36.8%, 14/38) than the RTX plus CsA regimen (13.6%, 6/44) (log-rank P = 0.013). In this retrospective cohort, the RTX plus CsA regimen demonstrated durable efficacy, with a more favorable safety profile and a lower relapse rate. These preliminary findings support formal comparison of this regimen with current therapies in randomized controlled trials (RCTs).

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2026-09-01 | Abstract No: 335 Efficacy and safety of obinutuzumab β in primary membranous nephropathy: 104-week results from a phase 3, randomized, controlled trial

Primary membranous nephropathy (pMN) is driven by autoreactive B cells producing antibodies to podocyte antigens. Obinutuzumab β (MIL62) is a novel near-completely glycoengineered type II anti-CD20 monoclonal antibody to enhance antibody-dependent cellular cytotoxicity (ADCC) and deepen B-cell depletion.

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cell therapies

2026-01-05 | Toward precision immunotherapy in nephrology: 1 step forward.

Membranous nephropathy is an autoimmune disease most commonly caused by autoantibodies against the phospholipase A2 receptor 1. The pathogenicity of these autoantibodies offers the chance to develop highly specific therapies by targeting their cellular source (i.e., the autoreactive B cells). In this issue, Altun et al. provide further evidence for the feasibility of chimeric autoantibody receptor T cells to selectively eliminate these cells in phospholipase A2 receptor 1-associated membranous nephropathy, offering unprecedented specificity. Future studies need to address important open questions to evaluate the translational potential of this approach.

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2025-11-03 | Preclinical evaluation of antigen-specific B-cell depletion for phospholipase A2 receptor membranous nephropathy with chimeric autoantibody receptor T cells.

Phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, driven by autoantibodies that target PLA2R on kidney podocytes. Antibody-based therapy with rituximab induces broad B-cell depletion but is associated with risks of serious infection and reduced efficacy in patients with high proteinuria. Here, we determined the feasibility of developing chimeric autoantibody receptor T-cell (CAART) therapy for PLA2R-specific B-cell depletion in PLA2R MN. PLA2R-CAART was produced by T-cell lentiviral transduction. In vitro cytotoxicity and specificity were evaluated against B-cell lines targeting PLA2R immunodominant epitopes and primary PLA2R MN B cells. Adsorption of PLA2R MN IgG was evaluated to determine the extent of pathogenic autoantibody targeting by candidate PLA2R-CAART designs. Specific cytotoxicity, engraftment capability, and off-target toxicity were evaluated in a xenografted anti-PLA2R Nalm-6 preclinical mouse model, with additional toxicology screening by human membrane proteome arrays. We engineered CAARTs targeting key PLA2R epitopes to selectively deplete autoreactive B cells. C17- and C178-CAART (encompassing CysR, CTLD1, and CTLD7, with/without CTLD8 domains) were successfully expressed on primary T cells and demonstrated specific in vitro cytotoxicity against anti-PLA2R B-cell lines targeting CysR, CTLD1, and CTLD7 epitopes. In co-incubation assays with primary B cells or plasma from patients with MN, C17- and C178-CAART significantly reduced anti-PLA2R B cells and adsorbed 69-97% of plasma anti-PLA2R antibody reactivity. In vivo, C17- and C178-CAART treatment in the Nalm-6 xenograft model resulted in significant reduction in target cell outgrowth with C17-CAART showing slight but consistently increased cytotoxic activity. Specificity testing through comprehensive in vivo pathologic analysis and a high-throughput membrane proteome array analysis showed no significant off-target binding for either C17- or C178-CAART. Our findings establish preclinical proof-of-concept for the therapeutic potential of antigen-specific B-cell depletion by PLA2R-CAART. Additional studies are required to determine clinical feasibility of PLA2R-CAART for PLA2R MN therapy.

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2025-09-15 | Gut Microbiota and Membranous Nephropathy: Novel Molecular Mechanisms and Natural Product Therapeutic Strategies

Membranous nephropathy (MN), a clinically significant chronic kidney disease (CKD) variant comprising primary and secondary forms, adversely affecting both individual patients and societal healthcare resources. Currently, both conservative treatment regimens for low-risk patients and immunosuppressive therapies for moderate-to-high-risk patients in clinical settings are confronted with the dual challenges of suboptimal efficacy and pronounced side effects. This clinical dilemma underscores the pressing need for innovative therapeutic strategies that can optimize treatment outcomes while minimizing adverse reactions. The deepening research into the gut–kidney axis has revealed that gut microbiota plays a critical role in the progression of MN. Emerging microbiota-targeted therapeutic strategies, particularly probiotic supplementation, fecal microbiota transplantation (FMT), standardized traditional Chinese medicine (TCM) formulations, and precision prebiotic administration, are increasingly recognized as promising interventions in MN management. Leveraging the advantages of TCM and adopting an integrated approach of traditional Chinese and Western medicine for MN intervention hold promising research and application prospects. This article reviews recent advances in the gut-kidney axis in MN, explores new diagnostic biomarkers and therapeutic interventions targeting gut microbiota modulation, and provides a novel perspective for MN treatment rooted in the integration of traditional Chinese and Western medicine.

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2025-06-05 | The Role of Glomerular and Serum Expression of Lymphocyte Activating Factors BAFF and APRIL in Patient with Membranous and IgA Nephropathies.

Increased activity of B lymphocytes underpins many autoimmune conditions. A key component of the humoral immune response involves the A PRoliferation-Inducing Ligand (APRIL) and B-cell-activating factor (BAFF) system. These proteins are responsible for the activation, maturation, and survival of B lymphocytes, playing a pivotal role in autoimmunity. Therefore, targeting the BAFF/APRIL system proves promising for the treatment of various autoimmune diseases. Meticulous research into pathomechanisms of lupus nephritis (LN) has enabled the introduction of biological treatments targeting the BAFF-mediated pathway, significantly improving prognosis. In certain types of glomerulonephritis (GN), increased levels of the BAFF/APRIL system might be associated with higher proteinuria, elevated serum creatinine, but also with specific histopathological features. This indicates that biological therapies currently available could be repurposed for conditions where increased activation of B lymphocytes plays a critical role in the disease's pathophysiology. Understanding the mechanisms underlying autoimmune diseases will facilitate the adaptation of novel drugs for orphan diseases. That is why the use of chimeric antigen receptor T (CAR-T) cells as agents against B-cells receptor (BCR), represents a highly targeted and potentially optimal treatment approach. This study summarizes current knowledge about the role of the BAFF/APRIL system in lymphocyte activation mechanisms, particularly in GN. It also discusses existing biological treatments and explores future directions for drug development based on the CAR-T cell technology.

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2025-06-04 | Targeting B Cells and Plasma Cells in Glomerular Disease.

Loss of tolerance and the production of self-reactive autoantibodies by the humoral immune system are central to the pathogenesis of many glomerular diseases. These antibodies are produced by plasmablasts and plasma cells, the end products of B-cell lineage development within the bone marrow and secondary lymphoid tissues. In addition to antibody production, B cells also present antigen to T cells and produce proinflammatory cytokines. Nontargeted immunosuppression has shown efficacy in glomerular disease but is associated with multiple side effects, and there remains a high proportion of patients with resistant disease. In this article, we will review the biology of antibody-secreting cells and focus on therapeutics that specifically target B cells and plasma cells. We will review B-cell depletion strategies, including anti-CD20 monoclonal antibodies, B-cell-activating factor, and a proliferation-inducing ligand inhibition and B-cell receptor inhibition, highlighting their role in different glomerular diseases and outlining reasons for therapeutic resistance. We will also review plasma cell-directed therapies including proteasome inhibition and anti-CD38 therapies and discuss novel treatments including chimeric antigen receptor-T therapy and bispecific T-cell engagers.

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proteins

2026-07-03 | The Synthetic Melanocortin Agonist NDP-MSH Ameliorates THSD7A-Associated Membranous Nephropathy in an Active Immunization Mouse Model.

Melanocortin-based therapies have demonstrated protective effects in experimental membranous nephropathy (MN). However, existing evidence is derived exclusively from passive immunization models that lack direct involvement of human MN-associated autoimmunity, limiting translational relevance. A clinically relevant model is essential to more precisely define melanocortin efficacy and mechanisms in MN. To address this gap, we established an active immunization model of THSD7A-associated MN by immunizing mice with recombinant THSD7A antigen. This clinically relevant and accessible model recapitulated cardinal features of human MN, including insidious onset, progressive proteinuria, and characteristic histopathology such as subepithelial immune deposition, complement fixation along glomerular tufts, glomerular basement membrane thickening, and podocyte injury with foot process effacement and loss of homeostatic markers. Rescue treatment with the pan-melanocortin receptor agonist NDP-MSH significantly reduced proteinuria and mitigated glomerular damage and podocyte injury. This was accompanied by a marked reduction in circulating anti-THSD7A autoantibody levels, reduced glomerular immune deposition, and diminished complement activation. Mechanistically, ex vivo treatment of primed B cells isolated from diseased mice demonstrated that NDP-MSH directly inhibited plasma cell differentiation and autoantibody production. This suppression was accompanied by increased expression of microphthalmia-associated transcription factor (MITF) and downregulation of interferon regulatory factor 4 (IRF4), indicating activation of the MITF/IRF4 signaling axis, a pathway implicated in negative regulation of B cell differentiation. Collectively, these findings extend the therapeutic potential of melanocortin signaling to a preclinical model that closely mirrors human MN and provide mechanistic insight into its immunomodulatory actions. These results support further investigation of targeted melanocortin-based therapies for MN.

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2026-04-02 | The role of TOMM20 in Mediating TERT translocation to mitochondria and its impact on mitophagy in membranous nephropathy.

BACKGROUND: In idiopathic membranous nephropathy (MN)—now a leading glomerular cause of end-stage kidney disease—mitochondrial quality control via mitophagy is increasingly recognized as a determinant of podocyte fate, yet the molecular switches governing this process remain undefined. We postulated that translocase of the outer mitochondrial membrane 20 (TOMM20), a gatekeeper of mitochondrial import, transcriptionally regulates telomerase reverse transcriptase (TERT) and thereby modulates podocyte mitophagy and disease progression. METHODS: Bioinformatics analysis was performed to identify common targets between mitophagy-related genes and differentially expressed genes in membranous nephropathy. An in vitro model of membranous nephropathy was established by treating human podocytes with Zymosan-Activated Serum (ZAS). Subsequently, cells were transfected to overexpress TOMM20 or knock down TERT. Cellular viability, apoptosis, and levels of inflammatory cytokines (IL-6, IL-1β) were assessed. Additionally, indicators related to mitophagy, including reactive oxygen species (ROS), mitochondrial membrane potential (MMP), LC3-II/I ratio, PTEN-induced putative kinase 1 (PINK1), Mitochondrial-associated Parkin protein (mito-Parkin), and p62 levels, were measured in each group. An in vivo model of membranous nephropathy was established by intravenously injecting rats with sheep anti-rat FX1A serum. The expression of TOMM20 was inhibited to investigate its effects on mitophagy and TERT mitochondrial translocation in membranous nephropathy. RESULT: Bioinformatics analysis identified TOMM20 as a key target for intervening in the progression of membranous nephropathy via the mitochondrial pathway. In vitro, compared with human podocytes treated with heat-inactivated serum (HIS), ZAS intervention resulted in decreased cell viability, increased apoptosis, elevated levels of IL-6, IL-1β, and ROS, reduced MMP, decreased LC3-II/I ratio, PINK1, and mito-Parkin, and enhanced p62 expression. Overexpression of TOMM20 ameliorated ZAS-induced cell injury and enhanced mitophagy. Additionally, compared with the ZAS + Ctrl-siRNA group, knockdown of TERT exacerbated ZAS-induced cell injury and inhibited mitophagy. However, co-overexpression of TOMM20 promoted TERT mitochondrial translocation and mitigated the adverse effects of TERT-siRNA transfection in human podocytes. In vivo, upregulation of TOMM20 improved renal function in rats, promoted TERT mitochondrial translocation, and activated mitophagy. CONCLUSION: TOMM20 activates mitophagy in membranous nephropathy by promoting the mitochondrial translocation and expression of TERT (The graphical abstract was shown in Fig. 1).

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2026-03-23 | MHC class II and PLA2R investigating the epitope presentation deficits driving antibody production in membranous nephropathy.

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults, particularly affecting the glomerular region of the kidney. While MN can occur at any age, its onset typically peaks in individuals in their 50s. It is characterized by subepithelial immune complex deposits that thicken the glomerular basement, impairing filtration and causing proteinuria. While secondary MN is linked to conditions, such as hepatitis B, malignancies, autoimmune diseases, and drug exposure, primary MN (PMN) is often autoimmune in origin and is distinguished by the presence of autoantibodies against the M-type phospholipase A2 receptor (PLA2R) predominance of IgG4, which are absent in most secondary forms. The discovery of PLA2R antibodies has revolutionized PMN diagnosis and monitoring, offering a non-invasive biomarker that correlates with disease activity and remission. Diagnostic techniques, such as immunofluorescence and transmission electron microscopy, reveal characteristic IgG4 and C3 deposition, and podocyte damage. For better prognostic and diagnostic outcomes, reliance on PLA2R-IgG4 specific antibodies is needed, as this approach offers higher specificity and sensitivity compared to simply detecting the concentration of PLA2R-IgG antibodies. While there are better diagnostic and therapeutic options, challenges remain in fully elucidating the mechanisms behind antibody production and their role in disease progression. This review highlights the central mechanism that triggers PLA2R-associated immune responses by T cells, which examined these molecular interactions. Additionally, identifying novel PLA2R epitopes that bind to MHC II molecules, which is an important step moving from the current unspecific immunosuppressive therapies toward antigen-specific MN treatments.

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2025-09-25 | Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.

Despite observational links between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP-1RAs on chronic kidney disease (CKD) and related renal outcomes. Using large-scale Genome - Wide Association Study (GWAS) data, we applied two-sample Mendelian randomisation (MR) to estimate the causal effects of GLP-1RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome - Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort-specific studies. Positive control analyses revealed that genetically predicted GLP-1R activation was associated with reduced levels of HbA1c (p = 4.93E-15) and blood glucose (p = 9.73E-5), as well as a decreased risk of T2DM (p = 2.45E-4) and DN (p = 6.35E-4), fully validating the reliability of the genetic instruments. Genetic proxies for GLP-1R activation lowered risks of CKD (odds ratio [OR] = 0.83, p = 9.22E-9), immunoglobulin A nephropathy (IgAN) (OR = 0.70, p = 2.11E-3) and kidney function preservation (β = 0.01, p = 9.11E-3), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high-density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy. This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.

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2025-09-04 | Exploring immunological alterations of B cells in peripheral immunity via single-cell RNA sequencing: insights into primary membranous nephropathy.

Primary Membranous Nephropathy (PMN) is characterized by dysregulated immune responses, with B cells playing critical roles in disease pathogenesis. However, the immunopathogenic mechanisms underlying B cell involvement in PMN remain elusive. We employed single-cell RNA sequencing on peripheral blood mononuclear cell samples (PBMC) obtained from 6 patients with PMN and 3 healthy controls (NC) to explore the transformation of B cells and their interaction with immune cells. Compared with NC, the most significant alterations were in plasma cells and regulatory B (Breg) cells in PMN patients. Within plasma cells, Subcluster 0 was increased in PMN patients and exhibited enhanced autoimmunity. Breg subset B10 cells were elevated in PMN patients and displayed increased immune regulatory capacity, marked by enhanced cytokine and interleukin-10 production. B cell activating factor (BAFF) and galectin-9, which were secreted by CD14 monocyte, as potential regulators of plasma and Breg cells activity. Additionally, serum galectin-9 levels increased in PMN patients and showed a correlation with proteinuria and renal function in PMN. We reveal novel insights into the heterogeneity and functional diversity of B cells in patients with PMN. And revealed distinct roles for subgroup 0 plasma cells and B10 Breg cells in the pathogenesis of PMN. Furthermore, targeting B cells, such as galectin-9, presents promising opportunities for modulating the immune response in patients with PMN.

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2026-09-30 | Immunotherapy of membranous nephropathy: strategic evolution from CD20 monoclonal antibodies to future vaccines.

Membranous nephropathy (MN) arises from autoantibody-mediated attack on podocyte antigens, with immune deposits forming subepithelially at the glomerular basement membrane to trigger complement activation and subsequent podocyte damage, eventually manifesting as proteinuria. Traditional therapy hinges on nonspecific immunosuppression, which is characterized by modest effectiveness and a substantial side-effect profile. In recent years, CD20-targeting monoclonal antibodies, most notably rituximab (RTX), have curtailed autoantibody production through peripheral B-cell depletion and consequently emerged as a first-line treatment option for patients at intermediate-to-high risk. However, a considerable proportion of patients still show no initial response or later relapse. Resistance mechanisms are heterogeneous, encompassing Fc receptor polymorphisms, plasma cell longevity, and anti-RTX antibody formation. To address these hurdles, novel biologics that target the BAFF/APRIL signaling axis, CD38-positive plasma cells, and the complement cascade have entered the clinical arena, further broadening the immunotherapeutic landscape for MN. In parallel, as our understanding of immune memory and autoantibody-generating cells continues to expand, a so-called "immune reset" approach is gaining traction, with its core rationale being the restoration of a robust yet self-tolerant immune system. This review charts the progression of MN therapies, from CD20 monoclonal antibodies and their optimized use, through novel biologics, to vaccine-based strategies that target autoantibody-specific B or T cells (including CAAR-T, Treg therapies, B-cell epitope vaccines, and T-cell vaccines). We further consider their theoretical promise for inducing antigen-specific immune tolerance and the barriers to clinical implementation.

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2026-04-05 | MiR-423-5p inhibition alleviates podocyte apoptosis in membranous nephropathy by targeting WT1/β-catenin axis.

Membranous nephropathy (MN) is the most common pathological type of primary nephrotic syndrome in adults. MicroRNAs (miRNAs) are involved in the pathogenesis of several renal diseases. Here we investigated the potential involvement of miRNAs in MN progression. miRNA sequencing was performed in the urinary exosomes of MN patients and normal controls (three cases per group). An experimental mouse MN model induced by cationic bovine serum albumin (CBSA) and MPC5 podocytes intoxicated by puromycin aminonucleoside (PAN) were used in this study. Compared with the normal controls, 19 miRNAs were downregulated and 13 upregulated in the urinary exosomes of MN patients. In an expanded cohort, we confirmed that miR-423-5p was significantly upregulated in the urinary exosomes of MN patients. Urinary particle concentrations and size distribution were assessed using transmission electron microscopy and NanoSight. Similarly, upregulated miR-423-5p was observed in PAN-intoxicated MPC5 cells. Lentiviral vector-mediated inhibition of miR-423-5p suppressed podocyte apoptosis and inactivated β-catenin signaling. Upon miRNA database prediction, WT1 was identified as a target of miR-423-5p. Consistently, downregulated WT1 expression in PAN-intoxicated MPC5 cells was rescued by miR-423-5p inhibition. The target relationship between miR-423-5p and WT1 mRNA 3'UTR was validated by the dual luciferase reporter assay. Knockdown of WT1 reversed the inhibitory effect of LV-anti-miR-423-5p on podocyte apoptosis and β-catenin signaling. Notably, miR-423-5p inhibition and WT1 overexpression attenuated renal injury and podocyte apoptosis in MN mice. Our study demonstrates that miR-423-5p expression is upregulated in urinary exosomes of MN patients and modulates WT1, affecting podocyte apoptosis by the β-catenin signaling pathway. Inhibition of miR-423-5p action may protect against MN.

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2025-05-08 | Rituximab, tacrolimus, cyclophosphamide and cyclosporin in primary membranous nephropathy with nephrotic syndrome: comparison of safety profiles, effect on remission rate, 24-h urinary total protein, serum albumin, and serum creatinine levels using network meta-analysis.

To compare the efficacy and safety of four immunosuppressive therapies, either alone or in combination, for primary membranous nephropathy through a network meta-analysis. A literature search was conducted for randomized controlled trials (RCTs) of Cyclophosphamide (CTX), Cyclosporin (CsA), Tacrolimus (TAC), and Rituximab (RIT) in the treatment of primary membranous nephropathy. Two researchers independently screened articles, extracted data, and evaluated the quality. Outcome indicators included dichotomous variables and continuous variables, which were represented by risk ratios (RR) and mean differences (MD), respectively. Then, various interventions were ranked according to the surface under the cumulative ranking curve (SUCRA). A total of 21 randomized controlled trials (RCTs) were included, encompassing 1396 patients. In terms of the overall response rate (ORR), RIT+TAC was superior to CsA (RR = 0.15, 95% CI: 0.04, 0.54), CTX (RR = 0.09, 95% CI: 0.03, 0.31), and RIT (RR = 7.06, 95% CI: 2.29, 21.80). The SUCRA value of RIT+TAC was the highest, reaching 93.5%. Regarding the total 24-h urinary protein (24UTP), RIT+TAC was better than RIT (MD = 17.05, 95% CI: 6.49, 44.79), RIT+CTX (MD = 6.99, 95% CI: 2.55, 19.17), TAC (MD = 0.12, 95% CI: 0.07, 0.18), CsA (MD = 0.06, 95% CI: 0.00, 0.86), and CTX (MD = 0.05, 95% CI: 0.03, 0.10). The SUCRA value of RIT+TAC was the highest, at 99.4%. For serum albumin, RIT+CTX was superior to CTX (MD = 0.00, 95% CI: 0.00, 0.29), and the SUCRA value of RIT+CTX was the highest, at 76.7%. For serum creatinine (Scr), RIT+TAC was better than TAC (MD = 0.00, 95% CI: 0.00, 0.13), and CsA was better than TAC (MD = 7.86e+07, 95% CI: 3.65e+06, 1.69e+09). The SUCRA value of RIT+TAC was the highest, at 79.9%. In terms of the incidence of adverse reactions, CTX had a higher rate than RIT+CTX (RR = 11.12, 95% CI: 1.34, 92.15). The SUCRA value of RIT+CTX was the lowest, at 5.3%. In terms of improving ORR, reducing 24UTP and lowering Scr, the RIT+TAC regimen may be the most optimal. Conversely, RIT+CTX demonstrated the best efficacy in improving ALB and also exhibited relatively better safety profile.

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2025-02-20 | CD8+ Regulatory T Cells Induced by Peptide Vaccination Ameliorates Experimental Model of Membranous Nephropathy.

CD8+ regulatory T cells (Tregs) are cross-protective across multiple animal models of autoimmunity. Recently, specific peptides from a yeast-peptide-major histocompatibility complex library that expanded CD8+ Tregs in murine experimental multiple sclerosis were reported. Whether these peptides also expand CD8+ Tregs and protect against Heymann nephritis (HN), an experimental model of membranous nephropathy is unknown. We aimed to assess the efficacy of peptide vaccination to induce CD8+ Tregs in HN. Lewis rats were immunised with Fx1A/complete Freund's adjuvant to induce HN and received peptide vaccination 1 week before (prevention vaccination) or 1 week after disease induction (treatment vaccination). To understand whether the effect of peptide vaccination was mediated by CD8+ Tregs, we adoptively transferred CD8+ T cells 1 week after peptide vaccination into HN rats. Prevention vaccination, but not treatment vaccination, significantly reduced anti-Fx1A autoantibody levels and serum creatinine. Both prevention and treatment vaccination reduced histological kidney injury. mRNA expression of Helios, the major CD8+ Treg transcription factor, was upregulated in both the spleen and kidney with prevention vaccination and in the kidney with treatment vaccination. Adoptive transfer of CD8+ T cells after peptide vaccination significantly reduced serum creatinine, proteinuria, histological kidney injury, anti-Fx1A autoantibody levels, germinal centre formation, and mRNA expression of markers of T follicular helper cells (Bcl6, interleukin-21), T helper 1 cells (interferon-γ, Tbet) and T helper 17 cells (interleukin-6, interleukin-17). Peptide vaccination induces CD8+ Tregs that ameliorate induction of experimental membranous nephropathy which may represent a further peripheral regulation of autoimmunity.

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2025-01-15 | Effectiveness of a Novel PLA2R1 Knock-In Rat Model in Repairing Renal Function Damage.

Phospholipase A2 receptor 1 (PLA2R1) exists in many animals and plays an important role in membranous nephropathy. In this study, we aimed to evaluate a PLA2R1 knock-in rat model with repaired kidney function to study the molecular mechanisms of membranous nephropathy. We constructed the PLA2R1 knockout [PLA2R1(-)] model and PLA2R1 knock in [PLA2R1(+)] model in rats. Consistent complement C3 and IgA expression was confirmed through colocalization studies. Urinary biochemical indicators were performed using Automatic Biochemistry Analyzer. The complement C3, IgG, and Nephrin were detected by immunofluorescence assay. The expression levels of complement C3, IgA, and PLA2R1 were detected by western blot. The differential expression proteins (DEPs) between control and PLA2R1(+) models were detected by liquid chromatography with tandem mass spectrometry. The PLA2R1(-) model showed proteinuria, complement C3 aggregation, and IgA and IgG deposition in the glomerulus. Comparing with the PLA2R1(-) model, the PLA2R1(+) model, the deposition of complement C3 and IgA in the glomerulus did not completely disappear, and IgG expression weakened. Moreover, the absolute value of urinary protein was much lower in the PLA2R1(+) model than in the PLA2R1(-) model, and some of the humanized PLA2R1 gene fragments repaired some of the kidney functions. Humanized PLA2R1-insertion in rats can repair part of the renal function and reduce proteinuria, which will help in studying the molecular mechanisms of membranous nephropathy, as well as the entire membranous nephropathy-related system and complement activation signaling pathway.

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