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Kidney transplant candidates with high anti-M-type phospholipase A2 receptor antibody activity may be at increased risk for early postkidney transplant recurrence and allograft loss. Pretransplant treatment to induce serological remission may be warranted to improve allograft survival. In this case report, a patient seeking their third kidney transplant, who lost 2 prior living donor transplants from early recurrent membranous nephropathy, underwent pretransplant treatment for membranous nephropathy with serological remission and no evidence of recurrent disease.

A 3-year-old boy initially presented with purpura-like rashes and nephrotic syndrome, suspected to be IgA vasculitis nephritis (IgAVN). The suggestion of kidney biopsy was rejected. Although the patient responded well to glucocorticoids, they later developed recurrent proteinuria, refractory diarrhea, and subsequent metabolic acidosis. Kidney biopsy showed membranous nephropathy with positive semaphorin 3B expression, indicative of other kidney diseases rather than IgAVN. Although his kidney responded well to glucocorticoid combined with cyclosporine A treatment regimen, enteropathy and severe food allergy still progressed afterwards as evidenced by villous atrophy on gastrointestinal endoscopy examination. Whole exome sequencing identified a heterozygous missense variant in exon 11 of FOXP3: c.1121 T > G, confirming the diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The case expanded the phenotypic spectrum of IPEX syndrome, suggesting high phenotypic heterogeneity despite similar genotypes. It also put emphasis on the significance of kidney biopsy to differentiate IgA vasculitis nephropathy from other immune disorders. [ABSTRACT FROM AUTHOR]

Background: Particulate matter (PM2.5) has been implicated in the development of membranous nephropathy (MN), but the underlying mechanism has yet to be fully understood. Oxidative stress is an essential factor of PM2.5-related toxicity and plays a significant role in the exposure of target antigenic epitopes in MN. This study aims to explore the pathogenic effects of PM2.5 in facilitating the crosstalk between the lung and kidney in MN. Method: We examined oxidative stress indicators and the circulating levels of extracellular vesicles (EVs) in patients diagnosed with MN. Additionally, we assessed the expression of M-type phospholipase A2 receptor (PLA2R) in human lung tissue ex vivo. To verify the impact of PM2.5 on PLA2R expression in the lung and the kidney, we stimulated human bronchial epithelial cells (Beas-2B) with lipopolysaccharide (LPS) or PM2.5. We then treated podocytes in vitro with the supernatants from PM2.5-exposed Beas-2B cells, intervening with GW4869, an inhibitor of EV release, to explore the role of EV-mediated cell-cell interactions. Results: We found that elevated serum markers of oxidative stress and increased levels of PLA2R + EVs correlated positively with anti-PLA2R antibody levels in the serum of patients with idiopathic MN (IMN). Notably, PLA2R expression was significantly higher in the lung tissue of smokers, suggesting a possible link between PLA2R and oxidative stress. In vitro experiments demonstrated that PLA2R expression in Beas-2B cells was upregulated upon stimulation with LPS and PM2.5, an effect that could be reversed by the antioxidant glutathione (GSH). Furthermore, the supernatants from PM2.5-exposed Beas-2B cells were found to induce PLA2R overexpression and injury in podocytes, with this effect being mitigated by GW4869, an inhibitor of EVs release. Conclusion: Our study contributes new knowledge to the understanding of how environmental pollutants, such as PM2.5, cause kidney damage through oxidative stress and EV-mediated signaling. The findings pave the way for further research into therapeutic strategies targeting oxidative stress and EVs, which could potentially improve patient outcomes of MN, particularly in high-risk populations like smokers and those exposed to air pollution. [ABSTRACT FROM AUTHOR]

Background: This review systematically evaluates the efficacy and safety of the combined treatment of glucocorticoids (GC) and cyclophosphamide (CTX) in patients with membranous nephropathy (MN). Methods: As of June 2024, a comprehensive literature search was performed utilizing several reputable databases, including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang. A meta-analysis was then carried out using Review Manager 5.4 and STATA/SE-15 software. Results: This research evaluated a total of 22 articles involving 1,971 patients. The findings revealed that patients with MN receiving combined GC and CTX therapy had significantly higher complete remission rates (odds ratio = 1.78, p = 0.02) and total remission rates (odds ratio = 2.14, p = 0.01) when the follow-up period exceeded 12 months. Additionally, this treatment demonstrated greater efficacy in lowering serum creatinine levels compared to the control group (standardized mean difference = −0.19, p = 0.04), while its relapse rate was also lower than that of the control group (odds ratio = 0.51, p = 0.009). However, it has a high incidence of serious adverse effects (odds ratio = 2.32, p = 0.03). Conclusion: Our systematic review highlights that the combination of GC and CTX demonstrates superior long-term effectiveness and reduced relapse rates in managing membranous nephropathy (MN). Furthermore, this drug combination is considered the optimal choice for normalizing serum creatinine levels. Data on the effectiveness and safety of glucocorticoids alone versus other drugs alone, and the treatment of secondary membranous nephropathy (SMN), are limited. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display%5frecord.php?RecordID=566477, identifier CRD42024566477. [ABSTRACT FROM AUTHOR]

RTX was initially used for non-Hodgkin's lymphoma treatment and has been used in the clinical treatment of various autoimmune diseases as well as in antirejection and immune induction therapy for kidney transplant recipients. Following RTX treatment, the time for B cell regeneration varies among patients, but there is no unified recommendation for the frequency of B cell monitoring. This study aimed to investigate the clinical significance of periodic monitoring of peripheral blood B lymphocytes in individualized immunotherapy following rituximab (RTX) treatment in patients with different diseases. This study included 488 patients with different diseases divided in four groups who were hospitalized and followed up from April 2017 to March 2024 (including 77, 161, 120, and 130 cases of neuromyelitis optica, pemphigus, membranous nephropathy, and kidney transplant recipients, respectively). Dynamic changes in percentage and absolute count of peripheral blood B lymphocytes before and after RTX treatment were investigated in the four groups, as well as the number of B cell subsets in 32 patients with optic neuromyelitis after RTX treatment. Although most patients showed high expression of B cells after 24 weeks, less than 6.8% of patients still began to experience B cell regeneration within 4 weeks. Thus, regular B cell monitoring following RTX treatment is helpful to better track the remission and recurrence of the disease and provide effective laboratory support for the selection and implementation of individualized immunotherapy. [ABSTRACT FROM AUTHOR]

Background and hypothesis The MENTOR trial (MEmbranous Nephropathy Trial Of Rituximab) showed that rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in maintaining proteinuria remission. However, the cost of rituximab may prohibit first-line use for some patients and health-care payers. Methods A Markov model was used to determine the incremental cost-effectiveness ratio (ICER) of rituximab compared with cyclosporine for the treatment membranous nephropathy from the perspective of a health-care payer with a lifetime time horizon. The model was informed by data from the MENTOR trial where possible; additional parameters including cost and utility inputs were obtained from the literature. Sensitivity analyses were performed to evaluate the impact of reduced-cost biosimilar rituximab. Results Rituximab for the treatment of membranous nephropathy was cost effective (assuming a willingness-to-pay threshold of $50 000 per quality-adjusted life year (QALY) gained; in $US 2021) compared with cyclosporine, with an ICER of $8373/QALY over a lifetime time horizon. The incremental cost of rituximab therapy was $28 007 with an additional 3.34 QALYs compared with cyclosporine. Lower cost of rituximab biosimilars resulted in a more favorable ICER, and in some cases resulted in rituximab being dominant (lower cost and great benefit) compared to cyclosporine. Conclusions Despite the greater cost of rituximab, it may be a cost-effective option for the treatment of membranous nephropathy when compared with cyclosporine. The cost-effectiveness of rituximab is further improved with the use of less expensive biosimilars. [ABSTRACT FROM AUTHOR]

Mercury contained in beauty‐enhancing cosmetics can cause chronic poisoning and membranous nephropathy (MN). We report two cases of nephrotic syndrome caused by MN with evidence of mercury poisoning due to the application of fairness cream in a short duration of a few months. The individuals were positive for neural epidermal growth factor‐like 1 [NELL‐1]. Discontinuation of the use of cosmetic products and modified Ponticelli regimen improved the nephrotic state in these individuals. We suggest that mercury poisoning should be considered in NELL‐1‐positive individuals with a history of application of beauty products. [ABSTRACT FROM AUTHOR]

This study aims to investigate the incidence and prognosis of malignancy in individuals with thrombospondin type-1 domain-containing 7A (THSD7A)-associated membranous nephropathy (MN). First, we performed a systematic literature review of prevalence of malignancy in THSD7A-associated MN. Then, we conducted a retrospective analysis of 454 patients diagnosed with MN through renal biopsy at our hospital between January 2016 and December 2020. We assessed the presence of serum anti-THSD7A antibodies and performed immunohistochemical staining of renal tissue for THSD7A. Subsequently, we followed patients with THSD7A-associated MN for a minimum of 3–5 years, collecting their clinical, pathological characteristics, and prognosis. Additionally, we conducted a literature review on patients with THSD7A-associated MN in conjunction with malignancy. We identified a total of nine articles containing comprehensive data on THSD7A-associated MN and malignancy. Among 235 patients with THSD7A-positive MN, 36 individuals had concurrent malignancies, resulting in a malignancy prevalence of 13.3% (95% CI: 8.9–17.7%). In our center, we followed up with 15 patients diagnosed with THSD7A-associated MN and observed three cases of concomitant tumors: two cases of lung adenocarcinoma and one case of small cell lung cancer with multiple metastases. The prevalence of malignancy in our cohort was 20%. Notably, we detected positive THSD7A staining in both renal and lung cancer tissues in one patient with small cell lung cancer. Patients with THSD7A-associated MN should undergo vigilant follow-up assessments, with a particular focus on actively seeking potential tumorigenic lesions to prevent misdiagnosis or oversight. [ABSTRACT FROM AUTHOR]

Idiopathic membranous nephropathy (IMN) with deposits of phospholipase A2 receptor (PLA2R) antigen in glomerular tissue (GAg+) but no circulating serum PLA2R antibody (SAb−) has been reported. However, little is known about the clinicopathological characteristics and prognosis of this subtype. A total of 74 IMN patients with GAg + identified by kidney biopsy were enrolled in this study. We categorized patients into two groups based on the presence or absence of serum PLA2R antibody. Data on clinical features, pathological features, and outcomes were collected. Kaplan–Meier analysis of complete remission (CR) and partial remission (PR) comparing SAb−/GAg + and SAb+/GAg + patients. Cox proportional hazards models was used to examine factors associated with CR and PR. Among 74 IMN patients, 14 were SAb−/GAg+. Compared with SAb+/GAg + patients, SAb−/GAg + patients presented with higher levels of albumin, lower levels of cholesterol and low density lipoprotein cholesterol (all p <.01), but similar pathological manifestations of kidney biopsy. Multivariate logistic analyses indicated that low albumin (0.79 [95%CI: 0.66–0.95], p =.01) and high cholesterol (1.81 [95%CI: 1.02–3.19], p =.04) were correlated with seropositivity of PLA2R antibody. SAb−/GAg + patients exhibited a significantly higher probability of CR (p =.03) than patients who were SAb+/GAg+. However, no difference was found in the PR rate. Cox regression analyses showed that compared to SAb+/GAg + patients, SAb−/GAg + was more predictive of complete remission (4.28 [95%CI: 1.01–18.17], p =.04). IMN with PLA2R staining on kidney biopsy but without serum PLA2R antibody has milder clinical manifestations and a better prognosis. [ABSTRACT FROM AUTHOR]

Historically, oxidants have been considered mechanisms of glomerulonephritis, but a direct cause–effect correlation has never been demonstrated. Several findings in the experimental model of autoimmune conditions with renal manifestations point to the up-regulation of an oxidant/anti-oxidant system after the initial deposition of autoantibodies in glomeruli. Traces of oxidants in glomeruli cannot be directly measured for their rapid metabolism, while indirect proof of their implications is derived from the observation that Superoxide Oxidase 2 (SOD2) is generated by podocytes after autoimmune stress. The up-regulation of other anti-oxidant systems takes place as well. Here, we discuss the concept that a second wave of antibodies targeting SOD2 is generated in autoimmune glomerulonephritis and may negatively influence the clinical outcome. Circulating and renal deposits of anti-SOD2 antibodies have been detected in patients with membranous nephropathy and lupus nephritis, two main examples of autoimmune disease of the kidney, which correlate with the clinical outcome. The presence of anti-SOD2 antibodies in circulation and in the kidney has been interpreted as a mechanism which modifies the normal tissue response to oxidative stress. Overall, these findings repropose the role of the oxidant/anti-oxidant balance in autoimmune glomerulonephritis. The same conclusion on the oxidant/anti-oxidant balance may be proposed in renal transplant. Patients receiving a renal graft may develop antibodies specific for Glutathione Synthetase (GST), which modulates the amount of GST disposable for rapid scavenging of reactive oxygen species (ROS). The presence of anti-GST antibodies in serum is a major cause of rejection. The perspective is to utilize molecules with known anti-oxidant effects to modulate the anti-oxidative response in autoimmune pathology of the kidney. A lot of molecules with known anti-oxidant effects can be utilized, many of which have already been proven effective in animal models of autoimmune glomerulonephritis. Many molecules with anti-oxidant activity are natural products; in some cases, they are constituents of diets. Owing to the simplicity of these drugs and the absence of important adverse effects, many anti-oxidants could be directly utilized in human beings. [ABSTRACT FROM AUTHOR]

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

Background Obinutuzumab is a humanized and glycoengineered anti-CD20 monoclonal antibody that has been shown to induce more profound B-cell depletion than rituximab. The effectiveness and safety of obinutuzumab in the treatment of membranous nephropathy remain unclear. Methods This was a retrospective study conducted in Huashan Hospital, Fudan University between 1 December 2021 and 30 November 2023. Patients with membranous nephropathy were included to assess the effectiveness and safety of obinutuzumab and prevalence of severe pneumonia during the outbreak of COVID-19 in China. Results Eighteen patients were included in the study assessing the effectiveness of obinutuzumab. After a 12-month follow-up, 14 patients (78%) achieved remission, with six (33%) achieving complete remission and eight (44%) achieving partial remission. Among the 18 obinutuzumab-treated patients contracting COVID-19 for the first time, six (33%) developed severe pneumonia, and one died. By contrast, two of the 37 patients receiving glucocorticoids combined with cyclophosphamide, and none of the 44 patients on calcineurin inhibitors or the 46 patients on rituximab developed severe pneumonia. However, compared to patients receiving rituximab or glucocorticoids plus cyclophosphamide, the obinutuzumab-treated patients had a longer duration of membranous nephropathy and immunosuppressive therapy. Therefore, cardinal matching was employed to balance these baseline characteristics. Owing to small sample size for each regimen, patients receiving all the three non-obinutuzumab immunosuppressive regimens were grouped as a control cohort. After matching for age, gender, remission status, duration of membranous nephropathy, duration of immunosuppressive therapy, and ongoing immunosuppression, the obinutuzumab-treated patients still had a significantly higher incidence of severe pneumonia compared to those on other regimens (P  = .019). Conclusion Obinutuzumab was an effective treatment option for patients with membranous nephropathy. On the other hand, it was associated with a higher incidence of severe pneumonia following COVID-19 infection compared to other immunosuppressive regimens. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To study the medication rules of traditional Chinese medicine in the treatment of membranous nephropathy, so as to provide references for the clinical treatment of membranous nephropathy. METHODS: CNKI, Wanfang Data and PubMed were retrieved to collect clinical studies of traditional Chinese medicine in the treatment of membranous nephropathy, and the data files were established. Excel 2019, Clementine 12. 0 and SPSS 21. 0 software were used to perform frequency statistics of syndrome types, usage frequency, classification, dosage, properties, tastes, and meridian tropism of drugs, association rule analysis, factor analysis and cluster analysis. RESULTS: A total of 179 traditional Chinese medicine compounds and 18 high-frequency drugs were included. Among them, Hedysarum Multijugum Maxim, Poria Cocos, Atractylodes Macrocephala Koidz, and Codonopsis Radix were the most frequently used, the most common efficacy classification was tonic drugs, the main properties was warm, and the main tastes was sweet, which was mostly attributed to the spleen meridians. Totally 16 drug combinations with high association strength were obtained by association rule analysis. Six common factors were extracted by factor analysis. Drugs could be divided into 4 groups by cluster analysis. CONCLUSIONS: The treatment of membranous nephropathy with traditional Chinese medicine mainly focuses on supplementing Qi, strengthening spleen, and tonifying kidney, replenish deficiency with sweet and warm, and the use of syndrome differentiation and combination of promoting blood circulation and resolving blood stasis, and promoting urination and draining dampness. [ABSTRACT FROM AUTHOR]

BACKGROUND: Membranous nephropathy (MN), also known as membranous glomerulonephritis, is a leading cause of adult nephrotic syndrome. The main pathological features encompass the deposition of immune complexes within the glomerular basement membrane epithelial cells, thickening of the basement membrane, and fusion of the foot process. OBJECTIVE: This study aims to investigate the role of the immune and inflammatory modulator miR-223 in the immunosuppressive and anti-inflammatory effects of cyclophosphamide (CTX) on membranous nephropathy (MN). METHODS: miR-223 mimetics or inhibitors was used to regulate miR-223 levels. LPS induced inflammatory cell model and cell polarization. CTX was used to treat Lipopolysaccharides (LPS) induced inflammatory response and polarization. Cationic bovine serum albumin (c-BSA) induced BALB/c mouse MN model, while CTX was used to treat c-BSA induced MN. RESULTS: The miR-223 level in LPS induced inflammatory model cells was lower than that in control cells. The levels of inflammatory factors in LPS + miR-223 mimetics and CTX + miR-223i cells were lower than those in LPS and miR-223i cells. The protein levels of LPS + miR-223 mimic, CTX + miR-223i macrophage M2 phenotype markers Arginase-1 (Arg1), transforming growth factor β 1 (TGF- β 1), anti-inflammatory factors interleukin-4 (IL4) and interleukin-13 (IL13) were significantly higher than those of LPS and miR-223i. The effect of CTX was confirmed in a BALB/c mouse MN model induced by cationic bovine serum albumin (c-BSA). CONCLUSION: CTX upregulates the expression of miR-223, promotes polarization of M2 macrophages, alleviates the inflammatory response and renal injury of MN. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome. The disease exhibits heterogeneous outcomes with approximately 30% of cases progressing to end-stage renal disease. Traditionally, the standard approach of diagnosing MN involves performing a kidney biopsy. Nevertheless, kidney biopsy is an invasive procedure that poses risks for the patient including bleeding and pain, and bears greater costs for the health system. The clinical management of MN has steadily advanced owing to the identification of autoantibodies to the phospholipase A2 receptor (PLA2R) in 2009 and thrombospondin domain-containing 7A (THSD7A) in 2014 on the podocyte surface. At present, serum anti-PLA2R antibody detection and glomerular PLA2R antigen staining have been used for clinical diagnosis and prognosis, but the related detection of THSD7A has not been widely used in clinical practice. Here, we summarized the emerging knowledge regarding the roles THSD7A plays in MN and its clinical implications as diagnostic, prognostic, and therapeutic response as well as Methods for detecting serum THSD7A antibodies. [ABSTRACT FROM AUTHOR]

Objective To detect the level of serum immunoglobulin （Ig）G/C3 in diabetes mellitus （DM） patients with proteinuria and negative serum T-type phospholipase A2 receptor （PLA2R） antibody and explore its non-invasive predictive value for membranous nephropathy （MN）. Methods A total of 52 DM patients with negative serum PLA2R antibody undergoing renal biopsy were retrospectively reviewed. The eligible subjects were assigned into two groups of diabetic kidney disease （DKD, n = 22） and MN with/without DKD （MN±DKD, n = 22） according to clinicopathological characteristics. Risk factors for MN were evaluated by multivariate Logistic regression analysis. The optimal predictive value for IgG/C3 was estimated by receiver operator characteristic （ROC） curve. Results Blood urea nitrogen was significantly higher in DKD group than that in MN±DKD group [（9.34±3.48） vs （6.88±2.44） mmol/L] （P＜0.05）. Blood creatinine became markedly elevated in DKD group than that in MN±DKD group [（159.68±94.08） vs （102.20±53.94） μmol/L] （P＜0.05）. As compared with MN±DKD group, IgG[（8.45±2.12） vs （5.85±2.65） g/L]（P＜0.01）, IgG/C3[（7.57±2.05） vs （4.66±1.77）]（P＜0.01）, diabetic duration [（7.11±6.02） vs （3.80±4.34） year] （P＜0.05） and proportion of DKD （72.73% vs 18.18%）（P＜0.01） were all significantly higher in DKD group than that in MN±DKD group. Multivariate Logistic regression indicated that serum IgG/C3 level （OR = 0.411, 95%CI: 0.185-0.910, P = 0.028） was an independent predictor of MN in diabetics. ROC curve indicated that the optimal cutoff value of IgG/C3 for predicting MN was 6.098 with a sensitivity of 77.3% and a specificity of 77.3%. And IgG/C3≤6.098 was an optimal predictor of MN in diabetics. Conclusion Lower IgG/C3 level is an independent indicator of MN in diabetics with isolated proteinuria and negative serum PLA2R antibody. Renal biopsy is recommended for these patients.

A 48-year-old male presented with proximal muscle weakness of the shoulder with difficulty in lifting objects above the shoulder in July 2012. Electromyogram was suggestive of chronic motor axonal loss with a myogenic pattern, and a deltoid muscle biopsy revealed groups of atrophic muscle fibers and hypertrophic fibers with pan fascicular atrophy suggestive of adult-onset spinal muscular atrophy. He was managed conservatively and developed bilateral pedal edema in August 2022. He had nephrotic range proteinuria, and renal biopsy revealed capillary wall thickening of glomeruli with serum PLA2R antibody positivity suggestive of primary membranous nephropathy. He was managed with telmisartan for 6 months, and there was a reduction in proteinuria. In January 2023, he was given Injection Rituximab due to worsening proteinuria. He failed to have a clinical resolution. This case report describes the management dilemma in membranous nephropathy with SMA due to the risk of toxic myopathies associated with tacrolimus and steroids.

Objective(s): To investigate the natural product sulforaphane (SFN) in protection of membranous nephropathy (MN) by inhibiting oxidative stress-associated podocyte pyroptosis. Materials and Methods: A passive Heymann nephritis (PHN) model was established and treated with SFN. Clinical manifestations were examined by testing 24-hr urine protein, albumin, total cholesterol, triglyceride, high-density and low-density lipoprotein levels. Podocyte injury was observed through glomerular ultrastructure and the expression of podocin and desmin. Intrarenal oxidative stress was evaluated through assessment of oxidative markers, including malondialdehyde, 8-isoprostane, and 8-hydroxydeoxyguanosine, and the activities of anti-oxidant enzymes, including total superoxide dismutase, catalase, and α-glutamylcysteine synthetase. Podocyte and intrarenal pyroptosis were investigated by observing the localization of the GSDMD N-terminus (GSDMD(N)) in podocytes; the expression of pyroptosis signaling pathway, including GSDMD, NF-κB p65, p-NF-κB p65 (Ser536), NLRP3, ASC, caspase-1, IL-1ß, and IL-18; and pyroptosis encounter Nrf2 in the glomeruli and kidney. Results: SFN has a protective effect on MN, as reflected by alleviation of nephrotic syndrome, amelioration of podocyte foot process fusion, increased expression and normalization of podocin, and decreased expression of desmin in the glomeruli. Mechanistically, SFN relieved intrarenal oxidative stress, as indicated by decreased renal malondialdehyde, 8-isoprostane, and 8-hydroxydeoxyguanosine and increased activity of total superoxide dismutase, catalase, and α-glutamylcysteine synthetase. SFN also inhibited podocyte and intrarenal pyroptosis, as revealed by decreased colocalization of GSDMD (N) with synaptopodin and ZO-1, decreased expression of pyroptosis signaling pathway, and increased expression of Nrf2 in the glomeruli and kidney. Conclusion: SFN could alleviate MN by inhibiting oxidative stress-associated podocyte pyroptosis. [ABSTRACT FROM AUTHOR]

Abstract Background We evaluated the efficacy of different immunosuppressive regimens in patients with primary membranous nephropathy in a large national cohort. Methods In this registry study, 558 patients from 47 centers who were treated with at least one immunosuppressive agent and had adequate follow-up data were included. Primary outcome was defined as complete (CR) or partial remission (PR). Secondary composite outcome was at least a 50% reduction in estimated glomerular filtration (eGFR), initiation of kidney replacement therapies, development of stage 5 chronic kidney disease, or death. Results Median age at diagnosis was 48 (IQR: 37–57) years, and 358 (64.2%) were male. Patients were followed for a median of 24 (IQR: 12–60) months. Calcineurin inhibitors (CNIs) with or without glucocorticoids were the most commonly used regimen (43.4%), followed by glucocorticoids and cyclophosphamide (GC-CYC) (39.6%), glucocorticoid monotherapy (25.8%), and rituximab (RTX) (9.1%). Overall remission rate was 66.1% (CR 26.7%, PR 39.4%), and 59 (10.6%) patients reached secondary composite outcome. Multivariate logistic regression showed that baseline eGFR (OR 1.011, 95% CI: 1.003–1.019, p = 0.007), serum albumin (OR 1.682, 95% CI: 1.269–2.231, p

Yi Yu,1 Ricong Xu,1 Zhijian Li,2,3 Qijun Wan1 1Department of Nephrology, The First Affiliated Hospital of Shenzhen University, The Second People’s Hospital of Shenzhen, Shenzhen, 518039, People’s Republic of China; 2Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China; 3NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, People’s Republic of ChinaCorrespondence: Qijun Wan, Department of Nephrology, The First Affiliated Hospital of Shenzhen University, The Second People’s Hospital of Shenzhen, Shenzhen, 518039, People’s Republic of China, Email yiyuan2224@sina.comAbstract: Primary membranous nephropathy (PMN) is one of the prevalent pathological types of adult primary nephrotic syndrome. Pathogenic autoantibodies targeting podocyte antigens such as phospholipase A2 receptor (PLA2R) lead to the disease. Patients frequently experience notable adverse effects when treated with conventional immunosuppressive therapies. Rituximab (RTX), a mouse/human monoclonal antibody, selectively depletes B cells and leads to a decrease in the antibody levels in the circulation, which helps to alleviate membranous nephropathy. Various RTX dosage regimens have been applied globally in the PMN treatment with satisfactory effects. Nevertheless, the optimal dosage of RTX has yet to be determined. This article reviews the application of different doses of RTX in the management of PMN so far.Keywords: membranous nephropathy, nephrotic syndrome, rituximab, dosage

Objective To explore the effect of allicin on renal injury in rats with membranous nephropathy （MN） and elucidate its potential mechanism. Methods A total of 65 male Wistar rats were assigned into two groups of normal （n = 10） and modeling （n = 55）. Modeling group received an injection of cationized bovine serum albumin （C-BSA） via tail vein for MN modeling. And 50 modeling rats were randomized into five groups of model, low-dose allicin （5 mg/kg）, medium-dose allicin （10 mg/kg）, high-dose allicin （20 mg/kg） and nenazepril hydrochloride （10 mg/kg） （n = 10 each）. After once daily continuous dosing for 4 weeks, 24 h urinary total protein （24 h UTP）, blood urea nitrogen （BUN） and serum creatinine （Scr） were detected by spectrophotometry; serum levels of total protein （TP） and albumin （Alb） by biochemistry; serum levels of interleukin-1β （IL-1β）, IL-6/10 and tumor necrosis factor-alpha （TNF-α） by enzyme-linked immunosorbent assay （ELISA）. Renal histopathology was observed after stains of hematoxylin eosin （HE） and periodic acid-Schiff （PAS） and immunoglobulin G （IgG） immunofluorescence. Apoptosis of renal cells was observed through TdT-mediated dUTP nick-end labeling （TUNEL） stain. The expressions of Toll-like receptor 4 （TLR4）, nuclear factor-κB p65 （NF-κB p65）, p-NF-κB p65, B lymphoblastoma 2 （Bcl-2）, Bcl-2-associated X protein （Bax）, caspase-3 and cleaved caspase-3 in renal tissue were detected by Western blot. Results 24 h UTP （45.07±6.19）mg, BUN （46.45±5.22）mmol/L, Scr （24.90±2.81）μmol/L were significantly higher in model group than 24 h UTP （6.41±0.82）mg, BUN （28.93±3.17）mmol/L and Scr （5.74±0.76）μmol/L in normal control group. The difference was statistically significant （P＜0.05）; TP （37.25±4.09）g/L and Alb （18.62±2.03）g/L were significantly lower in model group than TP （59.38±7.24）g/L and Alb （30.74±2.60）g/L in normal control group. The difference was statistically significant （P＜0.05）. Serum levels of IL-1β （638.14±69.22）ng/L, IL-6 （115.08±13.61）ng/L and TNF-α （341.75±40.93）ng/L were significantly higher in model group than IL-1β （157.42±18.06）ng/L, IL-6 （32.61±3.74）ng/L and TNF-α （60.28±6.51）ng/L in normal control group. Serum level of IL-10 was significantly lower in model group than that in normal control group [（24.90±3.01） vs （75.14±9.76）ng/L]. The difference was statistically significant （P＜0.05）. The pathological changes of renal tissue in model group included greater glomerular volume, mesangial hyperplasia, basement membrane thickening, vacuolar degeneration and necrosis of renal tubule cells, infiltration of inflammatory cells in renal interstitium and diffuse deposition of capillary loop IgG. Apoptotic index was statistically higher in model group than that in normal control group [（63.90±8.74）% vs （4.58±0.52）%]. The difference was statistically significant （P＜0.05）. Expressions of TLR4 （0.34±0.06） and Bax （0.27±0.05） and ratios of p-NF-κB p65/NF-κB p65 （0.93±0.18） and cleaved caspase-3/caspase-3 （0.67±0.09） were statistically higher in model group than those of TLR4 （0.03±0.01） and Bax （0.03±0.01） and those of p-NF-κB p65/NF-κB p65 （0.09±0.03） and cleaved caspase-3/caspase-3 （0.15±0.03） in normal control group. The differences were statistically significant （P＜0.05）. Expression of Bcl-2 was statistically lower in model group than that in normal control group [（0.08±0.02） vs （0.37±0.06）]. The difference was statistically significant （P＜0.05）. 24 h UTP [（25.72±3.49）, （13.35±1.60）, （23.11±3.57）mg], BUN [（39.28±4.38）, （34.17±3.62）, （40.35±4.81）mmol/L] and Scr [（14.61±1.85）, （9.05±1.12）, （12.72±1.50）μmol/L] were statistically lower in medium/high-dose allicin and benazepril hydrochloride groups than 24 h UTP （45.07±6.19）, BUN （46.45±5.22） and Scr （24.90±2.81）μmol/L in model group. TP [（46.39±5.02）, （53.47±6.58）, （45.63±5.17）g/L] and Alb [（23.38±2.91）, （27.50±3.04）, （24.08±2.86）g/L] were statistically higher than TP （37.25±4.09）g/L and Alb （18.62±2.03）g/L in model group. The differences were statistically significant （P＜0.05）. IL-1β [（349.18±44.06）, （201.33±26.07）, （317.92±38.64）ng/L], IL-6 [（73.83±9.17）, （50.90±5.25）, （82.76±9.83）ng/L] and TNF-α [（228.14±25.60）, （101.57±12.94）, （193.82±23.74）ng/L] were significantly lower than IL-1β [（638.14±69.22）, IL-6 （115.08±13.61） and TNF-α （341.75±40.93）ng/L] in model group. IL-10 was significantly higher than that in model group [（49.26±6.35）, （62.35±7.71）, （55.60±6.15） vs （24.90±3.01）ng/L]. The difference was statistically significant （P＜0.05）. Renal histopathological changes and apoptosis improved markedly and apoptotic index was significantly lower than that in model group [（63.90±8.74）%, （63.90±8.74）%, （63.90±8.74）% vs （63.90±8.74）%] . The difference was statistically significant （P＜0.05）. Expressions of TLR4 [（0.24±0.04）, （0.09±0.02）, （0.15±0.03）] and Bax [（0.14±0.02）, （0.08±0.02）, （0.16±0.03）] and ratios of p-NF-κB p65/NF-κB p65 [（0.45±0.07）, （0.21±0.04）, （0.31±0.05）] and cleaved caspase-3/caspase-3 [（0.47±0.07）, （0.20±0.04）, （0.38±0.06）] were significantly lower than those of TLR4 （0.34±0.06） and Bax （0.27±0.05） and those of p-NF-κB p65/NF-κB p65 （0.93±0.18） and cleaved caspase-3/caspase-3 （0.67±0.09） in model group. Expression of Bcl-2 was significantly higher than that in model group [（0.19±0.04）, （0.30±0.06）, （0.28±0.05） vs （0.08±0.02）]. The difference was statistically significant （P＜0.05）. Except for BUN, low/medium/high-dose allicin group demonstrated dose-dependent regulatory effects on other detection parameters （P＜0.05）. Except for IL-10/Bcl-2, regulatory effect of high-dose allicin group was better than that of benazepril hydrochloride group （P＜0.05）. Conclusion Allicin may reduce renal injury and protect renal function in MN rats through suppressing TLR4/NF-κB signaling pathway of modulating inflammatory responses and apoptosis.

Background. Along with hydrogen sulfide and carbon monoxide, nitrogen monoxide (NO) has earned a reputation as a powerful vasodilator. NO is synthesized from L-arginine by a group of enzymes called NO synthases (NOS). NOS catalyzes the conversion of L-arginine into L-citrulline and NO. There are three isoforms of NOS that are often described based on their expression in tissues: 1) neuronal NOS (nNOS), 2) inducible NOS (iNOS), and 3) epithelial NOS (eNOS). NO is a vital molecule involved in a number of signaling functions in the kidney and can be released by a variety of kidney cells, including endothelial and mesangial cells as well as podocytes. Podocyte damage mediated by antibodies against podocyte antigens deposited under glomerular visceral epithelial cells is called membranous nephropathy. Cell-free cryopreserved biological agents (CfBA) have attracted our attention as potential means for the treatment of patients with membranous nephropathy, in particular, cryoextract of human placenta, cryoextract of porcine spleen and mesenchymal stem cell-conditioned medium (MSC-CM). The purpose of the study was to assess the effect of cryoextracts of placenta (CEP) and spleen (CES), as well as MSC-CM on the state of NOergic system of the kidneys of rats with autoimmune membranous nephropathy. Materials and methods. Research on the effectiveness of CfBA in autoimmune nephritis (AIN) was conducted on 42 male rats. AIN was reproduced according to the method of W.R. Heymann et al. The studied drugs were administered to rats from the day 60 of the experiment. CfBA were injected intramuscularly with an interval of 2 days (total of 5 injections) on the day 60, 62, 64, 66 and 68 of the experiment, respectively. NOS activity was evaluated by the spectrophotometric method based on the amount of oxidizable NADPH2. The content of stable NO metabolites was determined by the spectrophotometric method according to the modified Griess test. Results. It was found that the development of AIN in rats was accompanied by an imbalance of NOS activity in renal tissues. The activity of iNOS was increased statistically significantly (р CES (36.4 %; p = 0.008) > CEP (31.8 %; p = 0.04). According to the ability to eliminate inhibition of constitutive NOS activity in renal tissues (percentage compared to the indicators of untreated rats with AIN), it is advisable to place them in the following sequence: MSC-CM (57.9 %; p = 0.05) > CEP (42.4 %; p = 0.015) > CES (21.2 %; p = 0.02). By the ability to normalize the content of stable NO metabolites in the blood (percentage compared to the indicators of untreated rats with AIN), it is advisable to place the studied CfBA in the following sequence: MSC-CM (41.3 %; p = 0.018) > CES (25.2 %; p = 0.1) > CEP (4.9 %; p = 0.7).

Membranous nephropathy is a glomerulopathy in which the primary target is the podocyte and damage to the glomerular basement membrane. The disease occurs more often in adults, mostly in people over 50 years old. The clinical manifestation is nephrotic syndrome, but in most cases, asymptomatic proteinuria may develop. In the mechanism of kidney damage, the deposition of immune complexes in the subepithelial space of the capillary loop of the glomerulus with subsequent activation of the complement system is important. Over the past twenty years, great progress has been made in the identification of potential target antigens, the main of which is the M-type phospholipase A2 receptor (PLA2R) protein with circulating anti-PLA2R antibody, which allows for assessment of the activity and prognosis of membranous nephropathy. This path of damage corresponds to approximately 70–80 % of cases of membranous nephropathy, which is characterized as primary.

Abstract Background Nephrotic syndrome (NS) is a rare complication that can occur after haematopoietic stem cell transplantation (HSCT). In patients with membranous nephropathy (MN) who have undergone allogeneic HSCT, a new antigen called protocadherin FAT1 has been identified. Our objective is to present a case series of MN patients after HSCT with a novel antigen-based stratification. Case presentations Patients who developed full-blown NS due to MN after an HSCT were enrolled in the University Hospital Centre Zagreb study. The first two patients were treated with an HSCT for acute myeloid leukaemia, and both developed NS after cessation of graft versus host disease (GVHD) prophylaxis. The first patient had reduced kidney function, while the second had completely preserved function. Kidney biopsy showed MN with only subepithelial deposits. A thorough examination revealed that there was no secondary cause of the disease. The patients achieved complete remission after undergoing immunosuppression treatment. The third patient underwent HSCT for acute lymphoblastic leukaemia. He developed both acute and chronic GVHD and also experienced avascular hip necrosis. After sixteen years, the patient developed NS with preserved kidney function. The kidney specimen showed membranous nephropathy (MN) with mesangial and subepithelial deposits. Extensive research was conducted, but no secondary cause for the MN was detected. All three cases tested negative for anti-PLA2R antibodies. Biopsy tissue samples were analysed using laser microdissection and tandem mass spectrometry of glomeruli for the detection of different specific antigens. Patients one and two tested positive for FAT1, whereas patient three tested positive for PCSK6. Conclusions MN can develop at various time intervals after HSCT. Specific antigen testing can help establish the relationship between MN and HSCT. In the future, serum testing for anti-FAT1 antibodies in HSCT patients could be significant in diagnosing FAT1-associated MN, similar to how anti-PLA2R antibodies are significant in diagnosing PLA2R-associated MN.

Abstract Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and is associated with high rates of end-stage renal disease. Early detection and precise interventions are crucial for improving patient prognosis and quality of life. However, the current diagnosis primarily relies on renal biopsies and traditional biomarkers, which have limitations. Additionally, targeted therapeutic strategies are lacking. Exosomes, small vesicles that facilitate intercellular communication, have emerged as potential noninvasive diagnostic markers due to their stability, diverse cargo, and rapid detectability. They also hold promise as carriers for gene and drug delivery, presenting innovative opportunities in renal disease prognosis and treatment. However, research on exosomes in the context of idiopathic membranous nephropathy (IMN) remains limited, with a focus on exploring urinary exosomes as IMN markers. In this review, we summarize the current status of MN diagnosis and treatment, highlight the fundamental characteristics of exosomes, and discuss recent advancements in their application to IMN diagnosis and therapy. We provide insights into the clinical prospects of exosomes in IMN and acknowledge potential challenges. This article aims to offer forward-looking insights into the future of exosome-mediated IMN diagnosis and treatment, indicating a revolutionary transformation in this field. Graphical Abstract

Abstract Background The prevalence of chronic kidney disease (CKD) is on the rise, posing a significant public health challenge. Although gut microbiome dysbiosis has been implicated in the impairment of kidney functions, the existence of pathological subtypes-linked differences remains largely unknown. We aimed to characterize the intestinal microbiota in patients with membranous nephropathy (MN), IgA nephropathy (IgAN), minimal change disease (MCD), and ischemic renal injury (IRI) in order to investigate the intricate relationship between intestinal microbiota and CKD across different subtypes. Methods We conducted a cross-sectional study involving 94 patients with various pathological patterns of CKD and 54 healthy controls (HCs). The clinical parameters were collected, and stool samples were obtained from each participant. Gut microbial features were analyzed using 16S rRNA sequencing and taxon annotation to compare the HC, CKD, MN, IgAN, MCD, and IRI groups. Results The CKD subjects exhibited significantly reduced alpha diversity, modified community structures, and disrupted microbial composition and potential functions compared to the control group. The opportunistic pathogen Klebsiella exhibited a significant enrichment in patients with CKD, whereas Akkermansia showed higher abundance in HCs. The study further revealed the presence of heterogeneity in intestinal microbial signatures across diverse CKD pathological types, including MN, IgAN, MCD, and IRI. The depression of the family Lachnospiraceae and the genus Bilophila was prominently observed exclusively in patients with MN, while suppressed Streptococcus was detected only in individuals with MCD, and a remarkable expansion of the genus Escherichia was uniquely found in cases of IRI. The study also encompassed the development of classifiers employing gut microbial diagnostic markers to accurately discriminate between distinct subtypes of CKD. Conclusions The dysregulation of gut microbiome was strongly correlated with CKD, exhibiting further specificity towards distinct pathological patterns. Our study emphasizes the significance of considering disease subtypes when assessing the impact of intestinal microbiota on the development, diagnosis, and treatment of CKD.

The discovery of the target antigen M-type phospholipase A2 receptor (PLA2R) with the possibility to detect anti-PLA2R antibodies in serum as well as the identification of several other antigens, overall accounting for almost all cases of membranous nephropathy, paved the way to a revolutionary change in the classification of membranous nephropathy. Serum anti-PLA2R autoantibody titers have been found to be highly specific diagnostic and prognostic biomarkers. Therefore, a positive test for anti-PLA2R serology in patients who present with nephrotic syndrome, normal kidney function, and no evidence of another process to account for proteinuria is believed to suffice to make a diagnosis of primary membranous nephropathy, thus removing the need for a renal biopsy. While technological advances will likely allow this proposal to prevail in the near future, the reasons why renal biopsy could still remain a critical tool for the management of membranous nephropathy in real life are discussed. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current knowledge regarding MN after allo-HSCT is limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT centers. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (P = 0.0102) and peripheral blood as the graft source (P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared to those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (P = 0.0002). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Reports of patients who have autoimmune nodopathies concurrent with nephrotic syndrome are increasing. We investigated whether proteinuria could be a biomarker of autoimmune nodopathies. Methods: Qualitative urinalysis results were retrospectively obtained from 69 patients who were diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) at a hospital in Japan. Proteinuria was graded as mild to severe (i.e., mild, 30–99; moderate, 100–299; severe, 300 mg/dL or more) according to the results of the urine dipstick test. Autoantibodies against the paranodal proteins contactin 1 (CNTN1), neurofascin 155 (NF155), and contactin‐associated protein 1 (Caspr1) and the nodal protein neurofascin 186 (NF186) were measured, and the predominant IgG subclass was determined by enzyme‐linked immunosorbent assay in sera from the 69 patients. Results: Four patients (6%), five patients (7%), and one (1%) patient were positive for anti‐CNTN1, anti‐NF155, and anti‐Caspr1 IgG4 antibodies, respectively. No patients had IgG4 antibodies against NF186. Proteinuria of mild or greater levels was found in three patients with anti‐CNTN1 IgG4 and two patients with anti‐NF155 IgG4 antibodies. The autoantibody‐positive patients more frequently had proteinuria of mild or greater levels than the seronegative patients (p = 0.01). Conclusions: Proteinuria is a possible biomarker of autoimmune nodopathies associated with autoantibodies targeting CNTN1 or NF155. Urinalysis results should be carefully checked for quick differentiation of autoimmune nodopathies from CIDP. Patients who present with nephrotic syndrome should be tested for anti‐CNTN1 IgG4 antibodies, and patients who exhibit mild proteinuria should be tested for anti‐NF155 IgG4 antibodies. [ABSTRACT FROM AUTHOR]

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

Background: We evaluated the efficacy of different immunosuppressive regimens in patients with primary membranous nephropathy in a large national cohort. Methods: In this registry study, 558 patients from 47 centers who were treated with at least one immunosuppressive agent and had adequate follow-up data were included. Primary outcome was defined as complete (CR) or partial remission (PR). Secondary composite outcome was at least a 50% reduction in estimated glomerular filtration (eGFR), initiation of kidney replacement therapies, development of stage 5 chronic kidney disease, or death. Results: Median age at diagnosis was 48 (IQR: 37–57) years, and 358 (64.2%) were male. Patients were followed for a median of 24 (IQR: 12–60) months. Calcineurin inhibitors (CNIs) with or without glucocorticoids were the most commonly used regimen (43.4%), followed by glucocorticoids and cyclophosphamide (GC-CYC) (39.6%), glucocorticoid monotherapy (25.8%), and rituximab (RTX) (9.1%). Overall remission rate was 66.1% (CR 26.7%, PR 39.4%), and 59 (10.6%) patients reached secondary composite outcome. Multivariate logistic regression showed that baseline eGFR (OR 1.011, 95% CI: 1.003–1.019, p = 0.007), serum albumin (OR 1.682, 95% CI: 1.269–2.231, p < 0.001), and use of RTX (OR 0.296, 95% CI: 0.157–0.557, p < 0.001) were associated with remission rates; whereas only lower baseline hemoglobin was significantly associated with secondary composite outcome (OR: 0.843, 95% CI: 0.715–0.993, p = 0.041). CYC use was significantly associated with higher remission (OR 1.534, 95% CI: 1.027–2.290, p = 0.036). Conclusions: Higher baseline eGFR and serum albumin levels correlated with increased remission rates. Remission rates were lower in patients treated with RTX, while those on GC-CYC showed higher rates of remission. Due to the study's retrospective nature and multiple treatments used, caution is warranted in interpreting these findings. [ABSTRACT FROM AUTHOR]

Aims/Background Both membranous nephropathy (MN) and immunoglobulin A nephropathy (IgAN) are immune complex-mediated glomerular diseases, but the concurrent occurrence of these two conditions in the same patient is not common, a phenomenon that is currently not supported by clinical data in terms of treatment and prognosis. This study explores the clinical and pathological characteristics, as well as the treatment outcomes, of patients affected by MN and IgAN simultaneously. Methods The clinical data, pathological features, and diagnostic and therapeutic information of seven cases of MN complicated by IgAN, treated between December 2015 and December 2022, were retrospectively analyzed. Results Among the seven cases, there were two male and five female patients, with an average age of 57.3 ± 9.2 years. All patients presented with clinical manifestations of proteinuria and edema upon admission, with an average 24-hour urine protein of 3716.6 ± 1519.4 mg/24 h. Phospholipase A2 receptor (PLA2R) expression was detected in all seven cases, and nephrotic syndrome was clinically diagnosed in five cases. Additionally, all seven cases showed microscopic hematuria, with intermittent gross hematuria in two cases. All seven patients included in this study underwent renal biopsy. After disease staging, the patients had MN stages I–III and IgAN stages II–III. Pathological findings revealed abnormal glomerular basement membrane (GBM) and diffuse immunoglobulin G (IgG) deposition in the subepithelial space, predominantly of the IgG4 subtype. Simultaneously, there was diffuse mesangial zone deposition of immunoglobulin A (IgA) to varying degrees, co-localization of complement component C3 and IgA, and mesangial cell proliferation. Treatment strategies included angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in combination with steroids or immunosuppressive therapies such as tacrolimus, cyclophosphamide, and rituximab. After 2–6 months of treatment, all patients achieved complete remission with a favourable prognosis. Conclusion MN accompanied by IgAN tends to occur more frequently in middle-aged and elderly individuals, with a relatively low incidence. The latent feature of the comorbidities manifests as a form of IgAN superimposed on the background of MN. Utilizing ACEI or ARB in combination with steroids or various immunosuppressive therapies represents a potentially effective treatment strategy. [ABSTRACT FROM AUTHOR]

Objective To observe the inhibitory effects of tert-butylhydroquinone (tBHQ) on renal injury and oxidative stress and its regulatory effect on the nuclear factor erythroid 2-related factor 2 (Nrf2)/nuclear factor-κB (NF-κB) signaling pathway in renal cortex and nucleus of rats with membranous nephropathy (MN), so as to illustrate the potential therapeutic effect and mechanism of tBHQ on MN. Methods Thirty-two rats were randomly divided into the normal control group, tBHQ control group, model group, and tBHQ intervention group, respectively. Rats in the normal control group were injected intraperitoneally with 3 mL of normal rabbit serum, rats in the tBHQ control group were injected with normal rabbit serum in the same way and then were gavaged with 50 mg/kg tBHQ once a day for a total of 15 injections, rats in the model group were injected intraperitoneally with 3 mL of rabbit Fx1A antiserum to establish passive Heymann nephritis (PHN) models, and rats in the tBHQ intervention group were injected with rabbit Fx1A antiserum in the same way and then were gavaged with 50 mg/kg tBHQ once a day for a total of 15 injections. At the end of the experiment, indicators related to nephrotic syndrome [24 h urinary protein (24 h-UPro) serum albumin (ALB), total cholesterol (T-CHOL), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL)], renal function-related indicators [serum creatinine (sCr), urea nitrogen], renal podocyte injury (podocyte foot process fusion, glomerular Podocin/Desmin expression and distribution), renal cortex oxidative stress markers [malondialdehyde (MDA), 8-isoprostaglandin (8- iso-PG), 8-hydroxydeoxyguanosine (8-OHDG)], renal cortex antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), γ-glutamylcysteine synthase (γ-GCS)] activities and the Nrf2/NF-κB signaling pathway in the renal cortex and nucleus of the rats in each group were detected. Results Compared with the normal control group, the 24 h-UPro, T-CHOL, TG, HDL, LDL, sCr, and urea nitrogen increased, and ALB decreased (all P<0. 05); subepithelial electron dense deposits in the glomeruli, diffuse fusion of the podocyte foot processes, and the width of the podocyte foot processes increased; the expression level and abnormal distribution of Podocin decreased, the expression level of Desmin was up-regulated; the MDA, 8-iso-PG, and 8-OHDG levels all increased in the renal cortex (all P<0. 05), and the activities of SOD, CAT, and γ -GCS decreased (all P<0. 05); Nrf2 was down-regulated, whereas NF- κB p65 and p-NF- κB p65 (Ser536) were up-regulated in the renal cortex and nucleus in the model group (all P<0. 05). Compared with the model group, the 24 h-UPro, T-CHOL, TG, HDL, LDL, and sCr levels all decreased, and the ALB increased (all P<0. 05); the diffuse fusion of the podocyte foot processes was relieved, the podocyte foot processes width decreased, and the expression and distribution of Podocin/Desmin tended to be normal; the MDA, 8-iso-PG, and 8-OHDG levels decreased in the renal cortex (all P<0. 05), and the activities of SOD, CAT, and γ-GCS increased (all P<0. 05); Nrf2 was up-regulated, whereas NF-κB p65 and p-NF-κB p65 (Ser536) were down-regulated in the renal cortex and nucleus of the tBHQ intervention group (all P<0. 05). Conclusions The tBHQ inhibits renal injury and oxidative stress of MN rats, and can regulate the Nrf2/NF-κB signaling pathway in the renal cortex and nucleus. The tBHQ may activate Nrf2 and inhibit NF-κB activation, thereby alleviating oxidative stress and renal injury in MN rats. [ABSTRACT FROM AUTHOR]

The primary pathological feature of Membranous Nephropathy (MN) is the presence of tiny spike-like projections on the glomerular basement membrane. Early detection and efficient treatment of spike-like projections are essential in halting disease progression. Renal pathology biopsy stands as the gold standard for diagnosing MN, and the accurate identification of glomerular spike-like projections plays a vital role in aiding diagnosis. Nevertheless, the tiny spike-like projection lesions and constraints in data quantity pose considerable challenges for supervised learning-based glomerular classification and quantification. We develop a Multi-Scale Annotation-based Multiple Instance Learning (MSA-MIL) model to address the issues. MSA-MIL utilizes image labels and box-level labels to jointly enhance the classification performance of the MIL model. Specifically, we first employ U-Net for glomerular image edge segmentation and subsequently train the MIL model on the dataset with image-level labels. Then, to overcome the limitations arising from the scarcity of positive instances and the relatively small size of spike-like projection features, we manually augment the number of instances with spike-like projections via using box-level annotation to further enhance the MIL model's classification performance. The designed MSA-MIL model enables the classification, visualization, and quantitative analysis of glomeruli with spike-like projections in renal pathology images. We validated and evaluated the designed MSA-MIL model. The model performed exceptionally well, achieving a high accuracy of 0.9847 and demonstrating a high recall rate, effectively preventing misdiagnosis. Additionally, we utilized heatmaps to visualize the locations of spike-like projections within glomeruli, enhancing the model's interpretability. Furthermore, through an analysis of the correlation between the stages of membranous nephropathy and the proportion of spike-like projections, we observed that as the disease advances, the proportion of spike-like projections increases. This finding serves to further validate the results obtained by the model. The MSA-MIL model is the first one specifically designed for classifying glomerular spike-like projections. It not only enhances classification performance but also proves to be more suitable for categorizing minute lesions compared to conventional Convolutional Neural Network (CNN) models. The visualization of glomerular lesions and the proportion of spike-like projections provide doctors with insights into the model's inference process, offering intuitive assistance for accurate diagnoses. This model brings significant hope for advancing research and diagnosis in the field of kidney diseases. [ABSTRACT FROM AUTHOR]

Background: Membranous glomerulonephritis, also known as membranous nephropathy (MN), is a common cause of nephrotic syndrome in adults. Despite extensive research on MN, bibliometric studies on the subject are scarce. Therefore, this study aimed to provide a visual analysis of global trends in membranous nephropathy research over the past 13 years. Methods: This study conducted a bibliometric and visual analysis of global trends in MN research from 2010 to 2023. Articles related to MN were retrieved from the Web of Science Core Collection (WoSCC) database. Tools such as CiteSpace and VOSviewer were utilized to analyze publications, countries, institutions, authors, publishing journals, co-cited references, and keywords to identify the current state and future trends in MN research. Results: The analysis encompassed 1,624 publications, showing an annual increase from 2010 to 2023. The People's Republic of China emerged as the most active country in this field, while France's Sorbonne Universite and Institut National de la Sante et de la Recherche Medicale (Inserm) led in publication volume among academic institutions. Debiec Hanna stood out as the most prolific author. BMC Nephrology had the highest number of publications, making it the most favored journal in the field. The article with the greatest co-citation intensity was "Primary Membranous Nephropathy," a review published in 2017. Conclusion: This study shows that there has been increasing interest in membranous nephropathy over the past 13 years. The most frequently encountered keywords were "membranous nephropathy" "nephrotic syndrome," and "glomerulonephritis." Analysis of emerging terms indicated that "a2 receptor antibody," "domain containing 7a," and "t cell" may remain prominent subjects of research in the forthcoming years. The findings highlight key research trends and areas of interest that can inform researchers, clinicians, and policymakers about the current state of MN research and help guide future research directions and clinical practice. [ABSTRACT FROM AUTHOR]

Background: Neural epidermal-like growth factor-like 1 (NELL-1) is a protein kinase C binding protein expressed in osteoblasts and renal tubules. It is expressed in 5%-25% glomerular cells at the mRNA level. Membranous Nephropathy (MN) is characterized by the presence of antibodies against certain types of antigens on the glomerular basement membrane. The most common one implicated in primary MN is an antibody against PLA2R. Many newer antigens have been discovered in the recent past, which are proven to cause secondary MN, one of which is NELL-1. NELL-1 has been associated with malignancy-associated MN and also recently associated with traditional indigenous medications containing mercury. In this study, we study the expression of NELL-1 in mercury-associated MN. Materials and Methods: Records of ten cases of Mercury -associated MN were retrieved from the Institute medical archives and NELL-1 Immunohistochemistry was performed in all ten cases. Results: NELL-1 was found to be positive in 50% of the cases of Mercury associated MN. In addition, mass spectrometric studies was performed, which revealed the common Mercuric compound associated to be 'Swaskalpa', 'Sudarshana Melugu' and 'Rasagandhi Mezhugu'. Conclusion: This study highlights why it is important to diagnose mercury-associated MN by a pathologist by picking up the finer histopathological clues and by using NELL-1 immunohistochemistry, especially in PLA2R-negative patients. The former is true as most of the time a history of mercuric compound intake is missed out. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is an antibody-mediated autoimmune disease and the most common cause of nephrotic syndrome in adults. The discovery of phospholipase A2 receptor 1 (PLA2R1) as the first target antigen in patients with MN 15 years ago has led to a paradigm shift in the pathobiological understanding of this disease. Autoantibodies against PLA2R1 as well as thrombospondin type-1 domain-containing 7A, the second identified antigen in adults, were shown to be disease-causing and act through local activation of the complement system, primarily via the classical and lectin pathways. These findings indicate that both plasma cells, the main source of antibodies and autoantibodies, as well as the complement system, the main pathogenic effector mechanism in MN, are rational and pathogenesis-based treatment targets in MN. This review summarizes pathomechanistic and clinical evidence for and against plasma cell– and complement-targeted treatments in MN. [ABSTRACT FROM AUTHOR]

Aim: Rhodojaponin VI (R‐VI) is the key compound of Rhododendron molle G. Don (Ericaceae) (RM) with effective clinical application in rheumatoid arthritis and chronic glomerulonephritis. In our study, we tried to explore the effect of R‐VI on the rat model of membranous nephropathy. Methods: The rat model of passive heymann nephritis (PHN) was established by injecting sheep anti‐rat Fx1A serum at a single dose through the tail. The rats were orally administered R‐VI (0.02 mg/kg) or FK506 (1 mg/kg) 1 day before PHN induction, which was kept for 4 weeks. Urine and blood samples as well as kidney tissue were collected for analysis. C5b‐9‐induced human podocyte cell (HPC) was employed for experiments in vitro. Results: R‐VI could alleviate glomerulonephritis progression and podocyte injury in PHN rats, as indicated by the decreased proteinuria and the elevated level of albumin, accompanied with reduced immune deposits, reversed podocyte injury in the kidneys. Furthermore, R‐VI suppressed murine double minute 2 (MDM2) expression without the alteration in the protein level of p53 and decreased Notch1 expression independent of Numb regulation. Pre‐treatment with R‐VI in C5b‐9‐induced HPC blocked MDM2/Notch1 signalling pathway. Conclusion: Thus, R‐VI ameliorates podocyte injury in rats with PHN, which was probably related with MDM2/Notch1 signalling pathway. [ABSTRACT FROM AUTHOR]

Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS). [ABSTRACT FROM AUTHOR]

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