Aggressive treatment may be needed for idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions.

OBJECTIVE: The purpose of this study was to analyze the clinical, pathological, prognostic features and treatment response of the coexistence of focal segmental glomerulosclerosis lesions with idiopathic membranous nephropathy. METHODS: This is a two-center retrospective cohort study. Patients of idiopathic membranous nephropathy were enrolled and divided into two groups with or without focal segmental glomerulosclerosis lesions according to the renal biopsy. Laboratory data and pathological manifestation were compared. Renal phospholipase A2 receptor was detected by immunofluorescence. During the follow-up, the effects of different therapies and renal function were estimated. RESULTS: A total of 236 patients were finally enrolled in this study, of which 60 and 176 idiopathic membranous nephropathy patients were enrolled in the FSGS+ and FSGS- groups, respectively. The FSGS+ group showed a higher percentage of hypertension history (38.3 vs. 20.0%, p=0.004), with a significantly higher level of systolic pressure [137 (120, 160) mmHg vs. 130 (120, 140) mmHg, p=0.009]. Main laboratory findings, including serial albumin (20.4±7.8 g/L vs. 24.5±6.7 g/L, p<0.001), 24-h proteinuria [5.61 (3.10, 7.87) g/day vs. 3.82 (2.31, 5.79) g/day, p=0.002], serial creatinine [80.8 (65.8, 97.9) µmol/L vs. 72.0 (58.7, 84.9) µmol/L, p=0.003], and estimated glomerular filtration rate [86 (66, 101) mL/min/1.73 m2 vs. 95 (81, 108) mL/min/1.73 m2, p=0.007] showed significant differences between the two groups. Pathologically, patients with focal segmental glomerulosclerosis lesions appeared with a higher percentage of crescents, a more severe degree of interstitial fibrosis, and a higher level of membranous nephropathy stage. Renal phospholipase A2 receptor showed a relatively lower positive rate of only 75.0% in the FSGS+ group in comparison with the positive rate of 90.3% in the FSGS- group (p=0.031). The prognosis was generally similar between the two groups. Among patients who were given non-immunosuppression treatment, those with focal segmental glomerulosclerosis lesions took a relatively longer period of time to achieve complete remission (29.3±7.0 m vs. 15.4±8.9 m, p=0.025) and experienced a higher rate of renal function deterioration (37.5 vs. 5.4%, p=0.033) compared with the other ones. While among those receiving immunosuppression treatment, both groups received similar remission rates. CONCLUSION: Compared with FSGS- group, idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions represented more severe nephrotic syndrome and worse renal function. In view of the renal function decline during the follow-up, more aggressive treatment with the use of immunosuppressants should be considered for idiopathic membranous nephropathy patients with focal segmental glomerulosclerosis lesions.

Potential therapeutic targets for membranous nephropathy: proteome-wide Mendelian randomization and colocalization analysis.

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

Predictive value of the domain specific PLA2R antibodies for clinical remission in patients with primary membranous nephropathy: A retrospective study.

BACKGROUND: M-type phospholipase A2 receptor (PLA2R) is a major auto-antigen of primary membranous nephropathy(PMN). Anti-PLA2R antibody levels are closely associated with disease severity and therapeutic effectiveness. Analysis of PLA2R antigen epitope reactivity may have a greater predictive value for remission compared with total PLA2R-antibody level. This study aims to elucidate the relationship between domain-specific antibody levels and clinical outcomes of PMN. METHODS: This retrospective analysis included 87 patients with PLA2R-associated PMN. Among them, 40 and 47 were treated with rituximab (RTX) and cyclophosphamide (CTX) regimen, respectively. The quantitative detection of -immunoglobulin G (IgG)/-IgG4 targeting PLA2R and its epitope levels in the serum of patients with PMN were obtained through time-resolved fluorescence immunoassays and served as biomarkers in evaluating the treatment effectiveness. A predictive PMN remission possibility nomogram was developed using multivariate logistic regression analysis. Discrimination in the prediction model was assessed using the area under the receiver operating characteristic curve (AUC-ROC).Bootstrap ROC was used to evaluate the performance of the prediction model. RESULTS: After a 6-month treatment period, the remission rates of proteinuria, including complete remission and partial remission in the RTX and CTX groups, were 70% and 70.21% (P = 0.983), respectively. However, there was a significant difference in immunological remission in the PLA2R-IgG4 between the RTX and CTX groups (21.43% vs. 61.90%, P = 0.019). Furthermore, we found differences in PLA2R-CysR-IgG4(P = 0.030), PLA2R-CTLD1-IgG4(P = 0.005), PLA2R-CTLD678-IgG4(P = 0.003), and epitope spreading (P = 0.023) between responders and non-responders in the CTX group. Multivariate logistic analysis showed that higher levels of urinary protein (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.26-0.95; P = 0.035) and higher levels of PLA2R-CTLD1-IgG4 (OR, 0.79; 95%CI,0.62-0.99; P = 0.041) were independent risk factors for early remission. A multivariate model for estimating the possibility of early remission in patients with PMN is presented as a nomogram. The AUC-ROC of our model was 0.721 (95%CI, 0.601-0.840), in consistency with the results obtained with internal validation, for which the AUC-ROC was 0.711 (95%CI, 0.587-0.824), thus, demonstrating robustness. CONCLUSIONS: Cyclophosphamide can induce immunological remission earlier than rituximab at the span of 6 months. The PLA2R-CTLD1-IgG4 has a better predict value than total PLA2R-IgG for remission of proteinuria at the 6th month.

Membranous lupus nephritis secondary to secukinumab therapy: A case report and literature review.

The interleukin (IL)-17 axis is involved in many inflammatory and autoimmune diseases. Secukinumab, an IL-17 inhibitor, has been approved for psoriasis treatment. There are accumulating cases of lupus erythematosus induced by IL-17 inhibition. Lupus nephritis after IL-17 inhibition has not been reported. We report the case of a 57-year-old man who developed membranous lupus nephritis after secukinumab treatment for psoriasis. Anti-SSA and PM-Scl antibodies were positive. dsDNA, anti-Smith, and anti-histone antibodies were negative, and serum complement was low. Secukinumab was discontinued, while tacrolimus was initiated, subsequently switched to cyclosporin, belimumab, glucocorticosteroid, and hydroxychloroquine with a good response. The relationship between lupus erythematosus and IL-17 inhibition requires further research.

Activation of the IL-6/STAT3 pathway contributes to the pathogenesis of membranous nephropathy and is a target for Mahuang Fuzi and Shenzhuo Decoction (MFSD) to repair podocyte damage.

BACKGROUND: Primary membranous nephropathy (PMN) is an autoimmune glomerular disease. IL-6 is a potential therapeutic target for PMN. Previous clinical studies have demonstrated the effectiveness of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in treating membranous nephropathy. However, the mechanism of action of MFSD remains unclear. METHODS: Serum IL-6 levels were measured in patients with PMN and healthy subjects. The passive Heymann nephritis (PHN) rat model was established, and high and low doses of MFSD were used for intervention to observe the repair effect of MFSD on renal pathological changes and podocyte injury. RNA-seq was used to screen the possible targets of MFSD, and the effect of MFSD targeting IL-6/STAT3 was further verified by combining the experimental results. Finally, the efficacy of tocilizumab in PHN rats was observed. RESULTS: Serum IL-6 levels were significantly higher in PMN patients than in healthy subjects. These levels significantly decreased in patients in remission after MFSD treatment. MFSD treatment improved laboratory indicators in PHN rats, as well as glomerular filtration barrier damage and podocyte marker protein expression. Renal transcriptome changes showed that MFSD-targeted differential genes were enriched in JAK/STAT and cytokine-related pathways. MFSD inhibits the IL6/STAT3 pathway in podocytes. Additionally, MFSD significantly reduced serum levels of IL-6 and other cytokines in PHN rats. However, treatment of PHN with tocilizumab did not achieve the expected effect. CONCLUSION: The IL-6/STAT3 signaling pathway is activated in podocytes of experimental membranous nephropathy. MFSD alleviates podocyte damage by inhibiting the IL-6/STAT3 pathway.

Prediction of immunotherapy response in idiopathic membranous nephropathy using deep learning-pathological and clinical factors.

Background: Owing to individual heterogeneity, patients with idiopathic membranous nephropathy (IMN) exhibit varying sensitivities to immunotherapy. This study aimed to establish and validate a model incorporating pathological and clinical features using deep learning training to evaluate the response of patients with IMN to immunosuppressive therapy. Methods: The 291 patients were randomly categorized into training (n = 219) and validation (n = 72) cohorts. Patch-level convolutional neural network training in a weakly supervised manner was utilized to analyze whole-slide histopathological features. We developed a machine-learning model to assess the predictive value of pathological signatures compared to clinical factors. The performance levels of the models were evaluated using the area under the receiver operating characteristic curve (AUC) on the training and validation tests, and the prediction accuracies of the models for immunotherapy response were compared. Results: Multivariate analysis indicated that diabetes and smoking were independent risk factors affecting the response to immunotherapy in IMN patients. The model integrating pathologic features had a favorable predictive value for determining the response to immunotherapy in IMN patients, with AUCs of 0.85 and 0.77 when employed in the training and test cohorts, respectively. However, when incorporating clinical features into the model, the predictive efficacy diminishes, as evidenced by lower AUC values of 0.75 and 0.62 on the training and testing cohorts, respectively. Conclusions: The model incorporating pathological signatures demonstrated a superior predictive ability for determining the response to immunosuppressive therapy in IMN patients compared to the integration of clinical factors.

Diosgenin protects against cationic bovine serum albumin-induced membranous glomerulonephritis by attenuating oxidative stress and renal inflammation via the NF-κB pathway.

CONTEXT: Membranous glomerulonephritis (MGN) is a leading cause of nephrotic syndrome in adults. Diosgenin (DG) has been reported to exert antioxidative and anti-inflammatory effects. OBJECTIVE: To investigate the renoprotective activity of DG in a cationic bovine serum albumin-induced rat model of MGN. MATERIALS AND METHODS: Fourty male Sprague-Dawley rats were randomized into four groups. The MGN model was established and treated with a DG dose (10 mg/kg) and a positive control (TPCA1, 10 mg/kg), while normal control and MGN groups received distilled water by gavage for four consecutive weeks. At the end of the experiment, 24 h urinary protein, biochemical indices, oxidation and antioxidant levels, inflammatory parameters, histopathological examination, immunohistochemistry and immunoblotting were evaluated. RESULTS: DG significantly ameliorated kidney dysfunction by decreasing urinary protein (0.56-fold), serum creatinine (SCr) (0.78-fold), BUN (0.71-fold), TC (0.66-fold) and TG (0.73-fold) levels, and increasing ALB (1.44-fold). DG also reduced MDA (0.82-fold) and NO (0.83-fold) levels while increasing the activity of SOD (1.56-fold), CAT (1.25-fold), glutathione peroxidase (GPx) (1.55-fold) and GSH (1.81-fold). Furthermore, DG reduced Keap1 (0.76-fold) expression, Nrf2 nuclear translocation (0.79-fold), and induced NQO1 (1.25-fold) and HO-1 (1.46-fold) expression. Additionally, DG decreased IL-2 (0.55-fold), TNF-α (0.80-fold) and IL-6 (0.75-fold) levels, and reduced protein expression of NF-κB p65 (0.80-fold), IKKß (0.93-fold), p-IKKß (0.89-fold), ICAM-1 (0.88-fold), VCAM-1 (0.91-fold), MCP-1 (0.88-fold) and E-selectin (0.87-fold), and also inhibited the nuclear translocation of NF-κB p65 (0.64-fold). DISCUSSION AND CONCLUSIONS: The results suggest a potential therapeutic benefit of DG against MGN due to the inhibition of the NF-κB pathway, supporting the need for further clinical trials.

Efficacy and safety of Mahuang Fuzi and Shenzhuo Decoction for treatment of primary membranous nephropathy: a multicenter prospective trial.

BACKGROUND: This study aims to undertake a comprehensive assessment of the effectiveness and safety profile of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in the management of primary membranous nephropathy (PMN), within the context of a prospective clinical investigation. METHODS: A multicenter, open-label clinical trial was executed on patients diagnosed with PMN. These individuals were subjected to MFSD therapy for a duration of at least 24 months, with primary outcome of clinical remission rates. The Cox regression analysis was employed to discern the pertinent risk factors exerting influence on the efficacy of MFSD treatment, with scrupulous monitoring of any adverse events. RESULTS: The study comprised 198 participants in total. Following 24 months of treatment, the remission rate was 58.6% (116/198). Among the subgroup of 130 participants subjected to a 36-month follow-up, the remission rate reached 70% (91/130). Subgroup analysis revealed that neither a history of immunosuppressive therapy (HIST) nor an age threshold of ≥60 years exhibited a statistically significant impact on the remission rate at the 24-month mark (p > .05). Multivariate Cox regression analyses elucidated HIST, nephrotic syndrome, or mass proteinuria, and a high-risk classification as noteworthy risk factors in the context of MFSD treatment. Remarkably, no fatalities resulting from side effects were documented throughout the study's duration. CONCLUSIONS: This trial establishes the efficacy of MFSD as a treatment modality for membranous nephropathy. MFSD demonstrates a favorable side effect profile, and remission rates are consistent across patients, irrespective of HIST and age categories.

Rituximab may affect T lymphocyte subsets balance in primary membranous nephropathy.

BACKGROUND: The aim of this study was to investigate the effects and significance of rituximab (RTX) on the levels of T lymphocyte subsets in patients diagnosed with primary membranous nephropathy (PMN). METHODS: A total of 58 PMN patients and 25 healthy donors were chosen as the subjects. Among the PMN patients, 40 individuals received RTX treatment and completed at least 6 months of follow-up. All subjects underwent flow cytometry analysis to determine the peripheral blood lymphocyte subsets. The changes in anti-PLA2R antibody titers and 24-hour urinary protein levels were evaluated by ELISA and Biuret method before and after treatment. RESULTS: (1) The PMN group exhibited a significantly greater percentage of peripheral blood CD3-CD19+ B cells than the healthy group, which is consistent with the findings of previous reports. Additionally, compared with those in the peripheral blood of healthy individuals, the numbers of CD4+ central memory T cells, CD4+ effector memory T cells, CD4+/CD8+, and CD4+CD25+ T cells in the PMN peripheral blood were markedly greater. However, the number of peripheral blood Treg cells was reduced in the PMN group. (2) After 6 months of RTX treatment, PMN patients exhibited significant decreases in anti-PLA2R antibody titers, 24-hour urinary protein levels, and peripheral blood CD3-CD19+ B cells. Importantly, RTX administration decreased CD4+CD25+ T cells and CD4+/CD8+ in the peripheral blood of PMN patients and improved Treg cell levels. (3) RTX treatment induced alterations in the CD4+ T lymphocyte subsets in PMN patients, which did not correlate with B lymphocyte counts or anti-PLA2R antibody titers. CONCLUSIONS: RTX treatment might have a beneficial impact on cellular immunity by effectively restoring the balance of CD4+ T lymphocyte subsets in PMN patients, which is beyond its effects on B cells and antibody production. TRIAL REGISTRATION: The research was registered at the First Affiliated Hospital of Soochow University. REGISTRATION NUMBER: MR-32-23-016211. Registration Date: May 31, 2023.

Optimized rituximab regimen versus recommended regimen for idiopathic membranous nephropathy: A single-center retrospective cohort study.

BACKGROUND: Rituximab (RTX) has become the first-line treatment for idiopathic membranous nephropathy (IMN). Compared with conventional therapy, rituximab therapy has a more favorable safety profile. However, the recommended RTX dose as a flux may have its limitations. The aim of this study was to investigate the clinical efficacy and safety of three regimens, including a cyclic corticosteroid-cyclophosphamide regimen and two different doses of RTX regimens, for the treatment of IMN. METHODS: We recruited 58 patients with IMN confirmed by renal biopsy. 20 patients were treated with a cycle regimen, 22 patients were received RTX with 500 mg per week, totaling a dose of 2000 mg (optimized RTX group), and 16 patients received RTX with 1000 mg at day 1 and day 15 (recommended RTX group). Treatment responses, including complete remission (CR) and partial remission (PR), and outcome adverse events such as steroid diabetes, infections and a drop in white blood cell count, were compared among the three groups after 9 months of follow-up. RESULTS: At 9-month follow-up, the composite remission rates (CR + PR) were 90 %, 72.7 %, and 75 % for the cycle regimen group, optimized RTX group, and recommended RTX group, respectively, with CR of 35 %, 22.7 %, and 25 %, respectively. There was no statistical difference between the three groups on CR and composite remission. Kaplan-Meier survival analyses showed no significant differences in cumulative CR rates and cumulative composite remission rates among the three groups (P = 0.632, P = 0.258). The cycle regimen group had a higher risk of steroid diabetes (35 %). Compared with the recommended RTX regimen, the optimized regimen reduced the incidence of adverse events of infection (9.1 % vs. 37.5 %, P = 0.049), especially in patients older than 60 years of age (P = 0.026). A lower anti-PLA2R at baseline may be associated with a higher risk of infection (P = 0.043). CONCLUSIONS: The efficiency of low-dose and long-course of RTX regiment is not inferior to the recommended treatment regimen, and this regimen can effectively reduce the incidence of infection in patients with IMN. Moreover, we recommend a low-dose, long course of RTX treatment for the elderly.

Idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis.

Membranous nephropathy has been associated with demyelinating polyneuropathies and antiglomerular membrane disease; however, an association with vasculitic neuropathy has not been described. This case describes a patient with biopsy-proven idiopathic membranous nephropathy and synchronous mononeuritis multiplex secondary to idiopathic small vessel vasculitis, who presented with lower limb microvascular ischaemia, peripheral neuropathy and active urinary sediment. Her extensive non-invasive screening for immunological disease and radiological investigations for occult malignancy were unremarkable. The patient received intravenous methylprednisolone and intravenous rituximab induction therapy resulting in complete remission of both the idiopathic membranous nephropathy and small vessel vasculitis at 7 months post treatment.

Two successful pregnancies in a membranous nephropathy patient: Case report and literature review.

BACKGROUND: Pregnancy in patients with nephrotic syndrome presents enormous challenges to both the mother and fetus, and there are no treatment guidelines for these patients. METHODS: We show a case of a woman with anti-PLA2R antibody-positive membranous nephropathy who did not have a kidney biopsy. Her clinical course during both pregnancies was closely followed and her medications were guided. RESULTS: She gave birth to 2 healthy babies and her condition was very well controlled with the help of medication. CONCLUSION: Patients with nephrotic syndrome can have successful pregnancies after drug treatment. In addition, similar to the non-pregnant population, percutaneous kidney biopsy is not required for the diagnosis of idiopathic membranous nephropathy (IMN) in pregnant nephrotic syndrome patients with anti-PLA2R antibody positive, but the etiology of secondary MN should be excluded.

Fangji Huangqi decoction ameliorates membranous nephropathy through the upregulation of BNIP3-mediated mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Fangji Huangqi Decoction (FJHQ), a traditional Chinese medicinal formula outlined in Zhang Zhongjing's "Jin Gui Yao Lue" during the Han Dynasty, is often used to treat conditions characterized by symptoms like edema and dysuria, including membranous nephropathy (MN). Despite its proven clinical effectiveness, the exact mechanisms through which FJHQ acts on MN remain elusive. AIM OF THE STUDY: This study aimed to investigate whether FJHQ enhances BNIP3-mediated mitophagy in podocytes by promoting BNIP3 expression and whether this improvement leads to the amelioration of MN. MATERIALS AND METHODS: In this study, by establishing passive Heymann nephritis (PHN) rats, an experimental rat model of MN induced by sheep anti-rat Fx1A serum, we evaluated the effects of FJHQ in vivo. In vitro experiments were carried out by treating primary podocytes with experimental rat serum. Furthermore, the potential mechanism by which FJHQ acts through BNIP3 was further examined by transfecting primary podocytes with the siRNA of BNIP3 or the corresponding control vector. RESULTS: After 4 weeks, significant kidney damage was observed in the rats in the model group, comparatively, FJHQ markedly decreased urine volume, 24-h urinary protein, blood urea nitrogen (BUN), creatinine (Scr), and increased serum total albumin (ALB). Histology showed that FJHQ caused significant improvements in glomerular hyperplasia, and IgG immune complex deposition in MN rats. JC-1 fluorescence labelling and flow cytometry analysis showed that FJHQ could significantly increase mitochondrial membrane potential in vivo. In the mitochondria of MN model rats, FJHQ was able to down-regulate the expression of P62 and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I, according to Western blot and immunofluorescence studies. Furthermore, FJHQ has been shown to significantly up-regulate mitochondrial membrane potential, down-regulate P62 expression in mitochondria, and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I in mitochondria at the cellular level. After the administration of the autophagy inhibitor chloroquine, the serum of rats treated with FJHQ further increased the expression of LC3 II/LC3 I in primary podocytes, showing higher autophagy flow. After the interference of BNIP3 in podocytes, the effect of FJHQ on mitochondrial membrane potential and autophagy-related proteins almost disappeared. CONCLUSION: FJHQ enhanced mitophagy in podocytes by promoting the expression of BNIP3, thereby contributing to the amelioration of MN. This work reveals the possible underlying mechanism by which FJHQ improves MN and provides a new avenue for MN treatment.

Hepatitis B Virus-related Membranous Nephropathy with Crescentic Formation in an Inactive Carrier of Positive Hepatitis B Surface Antigen with Undetectable DNA under Anti-viral Treatment.

A man who was an inactive hepatitis B virus (HBV) carrier with positive hepatitis B surface antigen (HBs antigen) and undetectable HBV-DNA under anti-viral treatment developed nephrotic syndrome at 52 years old, and a renal biopsy revealed advanced membranous nephropathy (MN) with focal cellular crescents, interstitial hemorrhaging, and peritubular capillaritis. Immunofluorescence studies demonstrated granular IgG deposition and HBs antigen-positivity along the capillaries. Glomeruli were negative for phospholipase A2 receptor 1. There were no clinical findings of systemic vasculitis. We considered MN combined with small-vessel vasculitis due to HBV infection. These results suggest that HBV-related kidney disease should be considered even in patients with an inactive HBV carrier status under treatment.

Colquhounia root tablet in the treatment of idiopathic membranous nephropathy with subnephrotic proteinuria.

PURPOSE: Idiopathic membranous nephropathy (IMN) is the most frequent global cause of nephrotic syndrome in non-diabetic people. In clinical practice, An effective and mild treatment for IMN patients with subnephrotic proteinuria has been adopted. Colquhounia root tablet (CRT) is a traditional Chinese medicine that is widely used in China to treat glomerulopathies. In this study, the effectiveness and safety of CRT in the treatment of IMN with subnephrotic proteinuria have been determined by reviewing the clinical records of 44 patients with IMN. METHODS: Retrospective analysis of IMN patients with subnephrotic proteinuria treated with CRT in combination with ACEI/ARB or ACEI/ARB alone. The remission rate (complete or partial remission) was the main outcome observed, and proteinuria, estimated glomerular filtration rate (eGFR), serum albumin levels, and adverse effects were the secondary outcomes. RESULTS: This clinical trial included 44 patients, and the overall remission rates at months 6, 9, and 12 after treatment were 68.2% versus 27.3% (p = 0.016), 72.7% versus 36.4% (p = 0.015), and 77.3% versus 36.4% (p = 0.006) in the treatment and control groups, respectively. The application of CRT treatment was an independent predictor of proteinuria remission (p = 0.024). In addition, in patients who were positive for phospholipase A2 receptor (PLA2R) antibodies, the overall remission rate was higher in the treatment group than in the control group after 9 months of treatment (75% versus 23.08%, p = 0.017). CONCLUSION: This retrospective study illustrates that, based on supportive therapy, CRT could be effective in the treatment of IMN with subnephrotic proteinuria with a good safety profile at the same time.

Targeted therapy in glomerular diseases.

Targeted therapy has emerged as a more precise approach to treat glomerular diseases, focusing on specific molecular or cellular processes that contribute to disease development or progression. This approach complements or replaces traditional immunosuppressive therapy, optimizes supportive care, and provides a more personalized treatment strategy. In this review, we summarize the evolving understanding of pathogenic mechanisms in immune-mediated glomerular diseases and the developing targeted therapies based on these mechanisms. We begin by discussing pan-B-cell depletion, anti-CD20 rituximab, and targeting B-cell survival signaling through the BAFF/APRIL pathway. We also exam specific plasma cell depletion with anti-CD38 antibody. We then shift our focus to complement activation in glomerular diseases, which is involved in antibody-mediated glomerular diseases, such as IgA nephropathy, membranous nephropathy, ANCA-associated vasculitis, and lupus nephritis. Non-antibody-mediated complement activation occurs in glomerular diseases, including C3 glomerulopathy, complement-mediated atypical hemolytic uremic syndrome, and focal segmental glomerulosclerosis. We discuss specific inhibition of terminal, lectin, and alternative pathways in different glomerular diseases. Finally, we summarize current clinical trials targeting the final pathways of various glomerular diseases, including kidney fibrosis. We conclude that targeted therapy based on individualized pathogenesis should be the future of treating glomerular diseases.

Successful treatment of coexisting membranous nephropathy and immune thrombocytopenia by eradicating gastric Helicobacter pylori infection: a case report.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in middle-aged and older adults. MN etiology is mainly primary or idiopathic; however, it may also be secondary to infections, drugs, neoplasms, and autoimmune diseases. We present the case of a 52-year-old Japanese man with coexisting nephrotic MN and immune thrombocytopenic purpura (ITP). Renal biopsy revealed glomerular basement membrane thickening with immunoglobulin (Ig) G and complement component 3 deposition. Glomerular IgG subclass analysis revealed predominant IgG4 deposition with weak IgG1 and IgG2 deposition. IgG3 and phospholipase A2 receptor deposits were negative. Upper endoscopy revealed no ulcers, but histological examination demonstrated Helicobacter pylori infection in the gastric mucosa with elevated IgG antibodies. After gastric Helicobacter pylori eradication, the nephrotic-range proteinuria and thrombocytopenia of the patient were markedly improved without initiation of immunosuppressive treatment. Therefore, clinicians should consider the possibility of Helicobacter pylori infection in patients with coexisting MN and ITP. Further studies are required to demonstrate the associated pathophysiological aspects.

An Unusual Case of Anti-Glomerular Basement Membrane Disease and Phospholipase A2 Receptor-Associated Membranous Nephropathy After Exposure to Hydrocarbons.

We present a rare case of a patient with toluene exposure manifesting as anti-glomerular basement membrane (GBM) disease on a background of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy. A 23-year-old man presented to the emergency department with hypertension, headache, hemoptysis, anemia, acute kidney injury, glomerular hematuria, and proteinuria. He endorsed repeated exposure to toluene-containing products while repairing dirt bikes. Serologies were positive for anti-GBM antibodies. Kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G and granular PLA2R staining by immunofluorescence. He was initially treated with high-dose steroids, plasmapheresis, and hemodialysis for pulmonary-renal syndrome followed by oral cyclophosphamide and prednisone, which were discontinued after 3 months when follow-up biopsies confirmed little chance for renal recovery. He remained on dialysis 1 year later. This case exhibits a unique presentation of anti-GBM syndrome and underlying membranous nephropathy following repeated hydrocarbon exposure. Inhaled toxins promote recurrent localized inflammation, unmasking previously hidden epitopes. Early diagnosis and appropriate use of immunosuppressive and extracorporeal therapies are necessary to prevent morbidity and to improve survival in this rare condition.

Effect of rituximab in patients with PLA2R-associated membranous nephropathy and malignancy.

INTRODUCTION: Phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) is a common cause of nephrotic syndrome in nondiabetic adults who are also within the common age group for malignancy. How to treat patients with PLA2R-associated MN and malignancy effectively and safely still requires careful consideration. The aim of our study was to examine the outcomes and safety of rituximab (RTX) in these patients. METHODS: Retrospective analysis of clinical data was performed on 15 patients with PLA2R-associated MN and malignancy. Patients were followed every 1-3 months for a minimum of 24 months. Clinical data were collected, including CD19+ B cells, anti-PLA2R antibodies, 24-hour urinary protein, serum albumin, and serum creatinine. The percentage of patients who achieved clinical remission and immunological remission was also measured. RESULTS: Among these 15 patients, 14 patients with solid tumors received treatment for malignant diseases with complete resection. One patient received chemotherapy for chronic myeloid leukemia, and achieved complete remission 36 months before the diagnosis of MN. There were 6 (40.00 %) patients who achieved complete remission and 14 (93.33 %) patients who achieved complete or partial remission at the last visit after RTX treatment. At the last visit, patients were clinically improved, as evidenced by significant improvements in anti-PLA2R antibody titer [2.00 (2.00, 2.00) vs 35.25 (11.18, 91.58) RU/ml, P = 0.002], 24-hour urine protein [0.39 (0.11, 2.28) vs 9.22 (4.47, 14.73) g/d, P = 0.001], and serum albumin [38.15 (34.80, 43.20) vs 23.70 (18.70, 25.70) g/L, P = 0.001]. During the follow-up, the renal function of those patients remained stable. Recurrence of malignant tumors or the occurrence of new tumor events were not observed. CONCLUSION: In this single-center retrospective study with a small sample size, RTX therapy might be an effective and safe treatment in patients with PLA2R-associated MN and malignancy.