Rituximab (RTX) is a first-line therapy targeting B cells; however, 30%-40% of patients exhibit treatment resistance or relapse. Studies have shown that anti-rituximab antibodies (ARA) may lead to RTX resistance through mechanisms such as drug neutralization. The objective of this study is to explore the relationship between the emergence of ARA and the clinical efficacy of initial RTX treatment in adult MN. Patients with MN who received RTX therapy were included in this study. Clinical data and laboratory results of the patients were collected, and ARA levels in serum samples were measured using a commercial ELISA kit. The impact of ARA on the clinical outcomes of MN patients treated with RTX was analyzed. Among 58 patients with membranous nephropathy who received initial RTX treatment, 11 patients (19.0%) tested positive for ARA. ARA were identified after a median of 9.3 months (IQR 8.2-11.1) following the last RTX injection. Among the patients who received initial RTX treatment and were monitored for over 6 months, ARA-positive patients (n=11) exhibited a higher relapse rate (80.0% vs. 24.1%, P=0.029) than ARA-negative patients (n=41), which was also confirmed by Kaplan-Meier analysis (log-rank test, P=0.027). At 6 months post-initial RTX, ARA-positive patients demonstrated higher B cell levels (p=0.021). Four RTX-resistant and ARA-positive patients achieved clinical remission with obinutuzumab, with a median remission time of 4.8 months (IQR 3.0-6.8). This study confirms that adult patients with MN who are ARA positive have a higher relapse rate after initial RTX treatment. Patients who are RTX-resistant and ARA positive can achieve rapid clinical remission after receiving obinutuzumab treatment.

Anti-glomerular basement membrane (GBM) nephritis is an autoimmune disease which typically presents rapid progressive glomerulonephritis. A subacute course and relapse are rare. We report the case of a 23-year-old woman with no prior medical history, who was referred for proteinuria and elevated serum creatinine (Cr) level of 3.3mg/dL. Two weeks later, upon her visit to our hospital, her creatinine level was 3.2mg/dL. Five months prior, her Cr was 1.2mg/dL. Urinalysis showed 2.3g/gCre of proteinuria and microscopic hematuria. The anti-GBM antibody titer was high at 135 U/mL. Anti-neutrophil cytoplasmic antibody and anti-nuclear antibody were negative. Kidney biopsy revealed crescentic glomerulonephritis with advanced glomerular sclerosis and diffuse linear staining of IgG along the GBM. She received corticosteroids, intravenous cyclophosphamide and 7 sessions of plasma-exchanges. After three months, her Cr improved to 1.9mg/dL and the antibody became undetectable. However, she self-discontinued prednisolone 2months later. Three weeks after discontinuation, she presented with nausea, oliguria. Her Cr level had risen to 9.6mg/dL and the anti-GBM antibody titer was 4.0U/mL. A second kidney biopsy showed progression of glomerulosclerosis, endothelial injury in the arterioles characterized by fibrin deposition, and extensive tubulointerstitial damage. Despite resuming treatment, her kidney function did not recover, and she required maintenance hemodialysis. This case highlights two atypical features of anti-GBM nephritis: subacute progression over 5months, and relapse after antibody negativity triggered by steroid discontinuation. This emphasizes the importance of adherence to immunosuppressive therapy, even after serological remission.

This single-center retrospective cohort study divided 176 adults with biopsy-proven primary glomerulonephritis (GN) between 2014 and 2021 into 4 groups based on cortical interstitial fibrosis (IF) percentage. The primary outcome was disease progression, defined as a ≥ 40 % decline in estimated glomerular filtration rate (eGFR) and/or the need for dialysis. The secondary outcome was complete remission, defined as proteinuria < 300 mg/24 hours. Baseline proteinuria and serum creatinine increased with greater IF severity, while eGFR decreased. Kaplan-Meier analysis showed a higher risk of progression in patients with severe IF. After adjusting for glomerulosclerosis, baseline eGFR, proteinuria, and treatments, IF severity remained an independent predictor of progression (HR 3.15). IF was not independently associated with achieving complete remission. Stratified analyses suggested a stronger association in immunoglobulin-A (IgA) nephropathy, while results for focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN) were inconclusive due to limited statistical power. In summary, the severity of IF on diagnostic biopsy is a strong and independent prognostic factor for disease progression in primary glomerular diseases, supporting its routine standardized assessment to improve risk stratification and personalized patient management.

We previously reported an association between cnm-positive Streptococcus mutans in the oral cavity and IgA nephropathy. However, whether this association is specific to IgA nephropathy among various kidney diseases remains unclear. This study aimed to investigate the presence of cnm-positive S. mutans in patients who underwent a renal biopsy and to evaluate its association with different kidney disease subtypes. We included 294 patients who underwent a renal biopsy and provided informed consent between May 2017 and March 2024 (renal biopsy group). The healthy control group consisted of 81 individuals with an estimated glomerular filtration rate > 60mL/min and no proteinuria. Saliva samples were collected from all participants, stored at - 20°C, and analyzed by polymerase chain reaction to detect S. mutans and cnm-positive S. mutans. Associations between cnm-positive S. mutans and the histopathological diagnosis were subsequently assessed. The prevalence of cnm-positive S. mutans was significantly higher in the renal biopsy group than in the control group (21.8% vs. 11.1%, p < 0.05). Among kidney disease subtypes in the renal biopsy group, a higher prevalence of cnm-positive S. mutans was observed in patients with lupus nephritis (31.6%), membranous nephropathy (29.2%), and IgA nephropathy (23.6%). However, a logistic regression analysis identified a significant association only between cnm-positive S. mutans and IgA nephropathy (p < 0.05). This study suggests that cnm-positive S. mutans is significantly associated with IgA nephropathy.

Membranous nephropathy is a disease that has been well documented, yet its etiopathogenesis has not been fully clarified and the distinction between its primary and secondary forms has not been completely categorized. The discovery of new antigens and antibodies reveals different percentages of positivity in secondary membranous nephropathy, which is a cause of great confusion and ambiguity not only in diagnosis but also in the choice of a therapeutic approach. The aim of this review is to summarize the literature on newly discovered antigens and antibodies, and to propose a pathogenetic model based on the role of the complement system and its activation pathways. In this model, antigens are categorized based on the type of immunoglobulin deposits and the putative complement pathways that they activate, which can help to differentiate primary from secondary membranous nephropathy. The model also reflects how the deposition of foreign antigens in the basement membrane can activate both the lectin and classical complement pathways, which may explain why positive antibodies are observed in both primary and secondary forms of membranous nephropathy.

Primary glomerulonephritis (GN) is a heterogeneous group of kidney disorders where understanding their pathophysiology remains incomplete. Despite the diagnostic potential of high-throughput proteomics, constrained proteomic depth and a reliance on binary comparisons have left the feasibility of using systemic signatures to differentiate multiple GN subtypes largely unexplored. To identify protein signatures that noninvasively differentiate major primary glomerular disease subtypes and provide mechanistic insights, we performed large-scale systemic proteome profiling of 5,416 plasma proteins via Olink Explore HT in a discovery cohort (n=147) and an external validation cohort (n=85) of Korean participants (mean age, 41±13 years; 46% female). The study population included patients with four GN subtypes-focal segmental glomerulosclerosis, IgA nephropathy, minimal change disease, and membranous nephropathy-alongside healthy controls. We developed a machine learning model using logistic regression with elastic net regularization to classify disease groups based on proteomic profiles and evaluated its performance in the independent validation cohort. Plasma proteome profiles were distinct among disease subtypes, emerging as a significant source of data variation independent of conventional markers such as eGFR or proteinuria levels. The machine learning model performed robustly in both the discovery and validation cohorts, achieving an area under the receiver operating characteristic curve (AUROC) > 0.8 for differentiating minimal change disease, membranous nephropathy, and IgA nephropathy. The model, even without clinical information, correctly identified 93% of minimal change disease cases (14 of 15) and 63% of IgA nephropathy cases (20 of 32), but its performance was limited for focal segmental glomerulosclerosis, with only 21% of cases (3 of 14) correctly classified. Functional analysis of key proteins highlighted distinct biological pathways, such as hemostasis in minimal change disease. We identified distinct systemic proteome signatures for primary glomerular diseases, where disease subtype served as a major determinant of proteomic variance alongside conventional clinical markers. Machine learning models demonstrated robust discriminatory performance for minimal change disease, membranous nephropathy, and IgA nephropathy, underscoring the potential for proteome-based classification.

Renal survival is crucial in patients with idiopathic membranous nephropathy (IMN). Our aim was to identify baseline clinical and histopathological predictors of long-term renal survival in patients with IMN. In this retrospective, single-center cohort study, we reviewed 50 adults with biopsy-proven IMN (January 2009 - February 2019) who completed at least 60 months of follow-up. We recorded baseline age, sex, serum creatinine, serum albumin, 24-hour proteinuria, and the total renal chronicity score (Mayo Clinic Chronicity Score). Chronicity was classified as minimal (score 0-1) or non-minimal (score ≥2). The renal endpoint was defined as a ≥two-fold increase in serum creatinine from baseline or the initiation of renal replacement therapy (RRT). Predictors of renal survival were assessed using univariate and multivariate Cox regression; renal survival probability was illustrated with Kaplan-Meier analysis. During the 5-year follow-up, 20 out of 50 patients (40%) reached the renal endpoint. Kaplan-Meier curves demonstrated a significant divergence: only 1 out of 30 patients (3.3%) in the minimal-chronicity group progressed, while 19 out of 20 patients (95%) with non-minimal chronicity experienced either a doubling of creatinine or required RRT (log-rank p<0.001). In univariate analysis, older age, higher serum creatinine, lower serum albumin, albumin levels below 3g/dL, and non-minimal chronicity were associated with poor outcomes. Multivariate Cox regression confirmed three independent predictors: baseline serum creatinine (HR 2.38, 95% CI 1.37-4.11, p=0.02), serum albumin (HR 0.43, 95% CI 0.23-0.80, p=0.008), and non-minimal chronicity score (HR 14.4, 95% CI 3.2-64.6, p < 0.001). In IMN, a high total renal chronicity score on biopsy, elevated baseline serum creatinine, and hypoalbuminemia (&lt;3g/dL) independently predict poor 5-year renal survival. Early recognition of non-minimal chronicity may facilitate timely therapeutic intervention and closer monitoring to mitigate progression to end-stage kidney disease.

Prospective Cohort Study of Obinutuzumab in Rituximab-Resistant Primary Membranous Nephropathy.

Development of machine learning-driven non-invasive diagnostic models for idiopathic membranous nephropathy in Chinese patients.

This is a single-center retrospective cohort study on the demographics and clinical outcomes including the response to therapy of patients with primary membranous nephropathy (PMN) over the past decade. With the spread of diverse therapeutic agents available today, this study seeks to present an interesting array of varied responses. All histology-proven PMN cases diagnosed between 2008 and 2018 were analyzed for their clinical, laboratory, and histological characteristics including treatment that could influence disease progression and renal outcome. There were two sub-groups of patients, those with nephrotic syndrome and those without nephrotic syndrome. All secondary causes of secondary membranous nephropathy were excluded. The response to therapy including RAS blockers, steroids, and immunosuppressants all showed a consistent reduction of proteinuria with therapy for the whole cohort, nephrotic as well as non-nephrotic syndrome with only 10% of the 102 patients in end-stage renal disease (ESRD) at 10 years. Our data show that membranous nephropathy is a disease responsive to most forms of therapy with decreasing proteinuria. The progression of the disease is slow with a gradual decline to ESRD.

The Complement System in Membranous Nephropathy: Pathogenesis and Targeted Therapies

While the pathogenic role of autoantibodies targeting the podocyte protein THSD7A in membranous nephropathy (MN) is well described, the consequences of autoantibody binding for podocyte homeostasis and the function of THSD7A remain unclear. Here, we induced an MN model in control and podocyte-specific Thsd7a knockout (Thsd7a-/-) mice using rabbit anti-THSD7A antibodies, followed by transcriptome and proteome analyses. Anti-THSD7A antibodies in WT mice caused significant loss of key slit diaphragm (SD) proteins such as nephrin and NEPH1, without transcriptional downregulation. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including disruptions in podocyte adhesion, cytoskeletal dynamics, and marked upregulation of ubiquitin-proteasome system components, cathepsins and ADAM proteases. Notably, experiments in C3-deficient mice revealed that proteolytic activation and SD protein loss are driven by complement-independent pathways. While Thsd7a-/- mice only displayed a mild phenotype under basal conditions, they were completely protected from MN development upon anti-THSD7A antibody transfer. Finally, interactomic analysis identified a protein complex including THSD7A and integrin α3, linking THSD7A complexes to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling in MN. Thus, anti-THSD7A antibodies induce profound molecular reconfiguration, including dysregulated proteolytic systems via a complement-independent pathway, revealing potential therapeutic targets in MN.

Amyloidosis is a group of heterogeneous diseases characterized by the deposition of amyloid fibrils in various organs and tissues. Membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults. We report three cases of early-stage MN occurring concurrently with distinct types of renal amyloidosis: apolipoprotein A-I (AApoA-I) amyloidosis, leukocyte chemotactic factor 2 (ALECT2) amyloidosis, and monoclonal immunoglobulin light-chain (AL) amyloidosis. Each case represents a different pathogenic mechanism, therapeutic approach, and clinical prognosis. These cases underscore the pivotal role of renal pathology in the accurate diagnosis of patients with coexisting amyloidosis and MN. Correct classification of renal amyloidosis is essential for guiding therapy and predicting outcomes. When amyloidosis coexists with MN or other potentially treatable renal diseases, therapeutic decisions should prioritize the condition with the greater potential for organ damage or the one most responsive to available treatment.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated renoprotective effects in chronic kidney disease (CKD), but their therapeutic potential in membranous nephropathy (MN) remains unclear. In this study, analysis of the GEO database revealed that CAV1 expression is significantly upregulated in MN, suggesting a potential role in disease progression. A rat MN model was induced with cationic bovine serum albumin (C-BSA) and treated with canagliflozin (10 mg/kg). Renal function and histopathological changes were assessed. In vitro, MPC-5 podocytes were injured with complement C5a and treated with canagliflozin or CAV1 overexpression to explore mechanisms related to mitochondrial fission and apoptosis. Canagliflozin treatment markedly reduced proteinuria, increased serum albumin, and improved renal histology, including attenuation of mesangial hyperplasia, basement membrane thickening, and subepithelial electron-dense deposits. It also restored the expression of podocyte markers nephrin and podocin, inhibited the CAV1/PKA/DRP1 signaling pathway, preserved mitochondrial membrane potential, reduced pro-apoptotic markers Bax and cleaved caspase-3, and upregulated the anti-apoptotic protein Bcl-2. These findings suggest that canagliflozin alleviates podocyte injury and renal damage in MN by suppressing mitochondrial fission and apoptosis through inhibition of the CAV1/PKA/DRP1 signaling axis.

Anti-phospholipase A2 receptor (PLA2R) antibody is a highly specific serological marker for primary membranous nephropathy, with a detection rate of <2% in minimal change disease (MCD). This case represents the first report of PLA2R-positive adult MCD complicated by active pulmonary tuberculosis (TB) and systemic osteoarthropathy, highlighting the potential for chronic infection to induce PLA2R antibodies through inflammatory activation or molecular mimicry. A 73-year-old male with 7-year steroid-dependent nephrotic syndrome developed pulmonary TB and systemic osteoarthropathy during immunosuppressive therapy. Serial renal biopsies confirmed MCD/focal segmental glomerulosclerosis (FSGS) without membranous nephropathy features. PLA2R antibody was transiently positive (16.6 RU/mL) during active TB but turned negative after anti-TB treatment. TB was confirmed by next-generation sequencing. A multidisciplinary strategy was implemented: rifapentine replaced rifampicin to maintain tacrolimus levels; rituximab was administered for refractory proteinuria; and TB was treated with a 9-month regimen. Osteoarthropathy was managed with Tripterygium glycosides and joint injections. Following rituximab administration, 24-hour urinary protein decreased from 6.32 g to 1.5 g. TB was controlled with sputum conversion within 2 months. PLA2R antibody became negative post anti-TB therapy, supporting the hypothesis of infection-induced seropositivity. No renal function decline or TB dissemination occurred. This case suggests that chronic infections like TB may transiently induce PLA2R antibodies via inflammatory activation, highlighting the need for dynamic serologic and histopathologic correlation to avoid misdiagnosis in PLA2R-positive non-MN patients. Multidisciplinary management is critical to balance immunosuppression and infection control.

Regulatory T (Treg) cells suppress autoimmunity and restrain inflammatory responses, showing promising potential in autoimmune glomerulonephritis (GN) therapy with minimizing nonspecific immunosuppression. Although low-dose interleukin-2 (IL-2) has been shown to promote Treg expansion, its clinical utility is constrained by its short half-life and concurrent effector T cell activation. An IL-2 mutein STS718 was engineered by introducing point mutations and fusing it to a human IgG1 Fc domain. The molecular characteristics of STS718, including its affinity, selectivity, and half-life were evaluated. In vivo expansion of Treg cells by STS718 was assessed in mice and cynomolgus monkeys. Experimental autoimmune GN models, including crescentic GN and membrane GN, were established to test the therapeutic potential of STS718. The ability of STS718 to induce human functional Treg cells was confirmed using human naïve CD4+ T cells from donors and peripheral blood mononuclear cells (PBMCs) from autoimmune GN patients. STS718 exhibited a lower affinity for IL-2 receptor (IL-2Rβγ) and comparable affinity for IL-2Rαβγ compared with wild-type IL-2-Fc of human, rat, and mouse, as well as a prolonged half-life. STS718 expanded Treg cells in mice and cynomolgus monkeys in a manner that was dependent on either time or dose, without significantly affecting the effector T cell activation. Proof-of-concept experiments confirmed that sustained Treg expansion mediated by STS718 effectively suppressed the progression of autoimmune GN models, exhibiting superior efficacy compared to wild-type IL-2-Fc. In addition, the STS718 was capable of inducing the expansion of human functional Treg cells from either naïve CD4+ T cells of healthy donors or PBMCs from autoimmune GN patients. Collectively, these findings suggest that engineered IL-2 mutein which selectively expands Treg cells in vivo holds significant promise as an alternative immunotherapeutic strategy for controlling autoimmune GN while reducing nonspecific immunosuppression.

Exposure to fine particulate matter (PM2.5) has been associated with an increased risk of chronic kidney disease (CKD), and exposure to PM2.5 is known to aggravate ischemia/reperfusion injury-induced acute kidney injury (AKI) in mice. The impact of PM2.5 concentration on the incidence of CKD, AKI, and glomerulopathy in the megacity of Sao Paulo is has never been described. We analyzed meteorological variables, PM2.5 concentrations, and hospital admissions in São Paulo, Brazil, from 2011 to 2021. Admissions were categorized by age and sex. We analyzed 37,170 records, 55% representing males. Exposure to PM2.5 was found to increase CKD hospitalization risk by 1-4 times (95% CI: 1.009-1.18), across different age groups and exposure levels. Long-term exposure to a high PM2.5 concentration (65μg/m3) increases that risk considerably for individuals aged 19-50years (relative risk [RR]: 1.01; 95% CI: 1.005-1.015 and RR: 1.013; 95% CI: 1.01-1.018, respectively), the risk being ≤ 2.5 times higher in men aged 51-75years (RR: 1.025; 95% CI: 1.015-1.032). The AKI hospitalization risk after prolonged exposure to high PM2.5 concentrations was highest for men aged 19-50years (RR: 1.04; 95% CI: 1.012-1.07). The risk of glomerulopathy was highest in the < 40-year age group, especially among men exposed to concentrations of 15μg/m3 (RR: 1.02; 95% CI: 1.007-1.025) and 65μg/m3 (RR: 1.07; 95% CI: 1.02-1.11). Such exposure also increased the cumulative risk of hospitalization for membranous nephropathy, regardless of sex and age. Our findings underscore the urgent need to develop global strategies for air pollution reduction.

Membranous nephropathy as a late manifestation of unrecognized IgG4-related disease — a case report and literature review

Idiopathic refractory membranous nephropathy (IRMN) is a subset of nephrotic syndrome with a high risk of progression to end-stage renal disease, yet treatment options remain limited. Obinutuzumab, a humanized type II anti-CD20 antibody, induces efficient CD20+ cell depletion, leading to favorable immunological and proteinuria responses in IRMN. This study sought to assess the effectiveness and safety of obinutuzumab for treating IRMN. A total of 31 patients with IRMN were enrolled and received obinutuzumab therapy. They were followed for 12 months. The primary endpoint was the remission rate (complete or partial remission). Secondary outcomes included changes in proteinuria, serum albumin, serum creatinine, anti-PLA2R antibody levels, CD20/CD19 cell counts, and adverse events. At 12 months, the overall remission rate was 80%, with 16% achieving complete remission and 64% achieving partial remission. The median time to remission was 4.5 months (IQR 2.0-7.0 months). The immunological remission rates at 3, 6, 9, and 12 months were 70, 83, 90, and 93%, respectively. Regarding anti-PLA2R antibodies, 80% of patients showed a rapid decline within the first 3 months (p < 0.001), with 64% achieving a > 50% reduction from baseline by month 3. At the last follow-up, all patients had achieved seroconversion to anti-PLA2R antibody negativity. Adverse events included infusion-related reactions such as fever, hypotension, tachycardia, and flushing. No deaths occurred. Obinutuzumab effectively induces remission in patients with IRMN and demonstrates a tolerable safety profile.

Renal biopsy has certain limitations for diagnosing membranous nephropathy (MN). The aim is to explore the value of MRI for diagnosing MN. MN patients were divided into two subgroups based on estimated glomerular filtration rate, including the mild group and moderate to severe group. Quantitative T1 mapping and renal blood flow (RBF) of bilateral kidneys were measured, including renal cortical T1 mapping (cT1) value, medullary T1 mapping (mT1) value, cortical RBF value (cRBF), and medullary RBF (mRBF) value. The Student's t-test, Mann-Whitney U test, chi-square test, and one-way analysis of variance were used. Forty-seven MN patients and 54 matched healthy controls (HC) were prospectively enrolled. The cT1 and mT1 average values of HC were significantly lower than those of both MN subgroups (all p < 0.001) after adjusting for age and sex. Compared with the mild group and HC group, the moderate to severe group had lower cRBF (all p < 0.050) and mRBF average values (p = 0.012 and p < 0.001, respectively). The combination model of the T1 mapping and RBF values for differentiating MN from HC had a higher area under the curve of 0.87 (95% confidence intervals, 0.80-0.95) than single-parameter models (all p < 0.050), except the mT1 value model. Multiparametric MRI shows potential as a noninvasive adjunct tool for assessing MN, offering a possibility to guide clinical decision-making. Multiparametric MRI provides a noninvasive approach to renal structural and perfusion changes in membranous nephropathy and offers an alternative to guide clinical treatment strategies. Renal biopsy has certain limitations for diagnosing membranous nephropathy, and there is an urgent need to develop a noninvasive method. Membranous nephropathy patients had higher cortex, medullary T1 mapping values and lower cortex, medullary renal blood flow values than healthy controls. Quantitative MRI parameters show potential as a noninvasive biomarker for assessing membranous nephropathy.