Pathogenesis Of Membranous Nephropathy Research Articles

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.

Astragaloside IV relieves passive heymann nephritis and podocyte injury by suppressing the TRAF6/NF-κb axis

The pathogenesis of membranous nephropathy (MN) involves podocyte injury that is attributed to inflammatory responses induced by local immune deposits. Astragaloside IV (AS-IV) is known for its robust anti-inflammatory properties. Here, we investigated the effects of AS-IV on passive Heymann nephritis (PHN) rats and TNF-α-induced podocytes to determine the underlying molecular mechanisms of MN. Serum biochemical parameters, 24-h urine protein excretion and renal histopathology were evaluated in PHN and control rats. The expression of tumor necrosis factor receptor associated factor 6 (TRAF6), the phosphorylation of nuclear factor kappa B (p-NF-κB), the expression of associated proinflammatory cytokines (TNF-α, IL-6 and IL-1β) and the ubiquitination of TRAF6 were measured in PHN rats and TNF-α-induced podocytes. We detected a marked increase in mRNA expression of TNF-α, IL-6 and IL-1β and in the protein abundance of p-NF-κB and TRAF6 within the renal tissues of PHN rats and TNF-α-induced podocytes. Conversely, there was a reduction in the K48-linked ubiquitination of TRAF6. Additionally, AS-IV was effective in ameliorating serum creatinine, proteinuria, and renal histopathology in PHN rats. This effect was concomitant with the suppression of NF-κB pathway activation and decreased expression of TNF-α, IL-6, IL-1β and TRAF6. AS-IV decreased TRAF6 levels by promoting K48-linked ubiquitin conjugation to TRAF6, which triggered ubiquitin-mediated degradation. In summary, AS-IV averted renal impairment in PHN rats and TNF-α-induced podocytes, likely by modulating the inflammatory response through the TRAF6/NF-κB axis. Targeting TRAF6 holds therapeutic promise for managing MN.

The influence of gut microbiota on membranous nephropathy: A two-sample Mendelian randomization study.

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. 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. 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. 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.

#1360 SARS-COV-2 protein in renal tissue enhanced activation of complement system in MN patients with COVID-19 infection

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Complement plays an important role in the pathogenesis of MN. COVID-19 infection has been reported to be associated with the occurrence and recurrence of MN. Only few kidney biopsies from COVID-19 patients demonstrate the presence of SARS-CoV-2 in the tissue. The clinical and pathological characteristics and complement system activation of patients with SARS-COV2 in renal tissue are unclear, needing to further study. Method From December 2022 to June 2023, patients with renal biopsy-proven MN at Beijing Anzhen hospital who had experienced COVID-19 infection before proteinuria onset and renal biopsy were enrolled. One hundred patients with primary MN diagnosed from December 2018 to June 2019 (with no COVID-19) were enrolled as control. Patient medical records were reviewed for clinical and pathological data. We performed immunofluorescence and in situ hybridization assays for detection of the SARS-COV2. Glomerular staining for factor H, FHR-5 and MAC were detected by immunohistochemical. Serum C5b-9 were detected by enzyme-linked immunosorbent assay. Clinicopathological and immunological features between MN patients with and without SARS-COV2 infection were analyzed. Results A total of 38 MN patients was proteinuria onset after COVID-19 infection, including 11 patients had SARS-COV protein positive staining along capillary loops in glomerular deposits or in cytoplasm of tubular epithelial cells. The immunofluorescence result shows strong colocalization of SARS-COV2 and IgG, which suggests that SARS-COV protein participated in the formation of immune complex. Compared with primary MN patients, the serum albumin level of 38 MN patients with COVID-19 infection were lower (p = 0.011). However, the clinical manifestations of 11 MN patients with SARS-COV2 renal positive staining were obviously serous. Compared with primary MN patients, urinary protein and serum creatine levels significantly increased (p = 0.027 and p = 0.005), while serum albumin levels decreased (p = 0.014) and the proportion of nephrotic syndrome (p = 0.037) was higher. There was no significant difference in pathological manifestations between MN patients with or without COVID-19 infection. In follow-up, the proportion of patients with urinary protein decreased greater than 50% in MN patients with COVID-19 infection was lower than that in primary MN patients. of urinary protein level Serum level of complement C3 (p = 0.007) and MAC (P = 0.001) in MN patients with COVID-19 infection was significantly higher than that of primary MN patients, especially MN patients with renal tissue positive staining of SARS-COV2 protein (p = 0.002 and p = 0.007). In 38 MN patients with COVID-19 infection, compared with patients with renal tissue negative for SARS-COV2 protein, patients with renal tissue positive for SARS-COV2 protein presented with stronger intensity of MAC deposition (p = 0.023) and factor H deposition (p = 0.002). Conclusion The clinical manifestation of MN patients who was onset after COVID-19 infection with renal tissue positive for SARS-COV2 protein were not only significantly worse than those of primary MN patients, but also worse than patients without tissue SARS-COV2 positive MN patients. We speculate that the reason is the enhanced activation of the complement system in renal tissue.

Lectin complement pathway and diabetes mellitus in the pathogenesis of membranous nephropathy.

Membranous nephropathy (MN) is a glomerulonephritis with growing incidence and its pathogenesis still remains unclear, despite discoveries of many new antigens. The understanding of MN pathogenesis has moved from antigen-antibody arena to the complement activation through the lectin pathway.

The role of the complement system in primary membranous nephropathy: A narrative review in the era of new therapeutic targets.

Primary membranous nephropathy (MN) is an important cause of nephrotic syndrome and chronic kidney disease (CKD) in the adult population. Although the discovery of different autoantibodies against glomerular/podocytic antigens have highlighted the role of B cells in the pathogenesis of MN, suboptimal response or even resistance to B cell-directed therapies occurs, suggesting that other pathophysiological mechanisms are involved in mediating podocyte injury. The complement system plays an important role in the innate immune response to infection, and dysregulation of the complement system has been observed in various kidney diseases. There is compelling evidence of complement cascade activation in primary MN, with the mannose-binding lectin (MBL) and alternative pathways particularly implicated. With appropriate validation, assays of complements and associated activation products could hold promise as adjunctive tools for non-invasive disease monitoring and prognostication. While there is growing interest to target the complement system in MN, there is concern regarding the risk of infection due to encapsulated organisms and high treatment costs, highlighting the need for clinical trials to identify patients most likely to benefit from complement-directed therapies.

Update on New Antigens in the Pathogenesis of Membranous Nephropathy

Previously, membranous nephropathies were divided into primary and secondary categories when the exact mechanism or pathogenetic factor were unknown. Approximately 70% accounted for primary membranous nephropathies. The remaining 30% were called secondary because they developed due to well-known diseases such as autoimmune diseases, tumours, infections, or drug assumptions. The discoveries of the M-type phospholipase A2 receptor and of thrombospondin type 1 domain containing 7A as causative antigens in a part of the so-called primary membranous nephropathies opened new knowledge on the effective causes of a large part of these diseases. The availability of novel techniques such as laser micro-dissection and tandem mass spectrometry, as well as immunochemistry with antibodies directed against novel proteins, allowed the confirmation of new antigens involved. The use of confocal microscopy and Western blot allowed detection of the new antigen on glomerular membrane, and the same antigen and relative antibodies have been detected in serum samples. Through these techniques, four new antigens were first detected, including neural epidermal growth factor 1 and semaphorin 3B in the so-called primary membranous nephropathy, and exostosin 1 and 2 and neural cell adhesion molecule 1 in lupus membranous nephropathy. The aim of this study is to describe the characteristics of the new antigens discovered and their association with other diseases. In addition, new antigens are on the horizon, and the story of primary membranous nephropathy is still to be completely written and understood.

Complement C3a and C3a Receptor Activation Mediates Podocyte Injuries in the Mechanism of Primary Membranous Nephropathy.

The complement system is highly activated in primary membranous nephropathy (MN). Identifying the complement components that damage podocytes has important therapeutic implications. This study investigated the role of C3a and the C3a receptor (C3aR) in the pathogenesis of MN. C3aR expression in kidneys and circulating levels of C3a of MN patients were examined. Human podocyte damage was assessed after exposure to MN plasma +/- C3aR blockade (SB290157, JR14a). C3aR antagonists were administered to rats with Heymann nephritis on day 0 or after proteinuria. Clinical and pathologic parameters, specific IgG and complement activation, and podocyte injuries were then assessed. In the glomeruli, C3aR staining merged well with podocin. Overexpression of C3aR correlated positively with proteinuria, serum creatinine, and no response to treatments. Human podocytes exposed to MN plasma showed increased expression of PLA2R, C3aR, and Wnt3/β-catenin, reduced expression of synaptopodin and migration function, downregulated Bcl-2, and decreased cell viability. C3aR antagonists could block these effects. In Heymann nephritis rats, C3aR blockade attenuated proteinuria, electron-dense deposition, foot process width, and glomerular basement membrane thickening in glomeruli. The increased plasma C3a levels and overexpression of C3aR were also alleviated. Specific, but not total, IgG levels decreased, with less deposition of rat IgG in glomeruli and subsequent reduction of C1q, factor B, and C5b-9. C3a anaphylatoxin is a crucial effector of complement-mediated podocyte damage in MN. The C3aR antagonist may be a potentially viable treatment for this disease.

Gut Microbiome Analysis Can Be Used as a Noninvasive Diagnostic Tool and Plays an Essential Role in the Onset of Membranous Nephropathy.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome. The aim is to establish a non‐invasive diagnostic model of MN using differential gut microbiome analysis, and to explore the relationship between the gut microbiome and MN pathogenesis in vivo. 825 fecal samples from MN patients and healthy participants are collected from multiple medical centers across China. Key operational taxonomic units (OTUs) obtained through 16S rRNA sequencing are used to establish a diagnostic model. A rat model of MN is developed to explore the relationship between the gut microbiome and the pathogenesis of MN. The diversity and richness of the gut microbiome are significantly lower in patients with MN than in healthy individuals. The diagnostic model based on seven OTUs achieves an excellent efficiency of 98.36% in the training group and also achieves high efficiency in cross‐regional cohorts. In MN rat model, gut microbiome elimination prevents model establishment, but fecal microbiome transplantation restores the phenotype of protein urine. Gut microbiome analysis can be used as a non‐invasive tool for MN diagnosis. The onset of MN depends on the presence of naturally colonized microbiome. Early intervention in the gut microbiome may help reduce urinary protein level in MN.

A Discussion on TCM Treatment and the Pathogenesis of Membranous Nephropathy in Primary Nephrotic Syndrome

Objective: To investigate the TCM treatment principle of membranous nephropathy and its effect. Methods: A total of 56 patients were selected from the Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine. They were then divided into the control group (western medicine standard therapy) and the study group (Qidi Gushen prescription), with 28 patients in each group. The treatment effect, treatment safety, and patients’ satisfaction were observed and compared between the two groups. Results: The results showed that the treatment effect of the study group was 96.43%, which was significantly better compared with the control group (75.00%) (p &lt; 0.05); in terms of safety, the probability of adverse events was 7.14% in the study group and 32.14% in the control group, in which the difference was statistically significant (p &lt; 0.05); in addition, the study group’s satisfaction with the treatment measures was significantly higher than that of the control group (p &lt; 0.05). Conclusion: In treating membranous nephropathy, traditional Chinese medicine can be tailored to its pathogenesis, which is not only beneficial to the treatment effect, but also has a high safety profile.

Novel Biomarkers in Membranous Nephropathy.

Membranous nephropathy (MN) is the main cause of adult nephrotic syndrome (NS). The pathogenesis of MN is complex and involves subepithelial immune complex deposition. Approximately one-third of patients with MN develop end-stage renal disease (ESRD). Timely diagnosis and reasonable intervention are the keys to improving prognosis. In recent years, with the development of high-throughput technologies, such as mass spectrometry (MS), microarray, and sequencing technologies, the discovery of biomarkers for MN has become an important area of research. In this review, we summarize the significant progress in biomarker identification. For example, a variety of podocyte target antigens and their autoantibodies have been reported. Phospholipase A2 receptor (PLA2R) is the most well-established target antigen in MN. PLA2R and its autoantibodies have clinical significance, with both diagnostic and therapeutic value for MN. In addition, a variety of new biomarkers, including proteins, metabolites, noncoding RNAs (ncRNAs), and immune cells, have recently been found. These MN-related biomarkers have great significance in the diagnosis, progression, prognosis, and treatment response of MN.

Complement induces podocyte pyroptosis in membranous nephropathy by mediating mitochondrial dysfunction

Podocyte damage mediated by in situ complement activation in the glomeruli is a key factor in the pathogenesis of membranous nephropathy (MN), but the molecular mechanism has not been fully elucidated. Pyroptosis is a special type of programmed cell death, mediate inflammatory response and induce tissue injury. However, it is not clear whether pyroptosis is involved in the development and progression of MN. Here, we report that pyroptosis plays an important role in promoting podocyte injury in MN. We first observed the occurrence of pyroptosis in the kidneys of MN patients and validated that complement stimulation triggered pyroptosis in podocytes and that inhibiting pyroptosis reversed complement-induced podocyte damage in vitro. In addition, stimulation of complement caused mitochondrial depolarization and reactive oxygen species (ROS) production in podocytes, and inhibition of ROS reversed complement-induced pyroptosis in podocytes. Interestingly, inhibition of pyroptosis in turn partially alleviated these effects. Furthermore, we also found the involvement of pyroptosis in the kidneys of passive Heymann nephritis (PHN) rats, and inhibitors of pyroptosis-related molecules relieved PHN-induced kidney damage in vivo. Our findings demonstrate that pyroptosis plays a critical role in complement-induced podocyte damage in MN and mitochondrial dysfunction is an important mechanism underlying this process. It provides new insight that pyroptosis may serve as a novel therapeutic target for MN treatment in future studies.

Exploring the Differences in Molecular Mechanisms and Key Biomarkers Between Membranous Nephropathy and Lupus Nephritis Using Integrated Bioinformatics Analysis.

Background: Both membranous nephropathy (MN) and lupus nephritis (LN) are autoimmune kidney disease. In recent years, with the deepening of research, some similarities have been found in the pathogenesis of these two diseases. However, the mechanism of their interrelationship is not clear. The purpose of this study was to investigate the differences in molecular mechanisms and key biomarkers between MN and LN. Method: The expression profiles of GSE99325, GSE99339, GSE104948 and GSE104954 were downloaded from GEO database, and the differentially expressed genes (DEGs) of MN and LN samples were obtained. We used Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for enrichment analysis of DEGs. A protein-protein interaction (PPI) network of DEGs was constructed using Metascape. We filtered DEGs with NetworkAnalyst. Finally, we used receiver operating characteristic (ROC) analysis to identify the most significant DEGs for MN and LN. Result: Compared with LN in the glomerulus, 14 DEGs were up-regulated and 77 DEGs were down-regulated in MN. Compared with LN in renal tubules, 21 DEGs were down-regulated, but no up-regulated genes were found in MN. According to the result of GO and KEGG enrichment, PPI network and Networkanalyst, we screened out six genes (IFI6, MX1, XAF1, HERC6, IFI44L, IFI44). Interestingly, among PLA2R, THSD7A and NELL1, which are the target antigens of podocyte in MN, the expression level of NELL1 in MN glomerulus is significantly higher than that of LN, while there is no significant difference in the expression level of PLA2R and THSD7A. Conclusion: Our study provides new insights into the pathogenesis of MN and LN by analyzing the differences in gene expression levels between MN and LN kidney samples, and is expected to be used to prepare an animal model of MN that is more similar to human.

补体系统在膜性肾病发病机制中的研究进展

补体系统在膜性肾病发病机制中的研究进展

Bioinformatic investigation for candidate genes and molecular mechanism in the pathogenesis of membranous nephropathy.

We aimed to explore the detailed molecular mechanism of immune-associated genes in membranous nephropathy (MN). A microarray data set (GSE133288) was retrieved from the Gene Expression Omnibus database. Differentially expressed mRNAs (DEMs) in MN vs control groups were identified, and MN-related DEMs (MN-DEMs) were further verified and screened using the comparative toxicogenomics database (CTD) database. The publicly available database, InnateDB was used to investigate immune genes, and the overlapped genes between MN-DEMs and the immune genes were considered as MN-related immune genes (iDEMs). A protein-protein interaction network (PPI) was constructed based on these iDEMs, followed by function and pathway enrichment analysis. Finally, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) associated with iDEMs were predicted, followed by a lncRNA-miRNA-mRNA (competing endogenous RNAs, ceRNA) network construction. A total of 327 DEMs and 48 iDEMs were revealed; a PPI network was constructed with 100 PPI pairs and 37 iDEMs. iDEMs including JUN and FOS were mainly enriched in pathways such as osteoclast differentiation and function including response to immobilization stress, respectively. Based on mRNA-associated miRNA and lncRNA prediction, 30 ceRNA interactions including KCNQ1OT1-miR-204-5p-SRY-Box Transcription Factor 4 (SOX4) were explored. mRNAs including FOS and JUN might participate in MN development via response to immobilization stress function and the osteoclast differentiation pathway. The mRNA SOX4 might contribute to MN progression via sponging KCNQ1OT1-miR-204-5p interaction.

Is primary membranous nephropathy a complement mediated disease?

Membranous nephropathy (MN) is an immune complex mediated disease. Although limited to the kidney, in up to 20% of patients MN is associated with other autoimmune, infectious or malignant diseases. The initial pathogenetic event in what is still considered “primary” MN is the binding of circulating autoantibodies to proteins (autoantigens) expressed in glomerular podocytes. This antibody binding leads to the formation of immune complexes in the glomerular basement membrane. There is clinical and experimental evidence that these immune deposits lead to the activation of the complement system. Experimental studies in the MN model of Heymann’s nephritis show that the terminal membrane attack complex (MAC) of the complement system induces a disturbance of the glomerular filtration barrier and leads to proteinuria, the clinical hallmark of MN. After the discovery of the phospholipase A2 receptor 1 and thrombospondin type 1 domain containing protein 7A as endogenous antigens, it is assumed that IgG4 antibodies directed against these proteins induce MN in over 85% of patients with primary MN. As a result, the role of complement in the pathogenesis of MN needs to be defined in light of these developments. In this review we describe the current knowledge on the function of the complement system in primary MN and discuss the open questions, which have to be solved for a better understanding of the potential role of complement in the pathophysiology of primary MN.

Autoantibodies against phospholipase A2 receptor in Brazilian patients with glomerular diseases

Recently, great progress has been made in understanding the pathogenesis of membranous nephropathy (MN) with the discovery of autoantibodies (Abs) to M-type phospholipase A2 receptor (PLA2R) in serum and in immunocomplexes deposited in glomerulus in most adult patients with primary MN. To evaluate the diagnostic performance of anti-PLA2R in Brazilian patients with MN, as well as to verify the possible association of anti-PLA2R serum levels with disease activity. 117 patients with glomerular diseases confirmed by renal biopsy underwent routinely clinical and laboratory evaluation (serum creatinine and albumin, 24-h proteinuria, urinalysis, tests for etiological investigation) and determination of serum anti-PLA2R by ELISA. 67.5% of the patients had MN, 9.4% focal segmental glomerulosclerosis, 7.7% lupus nephritis class V and 15.4%, other proteinuric glomerular diseases. The mean level of glomerular filtration rate (estimated by the CKD-EPI formula) was 79.43mL/min (12.00-151.20mL/min), 24h proteinuria of 2.89g (0-14.90g), serum albumin of 3.79g/dL (1.20-4.80g/dL). Anti-PLA2R was detected in 27 patients, all with active MN, being 26 primary and 1 secondary MN. Sensitivity and specificity rates for the test were 60.5-94.7%, and positive (PPV) and negative (NPV) predictive values were 92.9 and 67.9%, respectively. Anti-PLA2R showed high specificity and PPV for the diagnosis of primary MN in Brazilian patients. There was a strong correlation between disease activity and positive anti-PLA2R. This biomarker represents an important diagnostic tool for primary MN and may contribute to the monitoring of disease activity in such patients.

Immune-Monitoring Disease Activity in Primary Membranous Nephropathy.

Primary membranous nephropathy (MN) is a glomerular disease mediated by autoreactive antibodies, being the main cause of nephrotic syndrome among adult patients. While the pathogenesis of MN is still controversial, the detection of autoantibodies against two specific glomerular antigens, phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A), together with the beneficial effect of therapies targeting B cells, have highlighted the main role of autoreactive B cells driving this renal disease. In fact, the detection of PLA2R-specific IgG4 antibodies has resulted in a paradigm shift regarding the diagnosis as well as a better prediction of the progression and recurrence of primary MN. Nevertheless, some patients do not show remission of the nephrotic syndrome or do rapidly recur after immunosuppression withdrawal, regardless the absence of detectable anti-PLA2R antibodies, thus highlighting the need of other immune biomarkers for MN risk-stratification. Notably, the exclusive evaluation of circulating antibodies may significantly underestimate the magnitude of the global humoral memory immune response since it may exclude the role of antigen-specific memory B cells. Therefore, the assessment of PLA2R-specific B-cell immune responses using novel technologies in a functional manner may provide novel insight on the pathogenic mechanisms of B cells triggering MN as well as refine current immune-risk stratification solely based on circulating autoantibodies.

Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy

BackgroundB-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition.MethodsWe randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed.ResultsA total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], −9 to 25; P=0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti–phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P=0.06).ConclusionsRituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.)

SUN-011 ISOLATED MEMBRANOUS NEPHROPATHY OCCURRING IN A PATIENT WITH MPO-ANCA RELATED ARTHRITIS WITH ABSENCE OF MYELOPEROXIDASE IN MEMBRANOUS DEPOSITS

The co-occurrence of membranous nephropathy (MN) with MPO-ANCA related crescentic glomerulonephritis (MPO-rCGN) has been well described. Recent reports identified the myeloperoxidase (MPO) in membranous deposits in these cases, suggesting a role for MPO-ANCA in the pathogenesis of the membranous lesion in these patients. For the first time, we report a case of isolated MN (i.e. without concurrent MPO-rCGN) occurring in a patient with MPO-ANCA related arthritis, without MPO in membranous deposits. Case report A 69 year old male presented with a 5 month history of migratory polyarthralgias. Past history included localised prostate cancer and paroxysmal atrial fibrillation. ESR 69mm/hr. Haemoglobin 118 g/L. pANCA positive on immunofluorescence; MPO-ANCA titre 88 U/ml (normal < 20U/ml) on ELISA. Rheumatoid factor negative. ANA 1:80, with negative dsDNA and normal complement studies. Hepatitis B and C, and HIV serology negative. A diagnosis of MPO-ANCA related arthritis was made. He was noted to have microscopic haematuria (74 X 106 erythrocytes/L) and significant proteinuria – urinary protein excretion 5.5g/day. Renal function was normal – serum creatinine 75 umol/L, eGFR 89 ml/min/1.73m2. Serum albumin 29g/L. Blood pressure 127/74mmHg. No oedema. A renal biopsy demonstrated extensive basement membrane spikes along capillary loops, with intervening subepithelial deposits, consistent with stage 2 MN. Immunohistochemistry revealed moderate to strong capillary loop staining for IgG, IgG4, C3c and C1q. IHC staining with anti-MPO antibody was negative. PLA2R-antibody negative. Screening for malignancy revealed a new L1 vertebral lesion consistent with a metastasis from his known prostate cancer. Prednisolone 15mg daily was commenced which rapidly improved the joint symptoms and inflammatory markers. Methotrexate 10mg weekly was added 1 month later, and prednisolone weaned to 2.5mg over 6 months. Proteinuria improved rapidly, with protein excretion falling to 1.5g/day after 1 month of prednisolone. Complete remission of proteinuria occurred within 6 months. MPO-ANCA remained positive with no significant change in titre. Initial reports of concurrent MN and MPO-rCGN proposed that the lesions occurred together by chance. Recent reports have challenged this idea by demonstrating the presence of MPO in membranous deposits in these patients. Furthermore, the IgG subclasses in deposits have been shown to be IgG1 and IgG4, the subtypes which comprise most MPO-ANCA antibodies in the serum in ANCA vasculitis. It has thus been proposed that MPO/MPO-ANCA antibody complexes are pathogenic in forming the membranous deposits. The current case is the first report of isolated MN occurring in a patient with active MPO-ANCA related disease without concurrent MPO-rCGN. MPO was not identifiable in membranous deposits in this case, suggesting an alternative mechanism of injury. While it is possible the MN occurred secondary to prostate cancer, the strong IgG4 staining is atypical for malignancy associated MN. Additionally, the temporal relationship and parallel courses of activity of the MN and ANCA-related arthritis in response to treatment favours a pathogenetic link between the conditions. This case calls into question the role of MPO/MPO-ANCA antibody complexes in the pathogenesis of MN in patients with MPO-ANCA vasculitis.