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Primary membranous nephropathy (pMN) is an autoimmune kidney disease and a common cause of nephrotic syndrome in adults. Rituximab is becoming a first line therapy for patients with persistent nephrotic syndrome with proven safety and efficacy, achieving remission in 60%–80% of cases. For the remaining 20%–40% of patients there is an urgent need to identify early biomarkers of resistance to rituximab to adapt therapeutic management. In nephrotic patients, rituximab is found in the blood more transiently than in other autoimmune diseases without proteinuria, due to rituximab wasting in the urine. However, rituximab immunomonitoring is not routinely performed. We evaluated the predictive value of serum rituximab levels in patients with pMN three months after rituximab injection (month-3) on clinical remission rates six months (month-6) and 12 months (month-12) after injection and investigated predictive factors for serum rituximab levels at month-3. Sixty-eight patients treated with rituximab between July 2015 and January 2020 from two French nephrology centers were included. We identified residual rituximab levels at month-3 as a novel early predictor of remission at month-6 ( p  <0.0001) and month-12 ( p = 0.001). Reduced likelihood of remission in patients with undetectable rituximab at month-3 was associated with lower serum albumin and higher anti-PLA2R1 titers at baseline and with lower serum albumin, higher proteinuria, higher CD19 + counts and higher anti-PLA2R1 titers during follow-up. In multivariate analysis, high baseline proteinuria and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-6 and high baseline weight and undetectable rituximab levels at month-3 were independent risk factors for treatment failure at month-12. We identified serum albumin at baseline as a predictive factor for serum rituximab levels at month-3. Patients with serum albumin below 22.5 g/L at baseline had an 8.66-fold higher risk of having undetectable rituximab levels at month-3. Therefore, rituximab immunomonitoring in pMN patients treated with rituximab would allow the detection of patients at risk of treatment failure as early as month-3. Studies are needed to assess whether patients with low residual rituximab levels at month-3 may benefit from an early additional course of rituximab.

This retrospective study aims to investigate the prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy (HBV-MN). Clinicopathologic and serologic records of 420 patients with histologically confirmed HBV-MN between January 2014 and July 2021 were examined to determine the prevalence of seropositive and seronegative HBV-MN. Serum anti-PLA2R antibody testing was conducted on 280 patients with HBV-associated membranous nephropathy (HBV-MN) from August 2018 to July 2021. Immunopathologic characteristics of HBV-MN patients and anti-PLA2R antibody positivity were analyzed. Among 420 pathologically confirmed HBV-MN patients, 230 (54.8%) were seropositive for HBV. The seropositive group exhibited higher blood creatinine values and incidence of liver function abnormalities than the seronegative group (  < .05). Serum anti-PLA2R antibody testing on 280 HBV-MN patients revealed a total positive rate of 44.6%, with the seronegative group showing a significantly higher rate (62.6%) compared to the seropositive group (32.1%) (  < .01). The anti-PLA2R antibody-positive group displayed higher levels of urine protein (  < .05), serum cholesterol (  < .01), and IgG4 subtypes (  < .05) compared to the negative group. Additionally, the positive group had significantly lower levels of serum albumin and IgG than the negative group (  < .01). This comprehensive study reveals a significantly higher prevalence of seronegative HBV-MN than previously thought. The blood creatinine values and incidence of liver function abnormalities was higher in the serology-positive group than in the serology-negative group. Notably, the seronegative group displayed a higher positive rate of anti-PLA2R antibodies compared to the seropositive group, indicating distinctive clinical and immunopathologic features.

Membranous nephropathy (MN) is a common cause of proteinuria and nephrotic syndrome all over the world. It can be subdivided into primary and secondary forms. Primary form is an autoimmune disease clinically characterized by nephrotic syndrome and slow progression. It accounts for ~70% cases of MN. In the remaining cases MN may be secondary to well-defined causes, including infections, drugs, cancer, or autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), urticarial vasculitis, sarcoidosis, thyroiditis, Sjogren syndrome, systemic sclerosis, or ankylosing spondylitis. The clinical presentation is similar in primary and secondary MN. However, the outcome may be different, being often related to that of the original disease in secondary MN. Also, the treatment may be different, being targeted to the etiologic cause in secondary MN. Thus, the differential diagnosis between primary and secondary MN is critical and should be based not only on history and clinical features of the patient but also on immunofluorescence and electron microscopy analysis of renal biopsy as well as on the research of circulating antibodies. The identification of the pathologic events underlying a secondary MN is of paramount importance, since the eradication of the etiologic factors may be followed by remission or definitive cure of MN. In this review we report the main diseases and drugs responsible of secondary MN, the outcome and the pathogenesis of renal disease in different settings and the possible treatments.

Background Membranous nephropathy is a glomerular disease characterized by the presence of immune-complexes deposited in the subepithelial space of the glomerular basement membrane. It is the main cause of nephrotic syndrome in adults, while in children it is very infrequent. Anti-CD20 monoclonal antibodies, mainly rituximab, represent a specific treatment for this disease. Case report We report the case of a child presenting at 2 years of age with steroid-resistant nephrotic syndrome diagnosed upon kidney biopsy as semaphorin 3B (SEMA3B)-associated primary membranous nephropathy. The patient responded to treatment with cyclosporine, but invariably relapsed upon tapering of this agent. Therefore, at age 9, he was successfully treated with rituximab to overcome cyclosporine dependence. However, after the second rituximab infusion, a rapid reconstitution of CD19 + B cells and a relapse of proteinuria occurred, requiring reintroduction of cyclosporine. Obinutuzumab, a type II anti-CD20 monoclonal antibody, was then infused inducing prolonged CD19 + B cell depletion and remission of proteinuria despite discontinuation of cyclosporine. A greater reduction in circulating anti-SEMA3B antibodies assessed by Western blot was observed after obinutuzumab compared with rituximab infusion. Discussion Obinutuzumab was safe and well-tolerated, and may therefore represent an effective therapeutic alternative in children with primary MN and rituximab resistance.

To evaluate the diagnostic utility of time-resolved fluoroimmunoassay (TRFIA) for detecting serum anti-Phospholipase A2 Receptor (PLA2R) antibodies, specifically the IgG (PLA2R-IgG) and IgG4 subclass (PLA2R-IgG4). A total of 175 patients with serum anti-PLA2R antibody range from 2 to 20 RU/ml, between January 2018 and December 2024, were retrospectively analyzed. 121 serum specimen were tested by TRFIA and ELISA. According to renal biopsy, 52% (91/175) patients were diagnosed with primary membranous nephropathy (PMN). Notably, TRFIA exhibited higher sensitivity and specificity in identifying patients with PMN. Based on the manufacturer’s recommended cutoff values, TRFIA demonstrated a higher sensitivity of 14.3% for PLA2R-IgG and 34.1% for PLA2R-IgG4 compared to ELISA (0%). Receiver operating characteristic analysis showed that TRFIA achieved an area under the curve (AUC) of 0.829 for PLA2R-IgG and 0.814 for PLA2R-IgG4.The optimal anti-PLA2R antibody cutoff values for diagnosing PMN were 0.44 RU/ml (PLA2R-IgG-TRFIA) and 25.07 ng/ml (PLA2R-IgG4-TRFIA) with a sensitivity/specificity of 83.3%/82.4% for PLA2R-IgG-TRFIA, and 83.3% /76.9% for PLA2R-IgG4-TRFIA, both of which were higher than those of ELISA (cutoff:2.84 RU/ml; sensitivity/specificity: 50%/88%). In conclusion, TRFIA demonstrates enhanced sensitivity and specificity in detecting anti-PLA2R antibodies, which may facilitate more accurate diagnosis of PMN and minimize the need for invasive renal biopsies.

The clinical significance of phospholipase A2 receptor (PLA2R) antigen domain-specific antibodies has not been determined. We investigated the role of serum PLA2R domain antibodies and epitope spreading in risk stratification and proteinuria remission in primary membranous nephropathy (PMN). Overall, 101 patients with PLA2R-associated MN diagnosed at the Wuxi People’s Hospital between January 2019 and May 2021 were included and divided into low-to-medium risk (n = 12) and high-to-extremely-high risk (n = 89) groups. Serum PLA2R-IgG4 levels were significantly different between the groups, no statistical difference was found in PLA2R-IgG levels. The proportion of IgG4 epitope spreading was greater in the high-to-extremely-high risk group than in the low-to-medium risk group. The result of random forest machine learning method showed that combining the three variables (PLA2R-CTLD678-IgG4, PLA2R-CysR-IgG4, and IgG4 epitope-spreading) showed no significant difference in PMN risk stratification than that of PLA2R-IgG. For predicting proteinuria at 12 months, the ACC values were significantly greater for PLA2R-CTLD1-IgG4, PLA2R-CTLD678-IgG4, and PLA2R-IgG4 than for PLA2R-IgG. Combining IgG4 epitope-spreading and PLA2R-IgG may improve the ACC value of proteinuria prediction after 6 months of treatment compared with PLA2R-IgG alone. PLA2R-CTLD1-IgG4, PLA2R-CTLD678-IgG4, and PLA2R-IgG4 can predict proteinuria remission more accurately at 12 months of treatment than PLA2R-IgG.

Idiopathic membranous nephropathy (IMN) is a leading cause of nephrotic syndrome in middle-aged and elderly populations. Early intervention can delay disease progression and improve patient outcomes. This study aims to identify urinary biomarkers for IMN and investigate their association with disease progression, offering new insights for precise diagnosis and treatment. This study began with RNA sequencing of three urine sample types (first-void morning urine, second-void morning urine, and random urine), combined with single-cell RNA sequencing of renal tissues. Bioinformatics analyses-including differential gene expression screening, machine learning, and molecular function annotation-were employed to identify potential IMN biomarkers. Furthermore, we established both a siRNA-mediated gene silencing model and a lentivirus transfection-mediated gene overexpression model in HK-2 cells. Subsequently, we investigated the functional mechanisms of the candidate biomarkers through qRT-PCR, Western blot, immunohistochemistry, and immunofluorescence assays. SPP1 was identified as a promising biomarker for IMN, demonstrating a critical role in promoting fibrosis and inflammatory responses associated with the disease. These findings suggest its potential as a novel therapeutic target for IMN intervention.

Idiopathic membranous nephropathy (IMN) is an organ-specific autoimmune disease of the kidney glomerulus. It may gradually progress to end-stage renal disease (ESRD) characterized by increased proteinuria, which leads to serious consequences. Although substantial advances have been made in the understanding of the molecular bases of IMN in the last 10 years, certain questions remain largely unanswered. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from 6 patients with anti-PLA2R positive IMN and 2 healthy control subjects using single-cell RNA sequencing. We then identified distinct cell clusters through unsupervised clustering analysis of kidney specimens. Identification of the differentially expressed genes (DEGs) and enrichment analysis as well as the interaction between cells were also performed. Based on transcriptional expression patterns, we identified all previously described cell types in the kidney. The DEGs in most kidney parenchymal cells were primarily enriched in genes involved in the regulation of inflammation and immune response including IL-17 signaling, TNF signaling, NOD-like receptor signaling, and MAPK signaling. Moreover, cell-cell crosstalk highlighted the extensive communication of mesangial cells, which infers great importance in IMN. IMN with massive proteinuria displayed elevated expression of genes participating in inflammatory signaling pathways that may be involved in the pathogenesis of the progression of IMN. Overall, we applied single-cell RNA sequencing to IMN to uncover intercellular interactions, elucidate key pathways underlying the pathogenesis, and identify novel therapeutic targets of anti-PLA2R positive IMN.

Idiopathic membranous nephropathy (IMN) is an autoimmune disease in which the immune system produces an antibody response to its own antigens due to impaired immune tolerance. Although antibodies are derived from plasma cells differentiated by B cells, the T-B cells also contribute a lot to the immune system. In particular, the subsets of helper T (Th) cells, including the dominant subsets such as Th2, Th17, and follicular helper T (Tfh) cells and the inferior subsets such as regulatory T (Treg) cells, shape the immune imbalance of IMN and promote the incidence and development of autoimmune responses. After reviewing the physiological knowledge of various subpopulations of Th cells and combining the existing studies on Th cells in IMN, the role model of Th cells in IMN was explained in this review. Finally, the existing clinical treatment regimens for IMN were reviewed, and the importance of the therapy for Th cells was highlighted.

Objective To evaluate the efficacy and safety of hydroxychloroquine sulfate (HCQ) in the treatment of low risk phospholipase A 2 receptor (PLA 2 R)-associated membranous nephropathy (MN). Methods A total of 110 patients with low risk PLA 2 R-associated MN were included in the study. Patients who met the inclusion and exclusion criteria were assigned randomly to two groups: the HCQ treatment group and the control group. The control group received standard supportive treatment according to the guidelines, while the HCQ treatment group received HCQ in addition to the supportive treatment. The clinical data of the patients were analyzed, with comparisons made at baseline and during the six-month follow-up period. Any adverse reactions were recorded. Results The baseline data were comparable between the HCQ treatment group and the control group. At the end of the six-month follow-up period, the reductions in urine protein excretion and serum PLA 2 R antibody titer were more notable in the HCQ treatment group than those in the control group, with these differences being statistically significant ( p  < 0.05). Compared to the control group, the HCQ treatment group had fewer patients who were converted from low risk to moderate-to-high risk ( p  = 0.084). There were also no severe adverse reactions in the HCQ treatment group. Conclusion In patients with low risk PLA 2 R-associated MN, adequate supportive therapy combined with HCQ is superior to supportive therapy alone in controlling proteinuria and reducing serum PLA 2 R antibody titers. Additionally, our study demonstrated that the incidence of adverse reactions did not increase. Trial registration This study was registered in the Chinese Clinical Trial Registry (Registration No.: ChiCTR1900021757, Date of registration: 2019-03-08).