Membranous Nephropathy Research Articles

Association between immune cells and membranous nephropathy: a two-sample Mendelian randomization study

IntroductionMultiple studies have indicated that immune cells play a significant role in the occurrence and development of membranous nephropathy (MN). However, the causal relationship between the two has not been fully established. To further investigate this, we employed a Mendelian randomization (MR) study design.Material and methodsGenetic instrumental variables for immune cells were sourced from an extensive genome-wide association study (GWAS). MN summary statistics, involving 2,150 cases and 5,829 controls, were obtained from a separate GWAS. The primary analysis employed the inverse-variance weighted (IVW) method. To explore reverse causation, a reverse MR analysis was undertaken. Rigorous sensitivity analyses were conducted to ensure the resilience and reliability of the study's findings.ResultsWe identified eight immunophenotypes associated with a reduced risk of MN and all of them were the protective factors for MN. The sensitivity analyses consistently yielded similar results for these immune traits. In the reverse MR analysis, we did not observe any statistically significant associations between MN and these eight immunophenotypes.ConclusionsOur study, utilizing genetic approaches, provides evidence for a causal relationship between immune cells and MN, which has implications for clinical diagnosis and treatment. Further comprehensive investigations are needed to explore the detailed mechanisms underlying the impact of immune cells on MN.

Overview of Immunological Response in Urological Membranous Nephropathy: Focus on Cytokine and Treatment Options.

Membranous nephropathy (MN) is an autoimmune disease that is caused by the production of autoantibody against glomerular podocyte antigens by immune cells due to the lack of self-tolerance mechanisms. Similar to many autoimmune diseases, the pathogenesis of MN is still vague and many experiments are being conducted to detect the antigens and genetic reasons for MN illness. Recently, new antigens, such as exotosin 1/exotosin 2, neural EGF-like-1, semaphorin 3B, and protocadherin 7 have been identified in MN patients who did not have presence of antiphospholipase A2 receptor antigen. What is more, cytokines, which are molecules that regulate immune responses, have been found to have harmful effects in various autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and MN. The role of cytokines and treatment strategies in MN patients is discussed in this article. As the understanding of the disease improves, targeted therapies that focus on specific antigens or cytokines may be developed to effectively manage MN.

Effects of immunosuppressive therapy on renal prognosis in primary membranous nephropathy

BackgroundImmunosuppressive therapy plays a crucial role in treating membranous nephropathy, with previous studies highlighting its benefits for patients with primary membranous nephropathy (PMN). Guidelines suggest that the management of membranous nephropathy should be tailored to individual risk levels. However, there is a lack of real-world studies examining the effects of immunosuppressive therapy on renal outcomes in PMN patients. This study aimed to investigate the relationship between immunosuppressive therapy and renal prognosis in PMN patients.MethodsThis was a real-world retrospective study including patients diagnosed with PMN in Shenzhen Second People’s Hospital and Hechi People’s Hospital. Univariate and multivariate Cox regression analysis and Kaplan-Meier survival analysis were used.ResultsAfter propensity score-matching, 464 PMN patients were included and they were assigned to conservative and immunosuppressive group in a 1:1 ratio. Immunosuppressive therapy was the protective factor of renal composite outcome (HR = 0.65, p < 0.01). Separately, the effect was significant in moderate- and high-risk but not in low-risk patients. Key influencing factors including age, blood pressure, albumin and total cholesterol levels, with slight differences among patients at different risk.ConclusionsThis study demonstrates the efficacy of immunosuppressive therapy in non-low-risk PMN patients. The key factors affecting renal prognosis in patients with different risk levels are emphasized to help provide individualized treatment.

Animal models of membranous nephropathy: more choices and higher similarity

Membranous nephropathy (MN) is an antibody-mediated autoimmune glomerular disease in which PLA2R1 is the main autoantibody. It has become the most common cause of adult nephrotic syndrome, and about one-third of patients can progress to end-stage kidney disease, but its pathogenesis is still unclear. Animal models can be used as suitable tools to study the pathogenesis and treatment of MN. The previous Heymann nephritis rat model and C-BSA animal model are widely used to study the pathogenesis of MN. However, the lack of target antigen expression in podocytes of model animals (especially rodents) restricts the application. In recent years, researchers constructed animal models of antigen-specific MN, such as THSD7A, PLA2R1, which more truly simulate the pathogenesis and pathological features of MN and provide more choices for the follow-up researchers. When selecting these MN models, we need to consider many aspects, including cost, difficulty of model preparation, labor force, and whether the final model can answer the research questions. This review is to comprehensively evaluate the mechanism, advantages and disadvantages and feasibility of existing animal models, and provide new reference for the pathogenesis and treatment of MN.

Epitope Spreading in Immune-Mediated Glomerulonephritis: The Expanding Target

Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and ANCA-associated vasculitis (AAV). In MN, intramolecular spreading within the phospholipase A2 receptor correlates with a worse prognosis, while LN exemplifies both intra- and intermolecular spreading, exacerbating renal involvement. Similarly, ANCA reactivity in AAV highlights the destructive potential of epitope diversification. Understanding these immunological cascades reveals therapeutic opportunities—targeting early epitope spreading could curb disease progression. Despite promising insights, the clinical utility of epitope spreading as a prognostic tool remains debated. This review provides a complete overview of the current evidence, exploring the dual-edged nature of epitope spreading, the intricate immune mechanisms behind it, and its therapeutic implications. By elucidating these dynamics, we aim to pave the way for more precise, targeted interventions in autoimmune glomerular diseases.

A Case of Idiopathic Multicentric Castleman Disease Developing in a Patient with a History of Biopsy Proven Membranous Nephropathy

Abstract Introduction/Objective Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disorder involving two or more lymph node sites. It is usually associated with systemic inflammatory symptoms and organ dysfunction related to hypercytokinemia. Renal involvement in iMCD has only been described in a limited number of studies and case reports. Of note, only one previous case report has described results from renal biopsies taken prior to the development of iMCD. Methods/Case Report Our patient is a 43 year old female who was first diagnosed with membranous nephropathy in early 2020. She had PLA2 R negative and Exostosin-2 positive disease. Age appropriate screening for malignancy was unremarkable. She had positive ANA titres and normal complement levels but did not meet criteria for SLE per rheumatology. Her proteinuria was improved and maintained on Lisinopril for 3 years. In October 2023, her proteinuria suddenly increased. Repeat renal biopsy was unchanged from the initial biopsy. This time, she also noticed acute swelling over her subpectoral region. PET-CT scan revealed multiple areas of avid lymphadenopathy on either sides of the diaphragm but the highest yield PET- avidity was in the subpectoral region. Biopsy of the right subpectoral lymph node was performed. According to the WHO Classification, 5th edition, diagnostic criteria for iMCD-NOS was met with the histological features displaying grade 3 plasmacytosis, grade 2 regressed germinal centers, follicular dendritic cell prominence, increased hyperplastic follicles and increased vascularity. Immunohistochemical staining for CD138 highlighted abundant plasma cells, CD21 highlighted follicular dendritic cell prominence. Vascular proliferation was seen by CD34 staining. Kappa and Lambda- ISH demonstrated polytypic staining pattern and HHV-8 was negative. Results (if a Case Study enter NA) NA Conclusion There is a significant clinical, histologic and immunologic overlap between iMCD, autoimmune or infectious disorders and malignancy. HHV-8 negative/iMCD is less well understood and has no specific biomarkers. It is important to follow the available clinicopathologic diagnostic criteria for early diagnosis, follow up and treatment. Timely recognition can help prevent multiple organ system dysfunction, systemic inflammatory symptoms, cytopenias and polyclonal lymphoproliferation. Although the pathophysiology maybe unclear, this case may also suggest that in patients with a previously diagnosed membranous nephropathy, iMCD may play a role in recurrence and worsening of the disease.

Improvement of proteinuria by upadacitinib in a patient with refractory lupus membranous nephropathy.

Improvement of proteinuria by upadacitinib in a patient with refractory lupus membranous nephropathy.

Obinutuzumab versus rituximab for the treatment of refractory primary membranous nephropathy.

Rituximab has been shown effective in patients with primary membranous nephropathy refractory to glucocorticoids plus cyclophosphamide (GC+CTX) or calcineurin inhibitors (CNIs), but the response rates remain limited. Compared with rituximab, obinutuzumab is a humanized anti-CD20 monoclonal antibody with greater B-cell depletion capacity. This study was performed to investigate the effectiveness of obinutuzumab compared to rituximab in treating patients with refractory primary membranous nephropathy. A retrospective study was conducted at Huashan Hospital, Fudan University between January 1, 2015 and July 31, 2024, and included adult patients with primary membranous nephropathy who met the following criteria, 1) resistance to GC+CTX and/or calcineurin inhibitor (CNI) regimens, 2) dependence on CNIs, or 3) relapse within 1 year after CTX discontinuation. The patients subsequently received either obinutuzumab or rituximab. The primary endpoint was treatment response, which was defined as overall remission of nephrotic syndrome with no need for rescue therapy after obinutuzumab versus rituximab treatment. The secondary measures included immunological remission and safety profiles. Among the 51 participants, 20 received obinutuzumab and 31 received rituximab. The response rate was significantly greater in patients receiving obinutuzumab than in those receiving patients (90.0% vs. 38.7%, p<0.001) during a follow-up period of 24 (IQR, 10-34) months. Cox proportional hazards survival regression analysis also revealed the superior effectiveness of obinutuzumab (p<0.001). Immunological remission rates were higher in patients receiving obinutuzumab at both 3 months (75.0% vs. 20.0%, p<0.001) and 6 months (87.5% vs. 21.4%, p<0.001). The safety profiles of the two treatments were comparable. Among the 19 nonresponders treated with rituximab, 10 subsequently received obinutuzumab, and 8 achieved remission during a follow-up period of 20.0 (IQR, 18.5-22.3) months. This retrospective study suggests that obinutuzumab is an effective treatment option for patients with primary membranous nephropathy refractory to GC+CTX, CNI, and rituximab regimens.

Why laser microdissection and mass spectrometry is the method of choice for detection of membranous nephropathy antigens

Why laser microdissection and mass spectrometry is the method of choice for detection of membranous nephropathy antigens

Clinical relevance of proteinuria selectivity index and fractional excretion of sodium in patients with nephrotic syndrome

Proteinuria selectivity index (PSI) is a potential tool for histological classification and prediction of treatment response in nephrotic syndrome, but evidence is insufficient. Clinical relevance of fractional excretion of sodium (FENa) in nephrotic syndrome remains largely unexplored. This multicenter retrospective study included patients with nephrotic syndrome who underwent kidney biopsy between January 2012 and June 2022. Optimal cutoffs for predicting complete remission based on PSI and FENa were determined using receiver operating characteristic curves. Patients were divided into two groups using these cutoffs and followed until complete remission. Of the 611 patients included, 177 had minimal change disease (MCD), 52 had focal segmental glomerulosclerosis (FSGS), and 149 had membranous nephropathy (MN). Median (interquartile range) PSI were 0.14 (0.09–0.19) for MCD, 0.33 (0.23–0.40) for FSGS, and 0.20 (0.14–0.30) for MN. FENa were 0.24 (0.09–0.68), 1.03 (0.50–2.14), and 0.78 (0.41–1.28). Patients with low PSI and FENa had a higher incidence of complete remission. Cox regression analyses demonstrated that both parameters were associated with achieving complete remission (HR 2.73 [95% CI 1.97–3.81] and HR 1.93 [95% CI 1.46–2.55], respectively). PSI and FENa may be useful for histological classification and predicting remission in nephrotic syndrome.

Obinutuzumab as a Promising Treatment for Membranous Nephropathy

Obinutuzumab as a Promising Treatment for Membranous Nephropathy

Self-Supervised Learning for Feature Extraction from Glomerular Images and Disease Classification with Minimal Annotations.

Deep learning has great potential in digital kidney pathology. However, its effectiveness depends heavily on the availability of extensively labeled datasets, which are often limited due to the specialized knowledge and time required for their creation. This limitation hinders the widespread application of deep learning for the analysis of kidney biopsy images. We applied self-distillation with no labels (DINO), a self-supervised learning method, to a dataset of 10,423 glomerular images obtained from 384 PAS-stained kidney biopsy slides. Glomerular features extracted from the DINO-pretrained backbone were visualized using principal component analysis (PCA). We then performed classification tasks by adding either k-nearest neighbor (kNN) classifiers or linear head layers to the DINO-pretrained or ImageNet-pretrained backbones. These models were trained on our labeled classification dataset. Performance was evaluated using metrics such as the area under the receiver operating characteristic curve (ROC-AUC). The classification tasks encompassed four disease categories (minimal change disease, mesangial proliferative glomerulonephritis, membranous nephropathy, and diabetic nephropathy) as well as clinical parameters such as hypertension, proteinuria, and hematuria. PCA visualization revealed distinct principal components corresponding to different glomerular structures, demonstrating the capability of the DINO-pretrained backbone to capture morphological features. In disease classification, the DINO-pretrained transferred model (ROC-AUC = 0.93) outperformed the ImageNet-pretrained fine-tuned model (ROC-AUC = 0.89). When the labeled data were limited, the ImageNet-pretrained fine-tuned model's ROC-AUC dropped to 0.76 (95% confidence interval [CI], 0.72-0.80), whereas the DINO-pretrained transferred model maintained superior performance (ROC-AUC 0.88, 95% CI 0.86-0.90). The DINO-pretrained transferred model also exhibited higher AUCs for the classification of several clinical parameters. External validation using two independent datasets confirmed DINO pre-training's superiority, particularly when labeled data were limited. The application of DINO to unlabeled PAS-stained glomerular images facilitated the extraction of histological features that can be effectively utilized for disease classification.

Clinical correlates and pathology of non-diabetic renal disease in diabetes mellitus

Objectives: Early identification and differentiation of patients with non-diabetic renal disease (NDRD) from diabetic nephropathy (DN) or those with NDRD superimposed on DN improves the prognosis and reduces associated morbidity. The objectives of the study were to compare the clinical profile, nature of renal involvement, and etiopathogenesis (renal biopsy) of patients with isolated NDRD and NDRD superimposed on DN. Materials and Methods: It is a descriptive study in patients with T2D and renal involvement suggestive of non-diabetic etiology further evaluated with renal biopsy and grouped as NDRD alone or NDRD with DN. Results: Of the total 50, 66% were male, the mean age was 55.57 ± 12.28 years, and all were proteinuric. Overall, isolated NDRD and NDRD superimposed on DN were observed in 64% and 36% of patients, respectively. Diabetic retinopathy was absent in 82% of cases. The most common finding in isolated NDRD was membranous nephropathy, followed by immunoglobulin A (IgA) nephropathy and rapid progression of glomerular nephritis (RPGN). At the same time, in the NDRD and DN group, maximum patients displayed IgA nephropathy followed by acute tubular necrosis and RPGN. The incidence of atypical features of renal disease was almost twice as high in the isolated NDRD group than in the group with both NDRD + DN. Conclusion: NDRDs are highly prevalent, and DN may superimpose these. Recognizing NDRD solely on the basis of clinical indicators is challenging. Therefore, histopathological analysis seems essential to accurately diagnose NDRD in diabetic patients to reduce the probability of missed NDRD diagnosis and initiate prompt treatment.

Causality between diabetes and membranous nephropathy: Mendelian randomization.

Membranous nephropathy (MN) has not yet been fully elucidated regarding its relationship with Type I and II Diabetes. This study aims to evaluate the causal effect of multiple types of diabetes and MN by summarizing the evidence from the Mendelian randomization (MR) study. The statistical data for MN was obtained from a GWAS study encompassing 7979 individuals. Regarding diabetes, fasting glucose, fasting insulin, and HbA1C data, we accessed the UK-Biobank, within family GWAS consortium, MAGIC, FinnGen database, MRC-IEU, and Neale Lab, which provided sample sizes ranging from 17,724 to 298,957. As a primary method in this MR analysis, we employed the Inverse Variance Weighted (IVW), Weighted Median, Weighted mode, MR-Egger, Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) and Leave-one-out sensitivity test. Reverse MR analysis was utilized to investigate whether MN affects Diabetes. Meta-analysis was applied to combine study-specific estimates. It has been determined that type 2 diabetes, gestational diabetes, type 1 diabetes with or without complications, maternal diabetes, and insulin use pose a risk to MN. Based on the genetic prediction, fasting insulin, fasting blood glucose, and HbA1c levels were not associated with the risk of MN. No heterogeneity, horizontal pleiotropy, or reverse causal relationships were found. The meta-analysis results further validated the accuracy. The MR analysis revealed the association between MN and various subtypes of diabetes. This study has provided a deeper understanding of the pathogenic mechanisms connecting MN and diabetes.

A Clinicopathological Analysis of Membranous Nephropathy and Its Correlation With the Immunohistochemical Expression of Phospholipase A2 Receptor (PLA2R) in Renal Biopsies in a Tertiary Care Center

A Clinicopathological Analysis of Membranous Nephropathy and Its Correlation With the Immunohistochemical Expression of Phospholipase A2 Receptor (PLA2R) in Renal Biopsies in a Tertiary Care Center

An Updated Comprehensive Review on Diseases Associated with Nephrotic Syndromes.

There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and sometimes also avoid unnecessary exposure to potentially toxic immunosuppression. New biomarkers have led to easier and more accurate diagnoses and more targeted therapeutic decisions. The treatment landscape is becoming wider with a pipeline of promising new therapeutic agents with more sophisticated approaches. This review focuses on all aspects of entities that are associated with nephrotic syndromes with updated information on recent advances in each field. This includes podocytopathies (focal segmental glomerulosclerosis and minimal-change disease), membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary glomerulonephritis, amyloidosis, and monoclonal gammopathy of renal significance in the context of the nephrotic syndrome, but also renal involvement in systemic diseases, diabetic nephropathy, and drugs that are associated with nephrotic syndromes.

Aberrant serum-derived FN1 variants bind to integrin β1 on glomerular endothelial cells contributing to thin basement membrane nephropathy

The glomerular basement membrane (GBM) is a critical component of the glomerular filtration barrier (GFB), with its thickness directly influencing renal function. While a uniformly thinned GBM can cause hematuria while preserving normal renal function, this condition is typically diagnosed as thin basement membrane nephropathy (TBMN). However, the pathogenesis and potential progression to renal insufficiency of TBMN are not fully understood. In this study, we analyzed clinical cohorts presenting with microscopic hematuria who underwent genetic testing and identified five novel pathogenic FN1 mutations. Through bioinformatics analysis of these variants, expression localization analysis of GBM-related molecules in renal biopsies, and functional studies of the mutants, we found that these variants exhibited gain-of-function characteristics. This led to the excessive deposition of aberrant serum-derived FN1 variants on glomerular endothelial cells rather than cell-type-specific variants. The deposition competitively binds FN1 variants to Integrin β1, disrupting the interaction with Laminin α5β2γ1 and subsequently reducing the expression of key GBM components, resulting in TBMN. This study elucidated, for the first time, the genetic pathogenesis of TBMN caused by FN1 variants. It provides a crucial foundation for understanding the progression of renal dysfunction associated with simple hematuria, highlights the potential for targeted therapeutic strategies, and differentiates TBMN from early-stage Alport syndrome.

Obinutuzumab treatment for membranous nephropathy: effectiveness and safety concerns during COVID-19 pandemic

Obinutuzumab treatment for membranous nephropathy: effectiveness and safety concerns during COVID-19 pandemic

Does the standard proteinuria cut-off for renal biopsy in lupus nephritis as per the current guidelines hold good for Asian population? A single-centre study from South India.

Current rheumatology and nephrology society guidelines in lupus nephritis do not recommend renal biopsy for proteinuria of less than 500mg/24h. This might lead to a significant delay in the early diagnosis of lupus nephritis. The main aim of this study is to determine the nature of renal lesions in patients with low-grade proteinuria and to analyze the predictors for clinically significant lupus nephritis. This was a single-center, retrospective study. All consecutive patients of lupus nephritis, with low-grade proteinuria (200mg to 500mg/24h) undergoing renal biopsy were enrolled in this study. The renal biopsies were classified into significant lesions (Class III/IV/V) and non-significant lesions (Class I and II). Treatment naïve groups and treatment-modified groups were analyzed separately. Predictive factors for significant renal lesions were determined by univariate and multivariate analysis. We identified 183 patients of lupus with proteinuria between 200 and 500mg / 24h. Mean (SD) age was 30.2 (11.39) years with 167 (91.2%) of them being females. The mean (SD) baseline proteinuria was 351.03 (98.1) mg/24h 85 patients (46.5%) had proliferative lupus nephritis where whereas 17 patients (9.3%) had membranous nephropathy. Crescents and fibrinoid necrosis were seen in 10 (5.46%) and 24 (13.11 %) patients respectively. Isolated proteinuria without any other sediments was seen in 95 patients (51.9%) of which 29 patients had proliferative lupus nephritis. Elevated Anti-double stranded DNA (anti-dsDNA), low C3, low C4 and the presence of urinary sediments were significantly associated with significant renal lesions in biopsy. Significant renal lesions were seen in around half of the patients with low-grade proteinuria underscoring the importance of performing a renal biopsy in this set of patients. Low C3 and C4, urinary sediments, and elevated anti-dsDNA were predictors for significant renal lesions.

Soluble Epoxide Hydrolase Inhibition Attenuates Proteinuria by Alleviating Renal Inflammation and Podocyte Injuries in Adriamycin-Induced Nephropathy.

Soluble epoxide hydrolase (sEH) has previously been demonstrated to play an important part in kidney diseases by hydrolyzing renoprotective epoxyeicosatrienoic acids to their less active diols. However, little is known about the role of sEH in primary glomerular diseases. Here, we investigated the effects of sEH inhibition on proteinuria in primary glomerular diseases and the underlying mechanism. The expression of sEH in the renal tubules of patients with minimal change disease, IgA nephropathy, and membranous nephropathy was significantly increased. Renal sEH expression level was positively correlated with the 24 h urine protein excretion and negatively correlated with serum albumin. In the animal model of Adriamycin (ADR)-induced nephropathy, renal sEH mRNA and protein expression increased significantly. Pharmacological inhibition of sEH with AUDA effectively reduced urine protein excretion and attenuated renal pathological damage. Furthermore, sEH inhibition markedly abrogated the abnormal expressions of nephrin and desmin in glomerular podocytes induced by ADR. More importantly, AUDA treatment inhibited renal NF-κB activation and reduced TNF-α levels in rats with ADR-induced nephropathy. Overall, our findings suggest that sEH inhibition ameliorates renal inflammation and podocyte injury, thus reducing proteinuria and exerting renoprotective effects. Targeting sEH might be a potential strategy for the treatment of proteinuria in primary glomerular diseases.