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Background: Research has showcased a correlation between disruptions in gut microbiota and primary membranous nephropathy (pMN), giving rise to the concept of the 'gut-kidney axis'. However, the precise relationship between gut microbiota and pMN remains elusive. Hence, this study endeavors to investigate whether a causal relationship exists between gut microbiota and pMN utilizing Mendelian randomization (MR) analysis., Methods: The primary method employed for MR analysis is the inverse variance weighting method, supplemented by MR-Egger and the weighted median method, to infer causality. This approach was validated within the pMN cohort across two distinct populations., Results: At the species level, the abundance of Bifidobacterium bifidum and Alistipes indistinctus was negatively correlated with the risk of pMN. Conversely, pMN was positively associated with Bacilli abundance at the class level, Lachnospiraceae abundance at the family level, and Dialister abundance at the genus level. Specifically, at the species level, pMN was positively correlated with the abundance of Ruminococcus lactaris , Dialister invisus , and Coprococcus_sp_ART55_1., Conclusion: These findings lay the groundwork for future research exploring the interplay between pMN and the gut microbiota, with substantial implications for the prevention and treatment of pMN and its associated complications.

Background: This study performs a detailed bioinformatics and machine learning analysis to investigate the genetic foundations of membranous nephropathy (MN) in lung adenocarcinoma (LUAD)., Methods: In this study, the gene expression profiles of MN microarray datasets (GSE99339) and LUAD dataset (GSE43767) were downloaded from the Gene Expression Omnibus database, common differentially expressed genes (DEGs) were obtained using the limma R package. The biological functions were analyzed with R Cluster Profiler package according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Machine learning algorithms, including LASSO regression, support vector machine (SVM), Random Forest, and Boruta analysis, were applied to identify hubgenes linked to LUAD-associated MN. These genes' prognostic values were evaluated in the TCGA-LUAD cohort and validated through immunohistochemistry on renal biopsy specimens., Results: A total of 36 DEGs in common were identified for downstream analyses. Functional enrichment analysis highlighted the involvement of the Toll-like receptor 4 pathway and several immune recognition pathways in LUAD-associated MN. COL3A1, PSENEN, RACGAP1, and TNFRSF10B were identified as hub genes in LUAD-associated MN using machine learning algorithms. ROC analysis demonstrated their effective discrimination of MN with high accuracy. Survival analysis showed that lung adenocarcinoma patients with higher expression of these genes had significantly reduced overall survival. In patients with lung adenocarcinoma-associated MN, RACGAP1, COL3A1, PSENEN, and TNFRSF10B were higher expressed in the glomerular, especially RACGAP1, indicating an important role in the pathogenesis of LUAD-associated membranous nephropathy., Conclusions: Our study underscores the critical role of RACGAP1, COL3A1, PSENEN, and TNFRSF10B in the development of LUAD-associated MN, providing important insights for future research and the development of potential therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus, which mainly leads to nephrotic syndrome. This study investigates the associations between air pollution and MN risk and from an epigenomic perspective. In this study, we examine the associations between genetically predicted deoxyribonucleic acid methylation related to air pollution and MN risk. The data of air pollution included particulate matter (PM) with a diameter of 2.5 µm or less (PM2.5), PM with a diameter between 2.5 and 10 µm (PM2.5-10), PM with a diameter of 10 µm or less (PM10), nitrogen dioxide, and nitrogen oxides. Inverse variance weighted method was used as the main analysis method, and weighted median model and Mendelian randomization-Egger methods were selected for quality control. To assess the reliability of the results of the analyses, heterogeneity test, horizontal pleiotropy test, and the leave-one-out method were applied. There was a causal relationship between nitrogen oxides and MN risk (P = .010). Other types of air pollution were found no statistical association with MN disease (PM2.5: P = .378; PM2.5-10: P = .111; PM10: P = .035; nitrogen dioxide: P = .094). There was no heterogeneity or pleiotropy in the results. Our study suggests the association between nitrogen oxides and membrane nephropathy (MN) risk from the genetic perspective. This provides a theoretical basis for the prevention of MN disease., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Therapeutic approaches that target the gut microbiota may be helpful in the potential prevention and treatment of membranous nephropathy (MN). Several studies demonstrated a correlation between gut microbiota and MN. However, the confounding evidence cannot prove a causal relationship between gut microbiota and MN., Materials and Methods: The aim of our study is to assess genome-wide association study data for a causal relationship between gut microbiota and MN using a two-sample Mendelian randomization (MR) approach. Inverse variance weighted (IVW) was used as the primary technique to determine the association of genetic variants from gut microbiota and MN patients. Besides, sensitivity analyses confirmed the accuracy of the results. Finally, we applied false discovery rate (FDR) correction to results with IVW < 0.05 during multiple hypothesis testing., Results: The results from IVW estimates indicated that Bacillales exhibited a significant association with MN, acting as a risk factor (OR = 1.52, 95% CI: 1.14 - 2.02, p = 0.005). In addition, our univariable MR results showed that 7 bacterial taxa ( Melainabacteria , Butyricicoccus , Catenibacterium , Ruminiclostridium5 , RuminococcaceaeUCG003 , RuminococcaceaeUCG013 , and Gastranaerophilales ) had suggestive associations with MN. The sensitivity analysis did not reveal any significant heterogeneity in the instrumental variables or horizontal pleiotropy., Conclusion: Our findings provided causal evidence for the effect of gut microbiota on MN patients and broadened the spectrum of bacterial taxa that might be involved in the pathogenesis of MN. These selected bacterial taxa hold promise as new biomarkers, which may aid in designing targeted therapeutic modalities for MN, improving our comprehension of the gut-kidney axis.

Primary glomerular diseases are rare entities. This has hampered efforts to better understand the underlying pathobiology and to develop novel safe and effective therapies. NEPTUNE is a rare disease network that is focused on patients of all ages with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. It is a longitudinal cohort study that collects detailed demographic, clinical, histopathologic, genomic, transcriptomic, and metabolomic data. The goal is to develop a molecular classification for these disorders that supersedes the traditional pathological features-based schema. Pediatric patients are important contributors to this ongoing project. In this review, we provide a snapshot of the children and adolescents enrolled in NEPTUNE and summarize some key observations that have been made based on the data accumulated during the study. In addition, we describe the development of NEPTUNE Match, a program that aims to leverage the multi-scalar information gathered for each individual patient to provide guidance about potential clinical trial participation based on the molecular characterization and non-invasive biomarker profile. This represents the first organized effort to apply principles of precision medicine to the treatment of patients with primary glomerular disease. NEPTUNE has proven to be an invaluable asset in the study of glomerular diseases in patients of all ages including children and adolescents., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Celiac disease, characterized as an autoimmune disorder, possesses the capacity to affect multiple organs and systems. Earlier research has indicated an increased risk of kidney diseases associated with celiac disease. However, the potential causal relationship between genetic susceptibility to celiac disease and the risk of kidney diseases remains uncertain. We conducted Mendelian randomization analysis using nonoverlapping European population data, examining the link between celiac disease and 10 kidney traits in whole-genome association studies. We employed the inverse variance-weighted method to enhance statistical robustness, and results' reliability was reinforced through rigorous sensitivity analysis. Mendelian randomization analysis revealed a genetic susceptibility of celiac disease to an increased risk of immunoglobulin A nephropathy (OR = 1.44; 95% confidence interval [CI] = 1.17-1.78; P = 5.7 × 10-4), chronic glomerulonephritis (OR = 1.15; 95% CI = 1.08-1.22; P = 2.58 × 10-5), and a decline in estimated glomerular filtration rate (beta = -0.001; P = 2.99 × 10-4). Additionally, a potential positive trend in the causal relationship between celiac disease and membranous nephropathy (OR = 1.37; 95% CI = 1.08-1.74; P = 0.01) was observed. Sensitivity analysis indicated the absence of pleiotropy. This study contributes novel evidence establishing a causal link between celiac disease and kidney traits, indicating a potential association between celiac disease and an elevated risk of kidney diseases. The findings provide fresh perspectives for advancing mechanistic and clinical research into kidney diseases associated with celiac disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Fabry disease (FD) is a rare X-linked genetic disease that can coexist with multiple glomerulopathies. We report a 32-year-old female patient of FD coexisting with stage II membranous nephropathy (MN), who presented with proteinuria, normal renal function, and hypo-hidrosis as the only symptom. The renal biopsy manifested a subepithelial immunocomplex deposit in the glomeruli along with basement membrane thickening on light microscopy. Electron microscopy revealed myeloid bodies in some podocytes, which suggested the patient possibly coexistence with Fabry disease. The low activity of α-galactosidase A and one pathogenic heterozygous mutation (c.335G > Ap.Arg112His) in the α-galactosidase A gene confirmed the diagnosis of Fabry disease. This patient's son had the same gene mutation as his mother but without any symptoms at the time. Treatment with ramipril turned urine protein negative. The proteinuria had reoccurred, as shown by the presence of foamy urine, a protein to creatinine ratio of 1.54 g/g, and a blood albumin level of 34.4g/L. The patient was being treated with allisartan isoproxil. However, at the time, the urine protein did not turn negative.

Primary membranous nephropathy (PMN) is one of the leading causes of end-stage renal disease, and the most frequent cause of massive proteinuria in nondiabetic adults, resulting in fatal complications. However, the underlying pathomechanisms of PMN remain largely unclear. Here, single-cell RNA sequencing is employed to analyze kidney biopsies from eleven PMN patients and seven healthy subjects. Profiling 44 060 cells from patients allowed us to characterize the cellular composition and cell-type-specific gene expression in the PMN kidney. The complement-induced BMP2/pSMAD1/COL4 pathway is identified as the pathogenic pathway in podocytes, bridging two key events, i.e., complement system activation and glomerular basement membrane thickening in PMN. Augmented infiltration and activation of myeloid leukocytes and B lymphocytes are found, profiling delicate crosstalk of immune cells in PMN kidneys. Overall, these results provide valuable insights into the roles of podocytes and immune cells in PMN, and comprehensive resources toward the complete understanding of PMN pathophysiology., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Purpose: Multiple circulating proteins have been reported to participate in human diseases. However, the association between cardiovascular proteins and membranous nephropathy (MN) remained profoundly elusive., Methods: A bidirectional Mendelian randomization (MR) analysis was conducted to explore the causal correlation between ninety cardiovascular proteins and MN. Genome-wide association study (GWAS) data of cardiovascular proteins and MN were all from European research. Inverse variance weighted (IVW) was used as the main approach. Moreover, MR-Egger, weighted median, weighted mode, and simple mode were also performed. Cochrane's Q test, MR-Egger, and MR-PRESSO were conducted for sensitivity analysis., Results: According to IVW method, fatty acid-binding protein and thrombomodulin (TM) were identified as risk factors for MN, while a protective role was detected in tissue-type plasminogen activator. Additionally, MN was associated with an elevated level of macrophage colony-stimulating factor 1, stem cell factor, TM, and tissue factor. Reversely, MN was also correlated with a downregulated level of beta-nerve growth factor, Cathepsin D, hepatocyte growth factor, interleukin-6 receptor subunit alpha, macrophage colony-stimulating factor 1, and myeloperoxidase. In the sensitivity analysis, no significant pleiotropy and heterogeneity was detected., Conclusion: This was the first study to reveal the causal association between cardiovascular proteins and MN. These specific cardiovascular proteins could be novel biomarkers for MN, and is helpful for timely identify the risk of other diseases that might result from MN. However, further clinical studies are needed to confirm our results., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Monoclonal immunoglobulin (MIg) crystalline nephropathies are rare lesions resulting from precipitation of MIgs in the kidney as intracellular or extracellular crystals. We describe a patient with multiple myeloma (IgGλ) and diabetes who presented with nephrotic range proteinuria. Kidney biopsy revealed membranous nephropathy superimposed on diabetic glomerulosclerosis. Glomeruli were negative for PLA2R, THSD7A, and NELL-1. Ultrastructurally, the subepithelial deposits were composed of crystals (ranging from rhomboid to rod to needle shaped), which failed to stain for immunoglobulins by routine immunofluorescence but stained for IgG+λ by paraffin immunofluorescence after pronase digestion. RNA-based immunoglobulin repertoire sequencing performed on bone marrow aspirate identified an IgGλ (γ1) clone, which was highly atypical, combining an extensively mutated (23.6%) Ig heavy chain derived from the IGHV1-24 with low pI and unusual mutations and a light chain derived from an extremely rare germline gene (IGLV10-54). This report expands the pathologic spectrum of MIg crystalline nephropathies by describing a unique case of crystalline nephropathy with IgGλ deposits manifesting as membranous nephropathy., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Sarcoidosis is a multisystemic inflammatory disease, characterized by the presence of non-caseating, epithelioid granulomas. Glomerular disease in patients with sarcoidosis is rare and membranous nephropathy (MN) is cited as the most common. The association between the two diseases remained unclear. This article reported a case of co-occurrence of sarcoidosis and anti-PLA2R-associated MN, to provide a possible relationship between these two entities., Case Presentation: A 61-year-old Chinese Han woman with a history of sarcoidosis was admitted to our hospital for nephrotic syndrome. Her sarcoidosis was diagnosed according to the adenopathy observed on the computed tomography scan and the biopsy of lymph nodes. The MN presented with nephrotic syndrome with a PLA2R antibody titer of 357RU/ml, and the final diagnosis was based on a renal biopsy. The patient's sarcoidosis was remitted after treatment with prednisone. One year later MN was diagnosed, and she was treated with prednisone combined with calcineurin inhibitors, based on a full dose of renin-angiotensin system (RAS) inhibitor. The patient's sarcoidosis had been in remission while the MN was recurrent, and her renal function deteriorated to end-stage renal disease 6 years later due to discontinuation of immunosuppression. A genetic test led to the identification of the HLA-DRB1*0301 and HLA-DRB1*150 genes associated with both sarcoidosis and MN, which provides a new possible explanation of the co-occurrence of these two diseases., Conclusion: This case suggested for the first time a potential genetic connection between idiopathic MN and sarcoidosis which needs further studies in the future., (© 2024. The Author(s).)

Background: Various studies have reported that individuals with membranous nephropathy (MN) exhibit an elevated susceptibility to cancers. However, a causal relationship has not been clearly established., Methods: We constructed a genetic score that predicts MN by utilizing genetic variants linked to this condition as instrumental variables. These genetic scores were then compared with lung, colon, breast, and prostate cancer risks by a two-sample Mendelian randomisation analysis involving the following methods: MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode., Results: This study demonstrated a lack of empirical substantiation for a causal association between genetic variants in MN and the susceptibility to lung, colon, prostate, or breast cancer., Conclusion: Overall, we did not detect a causal link between MN and lung, colon, breast, or prostate cancer. Hence, additional research is imperative to elucidate the underlying factors contributing to the heightened occurrence of tumour in patients with MN., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Gut microbiota transplantation has been reported to improve the renal function of membranous nephropathy (MN). However, whether there is a causal effect of gut microbiota on MN remained unclear., Methods: We performed two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used as the main approach to evaluate the causal relationship between gut microbiota and MN. Additional methods including MR-Egger regression, weighted median, and MR-weighted mode were also conducted. Cochrane's Q test, MR-Egger regression, and MR-PRESSO were employed to detect heterogeneity and pleiotropy, respectively., Results: A total of 196 gut microbiota were examined. After IVW and sensitivity analysis, eight gut bacteria taxa were observed causal effects on the risk of MN. Specifically, Genus. Oscillibacter was a protective factor (OR: 0.57; 95% CI 0.328-0.979; P = 0.042), while Class. Melainabacteria (OR: 1.51; 95% CI 1.004-2.277; P = 0.048), Genus. Butyricicoccus (OR: 2.16; 95% CI 1.005-4.621; P = 0.048), Genus. Catenibacterium (OR: 1.49; 95% CI 1.043-2.134; P = 0.028), Genus.Ruminiclostridium5 (OR: 1.74; 95% CI 1.053-2.862; P = 0.030), Genus. Ruminococcaceae UCG-003 (OR: 1.73; 95% CI 1.110-2.692; P = 0.015), Order. Bacillales (OR: 1.52; 95% CI 1.135-2.025; P = 0.0048) and Order. Gastranaerophilales (OR: 1.45; 95% CI 1.010-2.085; P = 0.044) were risk factors. Heterogeneity was not significant for most single-nucleotide polymorphisms, and no statistical difference in pleiotropy., Conclusions: This study first indicated the causal association between specific gut microbiota and MN, which would be of great significance to guide clinical prevention and treatment in MN., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Membranous nephropathy (MN) is an autoimmune disease and represents the most prevalent type of renal pathology in adult patients afflicted with nephrotic syndrome. Despite substantial evidence suggesting a possible link between MN and cancer, the precise underlying mechanisms remain elusive., Methods: In this study, we acquired and integrated two MN datasets (comprising a single-cell dataset and a bulk RNA-seq dataset) from the Gene Expression Omnibus database for differential expression gene (DEG) analysis, hub genes were obtained by LASSO and random forest algorithms, the diagnostic ability of hub genes was assessed using ROC curves, and the degree of immune cell infiltration was evaluated using the ssGSEA function. Concurrently, we gathered pan-cancer-related genes from the TCGA and GTEx databases, to analyze the expression, mutation status, drug sensitivity and prognosis of hub genes in pan-cancer., Results: We conducted intersections between the set of 318 senescence-related genes and the 366 DEGs, resulting in the identification of 13 senescence-related DEGs. Afterwards, we meticulously analyzed these genes using the LASSO and random forest algorithms, which ultimately led to the discovery of six hub genes through intersection ( PIK3R1 , CCND1 , TERF2IP , SLC25A4 , CAPN2 , and TXN ). ROC curves suggest that these hub genes have good recognition of MN. After performing correlation analysis, examining immune infiltration, and conducting a comprehensive pan-cancer investigation, we validated these six hub genes through immunohistochemical analysis using human renal biopsy tissues. The pan-cancer analysis notably accentuates the robust association between these hub genes and the prognoses of individuals afflicted by diverse cancer types, further underscoring the importance of mutations within these hub genes across various cancers., Conclusion: This evidence indicates that these genes could potentially play a pivotal role as a critical link connecting MN and cancer. As a result, they may hold promise as valuable targets for intervention in cases of both MN and cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Zou, Wei, Zhang, Zhuo, Xu and Li.)

Introduction: The aim of this study was to test whether a combined risk score on the basis of genetic risk and serology can improve the prediction of kidney failure in phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy., Methods: We performed a retrospective analysis of 519 biopsy-proven PLA2R-associated primary membranous nephropathy patients with baseline eGFR ≥25 ml/min per 1.73 m 2 . The combined risk score was calculated by combining the genetic risk score with PLA2R ELISA antibody titers. The primary end point was kidney disease progression defined as a 50% reduction in eGFR or kidney failure. Cox proportional hazard regression analysis and C-statistics were applied to compare the performance of PLA2R antibody, genetic risk score, and combined risk score, as compared with clinical factors alone, in predicting primary outcomes., Results: The median age was 56 years (range, 15-82 years); the male-to-female ratio was 1:0.6, the median eGFR at biopsy was 99 ml/min per 1.73 m 2 (range: 26-167 ml/min per 1.73 m 2 ), and the median proteinuria was 5.3 g/24 hours (range: 1.5-25.8 g/24 hours). During a median follow-up of 67 (5-200) months, 66 (13%) had kidney disease progression. In Cox proportional hazard regression models, PLA2R antibody titers, genetic risk score, and combined risk score were all individually associated with kidney disease progression with and without adjustments for age, sex, proteinuria, eGFR, and tubulointerstitial lesions. The best-performing clinical model to predict kidney disease progression included age, eGFR, proteinuria, serum albumin, diabetes, and tubulointerstitial lesions (C-statistic 0.76 [0.69-0.82], adjusted R 2 0.51). Although the addition of PLA2R antibody titer improved the performance of this model (C-statistic: 0.78 [0.72-0.84], adjusted R 2 0.61), replacing PLA2R antibody with the combined risk score improved the model further (C-statistic: 0.82 [0.77-0.87], adjusted R 2 0.69, difference of C-statistics with clinical model=0.06 [0.03-0.10], P < 0.001; difference of C-statistics with clinical-serologic model=0.04 [0.01-0.06], P < 0.001)., Conclusions: In patients with PLA2R-associated membranous nephropathy, the combined risk score incorporating inherited risk alleles and PLA2R antibody enhanced the prediction of kidney disease progression compared with PLA2R serology and clinical factors alone., (Copyright © 2024 by the American Society of Nephrology.)

Primary membranous nephropathy (PMN) is one of the most frequent pathological subtypes of nephrotic syndrome in adults. The use of genome-wide association study (GWAS) technology has propelled the transition from conventional medicine to precision medicine, offering a fresh perspective for comprehending the pathogenesis of PMN and individual variations in greater detail. Furthermore, GWAS will aid in clinical translation, laying a firm foundation for the precise diagnosis and treatment of PMN.

Background: The currently available medications for treating membranous nephropathy (MN) still have unsatisfactory efficacy in inhibiting disease recurrence, slowing down its progression, and even halting the development of end-stage renal disease. There is still a need to develop novel drugs targeting MN., Methods: We utilized summary statistics of MN from the Kiryluk Lab and obtained plasma protein data from Zheng et al. We performed a Bidirectional Mendelian randomization analysis, HEIDI test, mediation analysis, Bayesian colocalization, phenotype scanning, drug bank analysis, and protein-protein interaction network., Results: The Mendelian randomization analysis uncovered 8 distinct proteins associated with MN after multiple false discovery rate corrections. Proteins related to an increased risk of MN in plasma include ABO [(Histo-Blood Group Abo System Transferase) (WR OR = 1.12, 95%CI:1.05-1.19, FDR=0.09, PPH4 = 0.79)], VWF [(Von Willebrand Factor) (WR OR = 1.41, 95%CI:1.16-1.72, FDR=0.02, PPH4 = 0.81)] and CD209 [(Cd209 Antigen) (WR OR = 1.19, 95%CI:1.07-1.31, FDR=0.09, PPH4 = 0.78)], and proteins that have a protective effect on MN: HRG [(Histidine-Rich Glycoprotein) (WR OR = 0.84, 95%CI:0.76-0.93, FDR=0.02, PPH4 = 0.80)], CD27 [(Cd27 Antigen) (WR OR = 0.78, 95%CI:0.68-0.90, FDR=0.02, PPH4 = 0.80)], LRPPRC [(Leucine-Rich Ppr Motif-Containing Protein, Mitochondrial) (WR OR = 0.79, 95%CI:0.69-0.91, FDR=0.09, PPH4 = 0.80)], TIMP4 [(Metalloproteinase Inhibitor 4) (WR OR = 0.67, 95%CI:0.53-0.84, FDR=0.09, PPH4 = 0.79)] and MAP2K4 [(Dual Specificity Mitogen-Activated Protein Kinase Kinase 4) (WR OR = 0.82, 95%CI:0.72-0.92, FDR=0.09, PPH4 = 0.80)]. ABO, HRG, and TIMP4 successfully passed the HEIDI test. None of these proteins exhibited a reverse causal relationship. Bayesian colocalization analysis provided evidence that all of them share variants with MN. We identified type 1 diabetes, trunk fat, and asthma as having intermediate effects in these pathways., Conclusions: Our comprehensive analysis indicates a causal effect of ABO, CD27, VWF, HRG, CD209, LRPPRC, MAP2K4, and TIMP4 at the genetically determined circulating levels on the risk of MN. These proteins can potentially be a promising therapeutic target for the treatment of MN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Su and Wan.)

Class 2 HLA and PLA2R1 alleles are exceptionally strong genetic risk factors for membranous nephropathy (MN), leading, through an unknown mechanism, to a targeted autoimmune response. Introgressed archaic haplotypes (introduced from an archaic human genome into the modern human genome) might influence phenotypes through gene dysregulation. Here, we investigated the genomic region surrounding the PLA2R1 gene. We reconstructed the phylogeny of Neanderthal and modern haplotypes in this region and calculated the probability of the observed clustering being the result of introgression or common descent. We imputed variants for the participants in our previous genome-wide association study and we compared the distribution of Neanderthal variants between MN cases and controls. The region associated with the lead MN risk locus in the PLA2R1 gene was confirmed and showed that, within a 507 kb region enriched in introgressed sequence, a stringently defined 105 kb haplotype, intersecting the coding regions for PLA2R1 and ITGB6, is inherited from Neanderthals. Thus, introgressed Neanderthal haplotypes overlapping PLA2R1 are differentially represented in MN cases and controls, with enrichment In controls suggesting a protective effect., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Phospholipase A2 receptor 1 (PLA2R1) plays a crucial role in various diseases, including membranous nephropathy. However, the precise implications of PLA2R1 deficiency remain poorly understood. In this study, we created PLA2R1 knockout rats to explore potential consequences resulting from the loss of the PLA2R1 gene. Unexpectedly, our PLA2R1 knockout rats exhibited symptoms resembling those of chronic kidney disease after an 8-week observation period. Notably, several rats developed persistent proteinuria, a hallmark of renal dysfunction. Immunohistochemical and immunofluorescence analyses revealed insignificant glomerular fibrosis, reduced podocyte count, and augmented glomerular expression of complement C3 (C3) compared to immunoglobin A (IgA) and immunoglobin G(IgG) in the rat model. These findings suggest that the loss of PLA2R1 may contribute to the pathogenesis of membranous nephropathy and related conditions. Our knockout rat model provides a valuable tool for investigating the underlying pathology of PLA2R1-associated diseases, and may facilitate the development of targeted therapies for membranous nephropathy and other related disorders., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We previously found that miR-664a-5p is specifically expressed in urinary exosomes of idiopathic membranous nephropathy (IMN) patients. Homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, plays an important role in nephropathy. But the function of these factors and their connection in MN are unclear. To investigate the function and mechanism of miR-664a-5p in MN, the miR-664a-5p expression in HK-2 cells, exosomes, podocytes and renal tissues were studied, as well as cell growth and apoptosis of these cells, the binding of miR-664a-5p to HIPK2 mRNA, the levels of relative proteins and autophagy. The MN progression in MN mice model was also studied. Albumin increased the miR-664a-5p content and apoptosis of HK-2 cells, which was blocked by miR-664a-5p antagomir. miR-664a-5p bound to the 3' UTR of HIPK2 mRNA, resulting in the up-regulation of Calpain1, GSα shear and the inhibition of autophagy level. Autophagy inhibitor CQ blocked the protective effect of miR-664a-5p antagomir, HIPK2 overexpression, Calpain inhibitor SJA6017 on albumin-mediated injury. MiR-664a-5p from albumin-treated HK-2 cells could be horizontally transported to podocytes through exosomes. Exosomes from albumin-treated HK-2 cells promoted progression of MN mice, AAV-Anti-miR-664-5p (mouse homology miRNA) could improve them. Albumin increases the miR-664a-5p level and causes changes of HIPK2/Calpain1/GSα pathway, which leads to autophagy inhibition and apoptosis up-regulation of renal tubular epithelial cells. miR-664a-5p can horizontally enter podocytes through exosomes resulting in podocytes injury. Targeted inhibition of miR-664a-5p can reduce the apoptosis of renal tubule cells and podocytes, and may improve the MN progression., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Annexin A1 is a membrane-associated calcium-binding protein that participates in the progression of many diseases by facilitating vesicle aggregation. It has been documented that reducing vesicle formation alleviates podocyte injury and albuminuria in idiopathic membranous nephropathy (IMN). However, the role of Annexin A1 (ANXA1) in IMN is unknown., Methods: Electron microscopy was used to observe the numbers of vesicles in podocytes. The expression of ANXA1 in IMN was investigated by bioinformatics analysis. We validated the hub genes with the Nephroseq V5 online tool and microarray data from the GEO. Immunohistochemical staining and qPCR were performed to measure gene and protein expression., Results: The numbers of vesicles in IMN podocytes were significantly increased. Bioinformatics analysis showed that ANXA1, one of the differentially expressed genes, was upregulated in glomeruli from IMN patients. In the validation database and dataset, we confirmed that ANXA1 expression was upregulated in the glomeruli of IMN patients. We revealed that the increased expression of ANXA1 was negatively correlated with the glomerular filtration rate (GFR) and proteinuria. Moreover, ANXA1 was enriched in the biological process of vesicle fusion, in which the expression of SNAREs and the SNARE complex was increased. Finally, the expression of ANXA1 and genes related to SNAREs and the SNARE complex was upregulated in glomeruli from IMN patients according to immunohistochemical staining and qPCR., Conclusion: We conclude that ANXA1 may mediate endocytic vesicle fusion and transport by promoting SNARE assembly, contributing to the morphological changes in podocytes and massive proteinuria in IMN., (© 2023 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

The deposition of antipodocyte autoantibodies in the glomerular subepithelial space induces primary membranous nephropathy (MN), the leading cause of nephrotic syndrome worldwide. Taking advantage of the glomerulus-on-a-chip system, we modeled human primary MN induced by anti-PLA2R antibodies. Here we show that exposure of primary human podocytes expressing PLA2R to MN serum results in IgG deposition and complement activation on their surface, leading to loss of the chip permselectivity to albumin. C3a receptor (C3aR) antagonists as well as C3AR gene silencing in podocytes reduced oxidative stress induced by MN serum and prevented albumin leakage. In contrast, inhibition of the formation of the membrane-attack-complex (MAC), previously thought to play a major role in MN pathogenesis, did not affect permselectivity to albumin. In addition, treatment with a C3aR antagonist effectively prevented proteinuria in a mouse model of MN, substantiating the chip findings. In conclusion, using a combination of pathophysiologically relevant in vitro and in vivo models, we established that C3a/C3aR signaling plays a critical role in complement-mediated MN pathogenesis, indicating an alternative therapeutic target for MN.

Membranous nephropathy (MN), the most prevalent form of nephrotic syndrome in non-diabetic adults globally, is currently the second most prevalent and fastest-increasing primary glomerular disease in China. Numerous renal disorders are developed partly due to ferroptosis. However, its relationship to the pathogenesis of MN has rarely been investigated in previous studies; actually, ferroptosis is closely linked to the immune microenvironment and inflammatory response, which might affect the entire process of MN development. In this study, we aimed to identify ferroptosis-related genes that are potentially related to immune cell infiltration, which can further contribute to MN pathogenesis. The microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Ferroptosis-related differentially expressed genes (FDEGs) were identified, which were further used for functional enrichment analysis. The common genes identified using the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression algorithm and the support vector machine recursive feature elimination (SVM-RFE) algorithm were used to identify the characteristic genes related to ferroptosis. The feasibility of the 7 genes as a distinguishing factor was assessed using the receiver operating characteristic (ROC) curve, with the area under the curve (AUC) score serving as the evaluation metric. Gene set enrichment analysis (GSEA) and correlation analysis of these genes were further performed. The correlation between the expression of these genes and immune cell infiltration inferred by single sample gene set enrichment analysis (ssGSEA) algorithm was explored. As a result, 7 genes, including NR1D1, YTHDC2, EGR1, ZFP36, RRM2, RELA and PDK4, which were most relevant to immune cell infiltration, were identified to be potential diagnostic genes in MN patients. Next, the signature genes were validated with other GEO datasets. In the subsequent steps, we conducted quantitative real-time fluorescence PCR (qRT-PCR) analysis and immunohistochemistry (IHC) method on the cationic bovine serum albumin (C-BSA) induced membranous nephropathy (MN) rat model and the passive Heymann nephritis (pHN) rat model to examine characteristic genes. Finally, we analysed the mRNA expression patterns of hub genes in MN patients and normal controls using the Nephroseq V5 online platform. In concise terms, our study successfully identified biomarkers specific to MN patients and delved into the potential interplay between these markers and immune cell infiltration. This knowledge bears significance for the diagnosis and prospective treatment strategies for individuals affected by MN., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Idiopathic membranous nephropathy (IMN) is a common type of primary glomerulonephritis, which pathogenesis are highly involved protein and immune regulation. Therefore, we investigated protein expression in different microregions of the IMN kidney tissue. We used laser capture microdissection and mass spectrometry to identify the proteins in the kidney tissue. Using MSstats software to identify the differently expressed protein (DEP). Gene ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used to predict and enrich the potential functions of the DEPs, and DEPs were compared to the Public data in the gene expression omnibus (GEO) database for screening biomarkers of IMN. Immune infiltration analysis was used to analyze the immune proportion in IMN. Three significantly up-regulated proteins were identified in the glomeruli of patients with IMN; 9 significantly up-regulated and 6 significantly down-regulated proteins were identified in the interstitium of patients with IMN. Gene ontology analysis showed that the DEPs in the glomerulus and interstitium were mostly enriched in "biological regulation, the immune system, and metabolic processes." Kyoto Encyclopedia of Genes and Genomes analysis showed that the DEPs in the glomerulus and interstitium were mostly enriched in the "immune system" and the "complement and coagulation cascades. " According to the public information of the GEO database, DEPs in our study, Coatomer subunit delta Archain 1, Laminin subunit alpha-5, and Galectin-1 were highly expressed in the IMN samples from the GEO database; in the immune infiltration analysis, the proportion of resting memory CD4 T cells and activated NK cells in IMN were significantly higher than in the normal group. This study confirmed that there were significant differences in protein expression in different micro-regions of patients with IMN, The protein Coatomer subunit delta Archain 1, Laminin subunit alpha 5, Galectin-1 are potential biomarkers of IMN, the memory T cells CD4 and NK cells, maybe involved in the immunologic mechanism in the development of IMN., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Membranous nephropathy (MN) is a chronic glomerular disease that leads to nephrotic syndrome in adults. The aim of this study was to identify novel biomarkers and immune-related mechanisms in the progression of MN through an integrated bioinformatics approach., Methods: The microarray data were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between MN and normal samples were identified and analyzed by the Gene Ontology analysis, the Kyoto Encyclopedia of Genes and Genomes analysis and the Gene Set Enrichment Analysis (GSEA) enrichment. Hub The hub genes were screened and identified by the weighted gene co-expression network analysis (WGCNA) and the least absolute shrinkage and selection operator (LASSO) algorithm. The receiver operating characteristic (ROC) curves evaluated the diagnostic value of hub genes. The single-sample GSEA analyzed the infiltration degree of several immune cells and their correlation with the hub genes., Results: We identified a total of 574 DEGs. The enrichment analysis showed that metabolic and immune-related functions and pathways were significantly enriched. Four co-expression modules were obtained using WGCNA. The candidate signature genes were intersected with DEGs and then subjected to the LASSO analysis, obtaining a total of 6 hub genes. The ROC curves indicated that the hub genes were associated with a high diagnostic value. The CD4 + T cells, CD8 + T cells and B cells significantly infiltrated in MN samples and correlated with the hub genes., Conclusions: We identified six hub genes (ZYX, CD151, N4BP2L2-IT2, TAPBP, FRAS1 and SCARNA9) as novel biomarkers for MN, providing potential targets for the diagnosis and treatment., (© 2023. The Author(s).)

To explore the mechanism of Tripterygium wilfordii polyglycoside (TWP) in the treatment of membranous nephropathy (MN) by network pharmacology. TCMSP and DrugBank databases were used to screen the main targets of the main active components of Tripterygium glycosides, and OMIM and Gene Cards databases were used to search the gene targets of MN. UniProt database was used to normalize all the targets to get the intersection targets of TGs and MNs. Synergistic genes were uploaded to the STRING platform to construct a protein-protein interaction network and screen related core targets. Gene Ontology and Kyoto Genome Encyclopedia analyses of core targets were performed using the DAVID database. AutoDockTools software was used to verify the molecular docking between the active components of TGs and the synergistic genes. We identified 126 potential targets for the active component of Tripterygium glycosides, 584 MN-associated disease targets, and 28 co-acting genes. It mainly involves AGE-RAGE signaling pathway, lipid and atherosclerosis, IL-17 signaling pathway, fluid shear stress and atherosclerosis, NF-kappa B signaling pathway and other pathways and biological pathways in diabetic complications. The active component of that Tripterygium glycosides and the active site of the synergistic core target can the bond energy is less than -5kJ/mol. Tripterygium glycosides can regulate the release of inflammatory factors to treat MN through multiple active components, multiple disease targets, multiple biological pathways and multiple pathways, which provides a basis for broadening the clinical use of traditional Chinese medicine in the treatment of MN., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Membranous nephropathy (MN) is an autoimmune glomerular disease that is predominantly mediated by immune complex deposition and complement activation. The aim of this study was to identify key biomarkers of MN and investigate their association with immune-related mechanisms, inflammatory cytokines, chemokines and chemokine receptors (CCRs)., Methods: MN cohort microarray expression data were downloaded from the GEO database. Differentially expressed genes (DEGs) in MN were identified, and hub genes were determined using a protein-protein interaction (PPI) network. The relationships between immune-related hub genes, immune cells, CCRs, and inflammatory cytokines were examined using immune infiltration analysis, gene set enrichment analysis (GSEA), and weighted gene co-expression network analysis (WGCNA). Finally, the immune-related hub genes in MN were validated using ELISA., Results: In total, 501 DEGs were identified. Enrichment analysis revealed the involvement of immune- and cytokine-related pathways in MN progression. Using WGCNA and immune infiltration analysis, 2 immune-related hub genes ( CYBB and CSF1R ) were identified. These genes exhibited significant correlations with a wide range of immune cells and were found to participate in B cell/T cell receptor and chemokine signaling pathways. In addition, the expressions of 2 immune-related hub genes were positively correlated with the expression of CCR1 , CX3CR1 , IL1B , CCL4 , TNF , and CCR2 ., Conclusion: Our study identified CSF1 and CYBB as immune-related hub genes that potentially influence the expression of CCRs and pro-inflammatory cytokines ( CCR1 , CX3CR1 , IL1B , CCL4 , TNF , and CCR2 ). CSF1 and CYBB may be potential biomarkers for MN progression, providing a perspective for diagnostic and immunotherapeutic targets of MN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Geng, Tang, Cao, Xiang, Yang and Chen.)

Membranous nephropathy (MN) patients are diagnosed by the presence of phospholipase A 2 receptor (PLA2R) before they progress to renal failure. However, the subepithelium-like immunocomplex deposit-mediated downstream molecular pathways are poorly understood. The aryl hydrocarbon receptor (AHR), NF-ƙB and Nrf2 pathways play central roles in the pathogenesis and progression of chronic kidney disease. However, their mutual effects on MN require further examination. Thus, we investigated the effect of AHR signalling on the NF-ƙB and Nrf2 pathways in IMN patients, cationic bovine serum albumin (CBSA)-injected rats and zymosan activation serum (ZAS)-treated podocytes. IMN patients show significantly decreased serum total protein and albumin levels, increased urine protein levels and intrarenal IgG 4 and PLA2R protein expression in glomeruli compared with controls. IMN patients exhibited increased mRNA expression of intrarenal AHR and its target genes, including CYP1A1, CYP1A2, CYP1B1 and COX-2. This increase was accompanied by significantly upregulated protein expression of CD3, NF-ƙB p65 and COX-2 and significantly downregulated Nrf2 and HO-1 expression. Similarly, CBSA-induced rats showed severe proteinuria and activated intrarenal AHR signalling. This was accompanied by significantly upregulated protein expression of intrarenal p-IκBα, NF-κB p65 and its gene products, including COX-2, MCP-1, iNOS, 12-LOX, p47 phox and p67 phox , and significantly downregulated protein expression of Nrf2 and its gene products, including HO-1, catalase, GCLC, GCLM, MnSOD and NQO1. These results were further verified in ZAS-induced podocytes. Treatment with the AHR antagonist CH223191 and AHRsiRNA significantly preserved podocyte-specific protein expression and improved the NF-ƙB and Nrf2 pathways in ZAS-induced podocytes. In contrast, similar results were obtained in ZAS-induced podocytes treated with the NF-ƙB inhibitor BAY 11-7082 and NF-κBp65 siRNA. However, neither method had a significant effect on AHR signalling. Collectively, these results indicate that the NF-ƙB pathway is a downstream target of AHR signalling. Our findings suggest that blocking AHR signalling inhibits oxidative stress and inflammation, thereby improving proteinuria and renal injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Context: Idiopathic membranous nephropathy (IMN) is a common pathologic type of nephrotic syndrome, and the level of the M-type phospholipase A2 receptor (PLA2R) antibody can serve as one index for predicting its progression and prognosis. However, patients with the same level can show great differences in their responses and prognoses., Objectives: The study aimed to explore the relationship between a PLA2R gene polymorphism combined with an immunoglobulin G (IgG) subclass in renal tissues and patients' responses to immunosuppressive therapy, to determine the clinical prognosis for IMN patients., Design: This is a prospective study. Patients with new onset membranous nephropathy who need treatment were selected and grouped according to the curative effect after 6 months of treatment., Setting: The study took place at the First Affiliated Hospital of Ningbo University, Ningbo, China., Participants: Participants were 60 patients with IMN, who had been admitted in the hospital between January 1, 2021 and June 30, 2022., Intervention: Participants first received standard immunosuppressive therapy for six months. The research team then clinically divided participants into two groups: (1) a remission group with 32 participants and (2) a nonremission group with 28 participants., Outcome Measures: The research team: (1) compared the groups, summarizing the demographic and clinical differences between the groups, (2) compared the PLA2R antibody titers at baseline and postintervention between the groups, (3) analyzed the genotyping of the PLA2R single nucleotide polymorphisms (SNPs) rs35771982 and rs4664308 loci as well as the human leukocyte antigen (HLA)-DQA1 SNP rs2187668 locus, and (4) compared the subclass IgG and PLA2R depositions in the renal tissues between the groups., Results: Compared with the remission group, the nonremission group included significantly more males (P < .05), was significantly older (P < .05), had significantly more participants with a BMI of >25 (P < .05), and included significantly more participants with a positive IgG3 (P < .01) than the remission group. The remission group's PLA2R antibody titers at baseline and postintervention weren't significantly different from those of the nonremission group. Postintervention, 24 participants in the remission group had a negative conversion of PLA2R antibodies, and 22 in the nonremission group had a negative conversion. The genotyping of the PLA2R SNP rs4664308 and the HLA-DQA1 SNP rs2187668 loci showed no relationship to the remission rate. The GC genotype on the PLA2R SNPrs35771982 locus may be a risk factor for a poor prognosis for IMN patients. Moreover, the patients with a positive IgG3 in the renal tissues and the GC genotype on the PLA2R SNPrs35771982 locus exhibited a poor response to immunosuppressive therapy and could need intensive treatment., Conclusions: The PLA2R gene polymorphism combined with the IgG subclass can predict the sensitivity of IMN patients to immunosuppressive therapy.

Idiopathic membranous nephropathy (IMN) is a leading pathological type of the adult primary nephrotic syndrome. Some patients develop end-stage renal disease due to poor response to treatment with steroid and immunosuppressive agents. In order to explore the molecular mechanism of IMN, we collected renal tissue samples from IMN patients and healthy controls and performed analysis by single-cell RNA sequencing (scRNA-seq). A total of 11 kidney cell clusters were identified, including multiple myeloid cell clusters, NK/T cell clusters, and B cell clusters. Most kidney parenchymal and immune cells were enriched in the regulation of immune response, inflammation, fibrosis and endoplasmic reticulum stress. The macrophage population in the IMN group showed a highly activated profile with up-regulated genes related to chemotaxis, inflammation, phagocytosis and fibrosis. CD8+ T cells continued to be cytotoxic in IMN; however, a transition to "inflammageing" GZMK+ CD8+ T cells was observed. The proportion of activated B cells in renal tissues of IMN patients was much higher than that of normal controls, indicating that B cells in IMN might be activated by constant antigenic stimulation. Moreover, the cell-cell interaction analysis revealed the potential communication between renal glomerular cells and immune cells in IMN. Overall, scRNA-seq was applied to IMN to unravel the characteristics of immune cells and elucidate possible underlying mechanisms involved in the pathogenesis of IMN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shi, Wang, Zhang, Ling, Chen, Wang, Liu and Ma.)

A risk association between membranous nephropathy (MN) and lung cancer is reported, but traditional observational studies cannot provide strong evidence of its causality. This study aimed to assess genome-wide association studies data for a causal relationship between MN and lung cancer using a two-sample Mendelian randomization (MR) approach. Inverse-variance weighted, and MR Egger regression techniques were used to determine the association of genetic variants from cohorts of MN and lung cancer patients. Independent genetic variants with genome-wide significance (P < 5×10 -8 ) were used to determine the direction of chance. Sensitivity analyses confirmed the accuracy of the results. The results suggest that MN is an exposure factor for lung cancer, validated using a second cohort of lung cancer patients (P < 0.001). There is insufficient evidence to suggest a causal relationship between lung cancer and MN; however, cigarette smoking may be a confounding factor for lung cancer due to MN. The findings provide causal evidence for the effect of MN on lung cancer risk and may be useful for patient management, especially in older patients with MN who should be systematically screened regularly., (© 2023. Springer Nature Limited.)

IgA Nephropathy (IgAN) and Membranous Nephropathy (MN) are primary immune-mediated glomerular diseases with highly variable prognosis. Current guidelines recommend that greater immunologic activity and worse prognosis should guide towards the best treatment in an individualized approach. Nevertheless, proteinuria and glomerular filtration rate, the current gold standards for prognosis assessment and treatment guidance in primary glomerular diseases, may be altered with chronic damage and nephron scarring, conditions that are not related to immune activity. In recent years, thanks to the development of new molecular technologies, among them genome-wide genotyping, RNA sequencing techniques, and mass spectrometry, we have witnessed an outstanding improvement in understanding the pathogenesis of IgAN and MN. In addition, recent genome-wide association studies have suggested potential targets for immunomodulating agents, stressing the need for the identification of specific biomarkers of immune activity. In this work, we aim to review current evidence and recent progress, including the more recent use of omics techniques, in the identification of potential biomarkers for immune monitoring in IgAN and MN.

Background: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia and eczema and is caused by a mutation in the WAS gene. WAS has heterogeneous clinical manifestations, and its clinically milder form is called X-linked thrombocytopenia (XLT). Patients with WAS/XLT sometimes have kidney complications, the most common of which is immunoglobulin (Ig)A nephropathy associated with aberrant glycosylation of IgA., Case Diagnosis/treatment: The patient was a 6-year-old girl who was diagnosed with female XLT at the age of 4 years; she presented with microscopic hematuria and proteinuria at a school urinalysis. Her father had thrombocytopenia and IgA nephropathy while in his 20 s. The patient and her father had the same WAS gene mutations. A kidney biopsy was performed, and no abnormal findings were observed by light microscopy. Immunofluorescence analysis revealed a granular pattern of IgG staining along the capillary wall. Electron microscopy revealed small electron-dense deposits in subepithelial lesions. Consequently, we diagnosed her with membranous nephropathy (MN). Tissue PLA2R and THSD7A were negative, and she was judged unlikely to have secondary MN on the basis of blood test findings and IgG staining. We started the administration of angiotensin-converting enzyme inhibitors, and her proteinuria gradually decreased., Conclusion: To our knowledge, this is the first report of MN in a female WAS/XLT patient. WAS protein expression defects affect all immune system cells; however, the mechanisms underlying the occurrence of autoimmunity are not completely understood. In WAS/XLT patients, MN may develop as a result of increased autoantibody production, similar to other types of immunodeficiency., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Membranous nephropathy (MN) is the most prevalent cause of nephrotic syndrome amongst the non-diabetic adult population. A fifth of idiopathic nephrotic syndrome cases can be attributed to MN, rising to more than 40% in older patients over 60 years. Most MN cases are classified as being of a primary cause, where there is absence of a secondary disease process explaining its manifestation. Traditionally, the standard approach of diagnosing MN involves performing a kidney biopsy as histological evaluation offers not only conclusive evidence of the diagnosis but also provides valuable information regarding disease chronicity and the presence of any other kidney histopathological features. Nevertheless, kidney biopsy is an invasive procedure which poses risks for the patient including bleeding and pain and bears greater costs for the health system. The identification of the phospholipase A2 receptor (PLA2R) antigen in 2009 was a landmark discovery, one which has evolved our understanding of the disease processes in MN and subsequently our management approach of this condition. Antibodies against PLA2R (PLA2RAb) have since emerged as an attractive non-invasive test option to be applied for the diagnosis and prognostication of primary MN. However, much debate and unknowns remain about the accuracy and reliability of testing for PLA2RAb across various primary MN scenarios. We provide a review summarizing the historical journey of PLA2R in relation to its significance in primary MN and, more importantly, evidence emerging over the years which contemplated the role of PLA2RAb as a diagnostic and prognostic tool in primary MN.

Background: The phospholipase A2 receptor (PLA2R) associated with membranous nephropathy (MN) is an organ-specific autoimmune disease associated with PLA2R and human leukocyte antigen (HLA) genes. Familial PLA2R-related MN is rarely reported. The combination of anti-GBM disease and MN has been well documented, though the mechanism behind it remains unclear., Case Presentation: We describe two siblings diagnosed with pathology-confirmed PLA2R-related MN 1 year apart. And one of the two siblings developed an anti-GBM disease. The high-resolution HLA typing showed identical alleles in both siblings, specifically heterozygotes of DRB1*15:01/*03:01., Conclusion: We describe a familial case of PLA2R-related MN supporting the role of genetic factors that HLA-DRB1*15:01 and DRB1*03:01 predispose patients in the development of PLA2R-related MN in the Han Chinese population. The combination of MN and anti-GBM disease may also partially be associated with the same susceptible HLA allele DRB1*15:01., (© 2023. The Author(s).)

Objective: To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients., Methods: A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment., Results: Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group ( P < 0.05)., Conclusion: Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.

Idiopathic membranous nephropathy (IMN), a single-organ autoimmune disease, is recognized by autoantibodies to podocyte proteins and identified as the most frequent cause of nephrotic syndrome in adults. T cells are important contributors in autoimmunity since they promote B-cell development, antibody production, direct inflammation, and organ tissue cytotoxicity. This study investigated the inhibitory immune checkpoint (ICP) receptors expressed on T lymphocytes and other immune cells. Thus, PBMCs from IMN patients were obtained before treatment, and the levels of ICPs such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte activation gene-3 (LAG-3), and T cell immunoglobulin-3 (TIM-3) were examined at both gene and protein expression using real time PCR and Western blot tests respectively. The results illustrated that gene expression levels of ICPs reduced significantly in comparison to the control which were verified by related fold changes of protein expression sequentially. Our study revealed that CTLA-4, PD-1, TIM-3, and LAG-3 expression is impaired in IMN patients before treatment which could be a potential target for therapy., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite MN being one of the most common causes of nephrotic syndrome worldwide, its biological and environmental determinants are poorly understood in large-part due to it being a rare disease. Making use of the UK Biobank, a unique resource holding a clinical dataset and stored DNA, serum and urine for ~500,000 participants, this study aims to address this gap in understanding., Methods: The primary outcome was putative MN as defined by ICD-10 codes occurring in the UK Biobank. Univariate relative risk regression modelling was used to assess the associations between the incidence of MN and related phenotypes with sociodemographic, environmental exposures, and previously described increased-risk SNPs., Results: 502,507 patients were included in the study of whom 100 were found to have a putative diagnosis of MN; 36 at baseline and 64 during the follow-up. Prevalence at baseline and last follow-up were 72 and 199 cases/million respectively. At baseline, as expected, the majority of those previously diagnosed with MN had proteinuria, and there was already evidence of proteinuria in patients diagnosed within the first 5 years of follow-up. The highest incidence rate for MN in patients was seen in those homozygous for the high-risk alleles (9.9/100,000 person-years)., Conclusion: It is feasible to putatively identify patients with MN in the UK Biobank and cases are still accumulating. This study shows the chronicity of disease with proteinuria present years before diagnosis. Genetics plays an important role in disease pathogenesis, with the at-risk group providing a potential population for recall., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2023 Hamilton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Little is known about the mechanistic significance of the ubiquitin proteasome system (UPS) in a kidney autoimmune environment. In membranous nephropathy (MN), autoantibodies target podocytes of the glomerular filter resulting in proteinuria. Converging biochemical, structural, mouse pathomechanistic, and clinical information we report that the deubiquitinase Ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced by oxidative stress in podocytes and is directly involved in proteasome substrate accumulation. Mechanistically, this toxic gain-of-function is mediated by non-functional UCH-L1, which interacts with and thereby impairs proteasomes. In experimental MN, UCH-L1 becomes non-functional and MN patients with poor outcome exhibit autoantibodies with preferential reactivity to non-functional UCH-L1. Podocyte-specific deletion of UCH-L1 protects from experimental MN, whereas overexpression of non-functional UCH-L1 impairs podocyte proteostasis and drives injury in mice. In conclusion, the UPS is pathomechanistically linked to podocyte disease by aberrant proteasomal interactions of non-functional UCH-L1., (© 2023. The Author(s).)

Background: Disparity in CKD progression among Black individuals persists in glomerular diseases. Genetic variants in the apolipoprotein L1 ( APOL1 ) gene in the Black population contribute to kidney disease, but the influence in membranous nephropathy remains unknown., Methods: Longitudinally followed participants enrolled in the Glomerular Disease Collaborative Network or Cure Glomerulonephropathy Network were included if they had DNA or genotyping available for APOL1 (Black participants with membranous nephropathy) or had membranous nephropathy but were not Black. eGFR slopes were estimated using linear mixed-effects models with random effects and adjusting for covariates and interaction terms of covariates. Fisher exact test, Kruskal-Wallis test, and Kaplan-Meier curves with log-rank tests were used to compare groups., Results: Among 118 Black membranous nephropathy participants, 16 (14%) had high-risk APOL1 genotype (two risk alleles) and 102 (86%) had low-risk APOL1 genotype (zero or one risk alleles, n =53 and n =49, respectively). High-risk APOL1 membranous nephropathy participants were notably younger at disease onset than low-risk APOL1 and membranous nephropathy participants that were not Black ( n =572). eGFR at disease onset was not different between groups, although eGFR decline (slope) was steeper in participants with high-risk APOL1 genotype (-16±2 [±SE] ml/min per 1.73 m 2 per year) compared with low-risk APOL1 genotype (-4±0.8 ml/min per 1.73 m 2 per year) or membranous nephropathy participants that did not identify themselves as Black (-2.0±0.4 ml/min per 1.73 m 2 per year) ( P <0.0001). Time to kidney failure was faster in the high-risk APOL1 genotype than low-risk APOL1 genotype or membranous nephropathy participants that were not Black., Conclusions: The prevalence of high-risk APOL1 variant among Black membranous nephropathy participants is comparable with the general Black population (10%-15%), yet the high-risk genotype was associated with worse eGFR decline and faster time to kidney failure compared with low-risk genotype and participants that were not Black., (Copyright © 2023 by the American Society of Nephrology.)

The major form of membranous nephropathy is characterized by autoantibodies to phospholipase A2 receptor 1 (PLA2R1). The study by Tomas et al. describes the first animal model where human PLA2R1 is ectopically expressed in mouse podocytes. Intriguingly, the transgenic mice spontaneously develop anti-human PLA2R1 antibodies and membranous nephropathy-like features, including immune deposits and nephrotic syndrome. The model raises questions about the spontaneous production of anti-human PLA2R1 antibodies and the additional steps to establish a bona fide animal model of membranous nephropathy., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. However, both the initiation pathways and the pathogenic significance of complement activation in MN are poorly understood. Here, we show that components from all three complement pathways (alternative, classical and lectin) are found in renal biopsies from patients with MN. Proximity ligation assays to directly visualize complement assembly in the tissue reveal dominant activation via the classical pathway, with a close correlation to the degree of glomerular C1q-binding IgG subclasses. In an antigen-specific autoimmune mouse model of MN, glomerular damage and proteinuria are reduced in complement-deficient mice compared with wild-type littermates. Severe disease with progressive ascites, accompanied by extensive loss of the integral podocyte slit diaphragm proteins, nephrin and neph1, only occur in wild-type animals. Finally, targeted silencing of C3 using RNA interference after the onset of proteinuria significantly attenuates disease. Our study shows that, in MN, complement is primarily activated via the classical pathway and targeting complement components such as C3 may represent a promising therapeutic strategy., (© 2023. The Author(s).)

Objective: To investigate the efficacy of cyclophosphamide combined with prednisone in membranous nephropathy (MN) patients with different cytochrome P450 (CYP) 2B6 gene polymorphisms and explore the factors influencing the efficacy., Methods: We performed a prospective and interventional study including 153 outpatients diagnosed with membranous nephropathy from April 2020 to June 2020 in the Bayannur Hospital. Based on the results of CYP2B6 gene polymorphisms, patients were divided into CYP2B6*4 group (785A>G) with 93 cases and CYP2B6*5 group (1459C>T) with 60 cases, and all patients were treated with cyclophosphamide and prednisone. The efficacy of the two groups was compared, and the serum levels of antibody against thrombospondin type-1 domain-containing 7A (THSD7A-Ab), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and antibody against the M-type phospholipase A2 receptor (PLA2R-Ab) determined by the enzyme-linked immunosorbent method were analyzed in the two groups before and after treatment., Results: After the treatment with cyclophosphamide and prednisone, serum levels of THSD7A-Ab, 8-OHdG, and PLA2R-Ab were higher in the CYP2B6*4 group than those in the CYP2B6*5 group (All three P <0.001). The univariate Logistic regression analysis showed that CYP2B6*4 (OR = 1.727, 95% CI: 1.028-2.654. P =0.012), CYP2B6*5 (OR = 1.802, 95% CI: 1.179-2.752. P =0.031), THSD7A-Ab (OR = 1.832, 95% CI: 0.871-2.348. P =0.023), 8-OHdG (OR = 1.661, 95% CI: 1.123-2.231. P =0.009), PLA2R-Ab (OR = 1.649, 95% CI: 1.083-2.761. P =0.017) were independent influencing factors on the efficacy of MN. The multivariate Logistic regression analysis showed that CYP2B6*4 (OR = 2.009, 95% CI: 1.327-2.703. P <0.001), CYP2B6*5 (OR = 3.009, 95% CI: 1.467-5.231. P =0.005), THSD7A-Ab (OR = 1.396, 95% CI: 1.002-1.897. P =0.019), 8-OHdG (OR = 0.704, 95% CI: 0.591-0.742. P <0.001), PLA2R-Ab (OR = 2.761, 95% CI: 1.231-3.918. P =0.017) were independent factors influencing the efficacy of cyclophosphamide and prednisone on MN., Conclusion: Cyclophosphamide combined with prednisone was effective in treating MN with different CYP2B6 gene polymorphisms. CYP2B6*4, CYP2B6*5, and serum levels of THSD7A-Ab, 8-OHdG, and PLA2R-Ab were independent influencing factors on the outcome of MN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Zhang et al.)

Tacrolimus has been widely used in membranous nephropathy in recent years. The drug interactions of the coadministration of tacrolimus with omeprazole in CYP3A5 nonexpresser membranous nephropathy patients have not been demonstrated. Here, we report an idiopathic membranous nephropathy patient who was with CYP2C19*2/*2, CYP3A5*3/*3 (nonexpresser) and ABCB1 (3435 TT, 1236 computed tomography, 2677 TT) genotype requiring treatment with tacrolimus and omeprazole and found to have fluctuating metabolism of tacrolimus. This study shows that tacrolimus and omeprazole have pharmacologic drug interactions in CYP3A5 nonexpressers, implying that the CYP3A and ABCB1 gene mutations linked to tacrolimus metabolism may alter tacrolimus levels in the blood. The observed concentrations of tacrolimus were decreased after the discontinuation of omeprazole therapy. It demonstrates that, in addition to genotype, clinical covariates, such as omeprazole are important when it comes to better understanding and prediction of tacrolimus dosage. It is deemed necessary to monitor tacrolimus blood concentrations and make dose adjustments when patients were coadministered with omeprazole., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Gitelman syndrome (GS) is a rare autosomal recessive inherited salt-losing tubulopathy (SLT). Here, we report, for the first time, a case of GS overlapping nephrotic syndrome (NS) related to PLA2R-associated membranous nephropathy (MN)., Case Presentation: We described a male patient had a 4-year history of recurrent fatigue. Serum biochemistry revealed hypokalemia with renal potassium wasting, hypomagnesemia, metabolic alkalosis, hyperreninemia, hypocalciuria, as well as nephrotic-range proteinuria, hypoalbuminemia, and elevated serum anti-phospholipase A2 receptor (PLA2R) antibody. Gene sequencing identified compound heterozygous mutations in SLC12A3 [c.536T > A(p.V179D) and c.1456G > A(p.D486N)]. The unusual association of SLTs and nephrotic-range glomerular proteinuria prompted us to perform a renal biopsy. Renal biopsy showed idiopathic MN. Due to the potential to activate the sodium-chloride co-transporter (NCC) and cause hyperkalemia, tacrolimus was selected to treat NS. Following treatment with potassium chloride, magnesium oxide, low-dose glucocorticoid combined with tacrolimus, the fatigue significantly improved, and concurrently hypokalemia, hypomagnesemia were corrected and NS was remitted., Conclusions: Renal biopsy should be warranted for GS patients with moderate to nephrotic-range proteinuria. Tacrolimus was preferred to the management of GS patients with NS., (© 2022. The Author(s).)

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic immunodeficiency disease caused by forkhead box protein3 (FOXP3) mutation. The kidney is commonly involved in IPEX syndrome, but there were few studies focusing on renal involvement., Methods: Whole-exome sequencing was used to identify the novel FOXP3 mutation. We collected clinical manifestations, kidney pathology, and gene function of the proband. All the previously published studies with IPEX-associated renal involvement were reviewed., Results: We report a late-onset Chinese child with IPEX-associated membranous nephropathy (MN). Type 1 diabetes mellitus and nephrotic-range proteinuria are the main clinical manifestations. Whole-exome sequencing shows a novel c.766A > G mutation in the FOXP3 gene. The literature review indicates that renal manifestations include proteinuria, microscopic hematuria, and renal insufficiency. MN is the most common pathological type in children with IPEX, followed by tubulointerstitial nephritis, interstitial nephritis, minimal change nephrotic syndrome, and membranoproliferative glomerulonephritis., Conclusion: In summary, we report a novel FOXP3 mutation (c.766A > G) with MN stage II in IPEX. In a literature review, MN is the most common pathological type in children with IPEX and proteinuria is the most prevalent clinical feature. IPEX should be considered in the differential diagnosis of MN patients with related endocrine diseases and immune disorders., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Abstract: Circular RNAs (circRNAs) have been verified as vital regulators in various diseases, including membranous nephropathy (MN). Therefore, the role of circ&#95;CDYL in podocyte apoptosis and MN was investigated. The real-time quantitative polymerase chain reaction was performed to measure the expression of circ&#95;CDYL, microRNA-149-5p (miR-149-5p), and tumor necrosis factor superfamily member 11 (TNFSF11) in podocytes. In addition, angiotensin II (Ang II) was used to induce apoptosis of podocytes. The apoptosis-related protein expression was quantified by western blot assay. The apoptosis of podocytes was evaluated by flow cytometry assay. The interaction relationship between miR-149-5p and circ&#95;CDYL or TNFSF11 was confirmed by dual-luciferase reporter assay. Circ&#95;CDYL was significantly overexpressed in MN patients and Ang II-induced podocytes compared with control groups. Importantly, loss-of-functional experiments indicated that knockdown of circ&#95;CDYL protected podocytes from Ang II-induced apoptosis. MiR-149-5p was verified as target of circ&#95;CDYL and negatively correlated with circ&#95;CDYL expression in MN patients. Knockdown of circ&#95;CDYL-mediated effects on Ang II-induced podocyte cells were abolished by silencing miR-149-5p. Besides, the upregulation of miR-149-5p could suppress apoptosis in Ang II-induced podocyte cells by targeting TNFSF11. Under Ang II stimulation, the upregulation of TNFSF11 could increase the expression of TNFSF11 and induce apoptosis in circ&#95;CDYL-silencing podocytes. Our results confirmed that circ&#95;CDYL specifically targeted miR-149-5p/TNFSF11 pathway to regulate Ang II-induced apoptosis in podocytes, which might be useful diagnostic biomarkers in MN., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Molecular characterization of nephropathies may facilitate pathophysiologic insight, development of targeted therapeutics, and transcriptome-based disease classification. Although membranous nephropathy (MN) is a common cause of adult-onset nephrotic syndrome, the molecular pathways of kidney damage in MN require further definition., Methods: We applied a machine-learning framework to predict diagnosis on the basis of gene expression from the microdissected kidney tissue of participants in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We sought to identify differentially expressed genes between participants with MN versus those of other glomerulonephropathies across the NEPTUNE and European Renal cDNA Bank (ERCB) cohorts, to find MN-specific gene modules in a kidney-specific functional network, and to identify cell-type specificity of MN-specific genes using single-cell sequencing data from reference nephrectomy tissue., Results: Glomerular gene expression alone accurately separated participants with MN from those with other nephrotic syndrome etiologies. The top predictive classifier genes from NEPTUNE participants were also differentially expressed in the ERCB participants with MN. We identified a signature of 158 genes that are significantly differentially expressed in MN across both cohorts, finding 120 of these in a validation cohort. This signature is enriched in targets of transcription factor NF-κB. Clustering these MN-specific genes in a kidney-specific functional network uncovered modules with functional enrichments, including in ion transport, cell projection morphogenesis, regulation of adhesion, and wounding response. Expression data from reference nephrectomy tissue indicated 43% of these genes are most highly expressed by podocytes., Conclusions: These results suggest that, relative to other glomerulonephropathies, MN has a distinctive molecular signature that includes upregulation of many podocyte-expressed genes, provides a molecular snapshot of MN, and facilitates insight into MN's underlying pathophysiology., (Copyright © 2022 by the American Society of Nephrology.)