Membranous Nephropathy Patients Research Articles

Development of a nomogram for membranous nephropathy prediction in patients with primary Sjögren's syndrome: a 6-year retrospective study.

Nephritis is a life-threatening complication of primary Sjögren's syndrome (pSS), with membranous nephropathy (MN) being prevalent. Renal biopsy is the gold standard for MN diagnosis, but it is invasive and cannot be repeatedly performed. This study aimed to develop a nomogram for the prediction of MN in patients with pSS. This retrospective study included patients with pSS admitted to the Rheumatology and Immunology Department of the First Affiliated Hospital of China Medical University between January 2015 and January 2021.A nomogram was developed using multivariable logistic regression analysis and evaluated using receiver operating characteristic (ROC) curve analysis. Bootstrap resampling analysis (1,000 times) was performed to evaluate the nomogram for discrimination and the calibration curve for consistency. A total of 237 patients with pSS [aged 53.00 (44.00, 61.00) years] were included, with 35 pSS-MN patients. Based on clinical practice and multivariable logistic regression analysis, seven variables associated with pSS-MN were selected, including white blood cells, creatine, complement 3, rheumatoid factor, antinuclear antibodies, anti-SSA antibody, and interstitial lung disease. The area under the ROC curve was 0.860 (95% confidence interval: 0.796-0.919), indicating good predictive power. In addition, the nomogram exhibited excellent performance, as demonstrated by the calibration curve and decision curve analysis. This study developed a risk prediction nomogram for MN in patients with pSS, with high predictive power. It may be used to improve the management of patients with pSS.

Combined Serologic and Genetic Risk Score and Prognostication of Phospholipase A2 receptor-Associated Membranous Nephropathy.

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

Development of Drug Efficacy Testing Platform for Glomerulonephritis.

We developed a 3D glomeruli tissue chip for glomerulonephritis (GN) testing, featuring a gravity-driven glomerular filtration barrier (GFB) with human podocytes and endothelial cells with a bidirectional flow in the bottom channel. Using puromycin-induced GN, we observed decreased cell viability, increased albumin permeability, and reduced WT1 and nephrin compared to the normal GFB. Tacrolimus restored cell viability, reduced albumin permeability, and increased WT1 expression. Using serum from five membranous nephropathy (MN) patients, we created MN models using a GFB-mimicking chip. A notable decline in cell viability was observed in the serum-induced MN1 and MN2 models. However, tacrolimus restored it. Albumin permeability was reduced in the MN1, MN2, and MN5 models by tacrolimus treatment. MN1 displayed the best clinical response to tacrolimus, exhibiting increased expression of WT1 in chip-based evaluations after tacrolimus treatment. We successfully evaluated the efficacy of tacrolimus using puromycin-induced and serum-induced GN models on a chip that mimicked the structure and function of the GFB. The GFB-mimicking chip holds promise as a personalized platform for assessing drug efficacy using patient serum samples.

Clinicopathological characteristics and outcomes of PLA2R related idiopathic membranous nephropathy in patients with seronegative PLA2R antibodies

Background 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. Methods 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. Results 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). Conclusion IMN with PLA2R staining on kidney biopsy but without serum PLA2R antibody has milder clinical manifestations and a better prognosis.

Defining the threshold: triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio's non-linear impact on tubular atrophy in primary membranous nephropathy.

Hyperlipidemia is common in primary membranous nephropathy (PMN) patients, and tubular atrophy (TA) is an unfavorable prognostic factor. However, the correlation between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and TA is controversial. Therefore, our study aimed to investigate the association between the TG/HDL-C ratio and TA in PMN patients. We conducted a cross-sectional study and collected data from 363 PMN patients at Shenzhen Second People's Hospital from January 2008 to April 2023. The primary objective was to evaluate the independent correlation between the TG/HDL-C ratio and TA using binary logistic regression model. We used a generalized additive model along with smooth curve fitting and multiple sensitivity analyses to explore the relationship between these variables. Additionally, subgroup analyses were conducted to delve deeper into the results. Of the 363 PMN patients, 75 had TA (20.66%). The study population had a mean age of 46.598 ± 14.462 years, with 217 (59.78%) being male. After adjusting for sex, age, BMI, hypertension, history of diabetes, smoking, alcohol consumption, UPRO, eGFR, HB, FPG, and ALB, we found that the TG/HDL-C ratio was an independent risk factor for TA in PMN patients (OR=1.29, 95% CI: 1.04, 1.61, P=0.0213). A non-linear correlation was observed between the TG/HDL-C ratio and TA, with an inflection point at 4.25. The odds ratios (OR) on the left and right sides of this inflection point were 1.56 (95% CI: 1.17, 2.07) and 0.25 (95% CI: 0.04, 1.54), respectively. Sensitivity analysis confirmed these results. Subgroup analysis showed a consistent association between the TG/HDL-C ratio and TA, implying that factors such as gender, BMI, age, UPRO, ALB, hypertension and severe nephrotic syndrome had negligible effects on the link between the TG/HDL-C ratio and TA. Our study demonstrates a non-linear positive correlation between the TG/HDL-C ratio and the risk of TA in PMN patients, independent of other factors. Specifically, the association is more pronounced when the ratio falls below 4.25. Based on our findings, it would be advisable to decrease the TG/HDL-C ratio below the inflection point in PMN patients as part of treatment strategies.

MiR-664a-5p promotes experimental membranous nephropathy progression through HIPK2/Calpain1/GSα-mediated autophagy inhibition.

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

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

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. 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. 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. 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.

A comparative urinary proteomic and metabolomic analysis between renal aa amyloidosis and membranous nephropathy with clinicopathologic correlations

Urinary omics has become a powerful tool for elucidating pathophysiology of glomerular diseases. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urine proteomic and metabolomic analysis between recently diagnosed renal AA amyloidosis (AA) and membranous nephropathy (MN) patients. Urine samples of 22 (8 AA, 8 MN and 6 healthy control) patients were analyzed with nLC-MS/MS and GC/MS for proteomic and metabolomic studies, respectively. Pathological specimens were scored for glomerulosclerosis and tubulointerstitial fibrosis grades. Functional enrichment analysis between AA and control groups showed enrichment in cell adhesion related sub-domains. Uromodulin (UMOD) was lower, whereas ribonuclease 1 (RNase1) and α-1-microglobulin/bikunin precursor (AMBP) were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = −0.48, p = 0.03) and AMBP-eGFR (r = −0.69, p = 0.003) variables. Metabolomic analysis showed myo-inositol and urate were higher in AA compared to MN group. A positive correlation was detected between RNase1 and urate independent of eGFR values (r = 0.63, p = 0.01). Enrichment in cell adhesion related domains suggested a possible increased urinary shear stress due to amyloid fibrils. UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be related with systemic inflammation in AA amyloidosis. SignificanceUrinary omics studies have become a standard tool for biomarker studies. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urinary omics analysis between recently diagnosed renal AA amyloidosis (AA), membranous nephropathy (MN) patients and healthy controls. Pathological specimens were scored with glomerulosclerosis (G) and tubulointerstitial fibrosis (IF) grades to consolidate the results of the omics studies and correlation analyzes. Functional enrichment analysis showed enrichment in cell adhesion related sub-domains due to downregulation of cadherins; which could be related with increased urinary shear stress due to amyloid deposition and disruption of tissue micro-architecture. In comparative proteomic analyzes UMOD was lower, whereas RNase1 and AMBP were higher in AA compared to MN group. Whereas in metabolomic analyzes; myo-inositol, urate and maltose were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = −0.48, p = 0.03), AMBP-eGFR (r = −0.69, p = 0.003) and between RNase1-Urate independent of eGFR values (r = 0.63, p = 0.01). This study is the first comprehensive urinary omics analysis focusing on renal AA Amyloidosis to the best of our knowledge. Based on physiologic roles and clinicopathologic correlations of the molecules; UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be increased with systemic inflammation and endothelial damage in AA amyloidosis.

Efficacy and safety of rituximab in elderly patients with membranous nephropathy.

Objectives: Advancing age is a risk factor for treatment-related side effects and mortality in membranous nephropathy (MN) patients treated with traditional immunosuppressive regimens. This study aimed to determine the efficacy and safety of rituximab (RTX) in the treatment of elderly patients with MN. Methods: We performed a single center retrospective review of 37 consecutive MN patients aged 70 and older at the time of RTX infusion. We also enrolled 76 young patients (<70years old) with MN as the control group. We assessed clinical and laboratory indices, remission rates, and adverse events at RTX infusion, 3months, and last visit. Results: A total of 37 elderly patients with MN were included, with a median follow-up period of 15.50 (10.00, 24.40) months. Of the 37 patients, 75.68% were male, and mean age was 71.89 ± 2.47years. At last visit, 7 (18.92%) patients achieved complete remission, and 26 (70.27%) patients achieved complete or partial remission. There were no differences in the complete remission rate and complete or partial remission rate at last visit compared to young patients (26.32% vs. 18.92%, p = 0.387; 85.53% vs. 70.27%, p = 0.055). After RTX treatment, three of 6 elderly patients with pneumonia died due to ineffective treatment of the infection in RTX therapy courses. The results of multivariant regression analysis showed that elderly patients have an increased risk of serious infection, compared with patients younger than 70years (OR = 32.874, 95% CI 1.300-831.490, p = 0.034). For each increase of 1g/L in serum albumin, the risk of serious infection would decrease by 43.2% (OR = 0.568, 95% CI 0.334-0.969, p = 0.038). Conclusion: This study demonstrates that RTX is effective in the treatment of elderly patients with MN. However, we also observed a high incidence of infectious complications. Our experience was limited by its retrospective design and relatively small sample size, and further randomized controlled studies with large sample size are needed to confirm our preliminary findings.

Target Antigens of Membranous Nephropathy With Syphilis Infection

IntroductionMembranous nephropathy is the most common cause of proteinuria in syphilis, and neuron-derived neurotrophic factor (NDNF) is recently demonstrated to be the target antigen in syphilis-associated membranous nephropathy. However, the prevalence and clinicopathological characteristics of both NDNF-positive and NDNF-negative membranous nephropathy in Chinese individuals with syphilis infection still remain unknown. MethodsA retrospective study was conducted in 17 membranous nephropathy patients with history of syphilis infection. The intensity and distribution of NDNF staining, as well as phospholipase A2 receptor (PLA2R) and neural epidermal growth factor-like 1 protein (NELL-1) staining in renal biopsies were assessed. ResultsAmong the 11 membranous nephropathy patients with active syphilis infection, positive NDNF staining was shown in 5 patients (46%). The remaining six patients demonstrated negative NDNF staining. Of which, 5 patients were PLA2R positive and the other one was PLA2R and NELL-1 negative. Antibiotics were also effective in three NDNF-negative patients, suggesting the possibility of syphilis-associated membranous nephropathy. Thus, the histological positivity rate of NDNF was 63% (5/8 patients) in syphilis-associated membranous nephropathy. In addition, positive NDNF antibody was first confirmed in the serum of one NDNF associated membranous nephropathy patient. NDNF staining was negative in all 6 membranous nephropathy patients with previous syphilis infection. ConclusionsNearly half of the patients with active syphilis infection and membranous nephropathy were NDNF-positive in our study. Positive NDNF staining favors syphilis-associated membranous nephropathy. Circulating anti-NDNF antibody can be detected in the patient’s serum sample. In addition, PLA2R or other unknown antigenic protein may also be the target antigens for syphilis-associated membranous nephropathy in Chinese population.

Clinical Manifestation and Prognosis of Membranous Nephropathy in Patients with Primary Sjögren Syndrome

Clinical Manifestation and Prognosis of Membranous Nephropathy in Patients with Primary Sjögren Syndrome

Serum PLA2R antibody as a predictive biomarker for venous thromboembolism risk in primary membranous nephropathy

BackgroundPatients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE. MethodsIn this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels. ResultsTwenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan–Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01). ConclusionsThe PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l.

Characteristics of Membranous Nephropathy Patients Presenting with an Arterial or Venous Thromboembolism: A Retrospective Cohort Study

Characteristics of Membranous Nephropathy Patients Presenting with an Arterial or Venous Thromboembolism: A Retrospective Cohort Study

Distribution spectrum and clinical significance of glomerular exostosin (EXT1) deposits in PLA2R-positive membranous nephropathy.

The discovery of antigen phospholipase A2 receptor (PLA2R) in 2009 ushered in the antigen-based study of membranous nephropathy. Thefurther putative antigen exostosin 1/2 (EXT1/2) was described in 2019. However, the distribution spectrum of glomerular EXT1 deposits in membranous nephropathy has not been fullyelucidated. We conducted a retrospective cohort study of biopsy-proven membranous nephropathy patients. Patients with complete baseline data and adequate tissue specimens were included in this study. Tests for glomerular expression of PLA2R and EXT1 and circulating anti-PLA2R antibodies were performed. Clinicopathological and outcome data were reviewed. We included 626 patients, namely, 487 (77.8%) PLA2R-positive patients and 54 (8.6%) EXT1-positive patients; 32 (5.1%) patients were dual-positive for PLA2R and EXT1 (PLA2R + /EXT1 +). A higher percentage of dual-positive patients had low C3 levels (P < 0.001) and were more likely to have autoimmune diseases (P = 0.013) than PLA2R-positive and EXT1-negative (PLA2R + /EXT1-) patients. Kidney biopsy findings revealed that there was a higher percentage of glomerular IgG1, IgG2, IgA, C4, and C1q deposits (P < 0.05), "full-house" staining (P < 0.001), and stronger intensity of C1q staining (P = 0.002) in PLA2R + /EXT1 + patients. Based on Kaplan-Meier analysis, a higher percentage of PLA2R + /EXT1 + patients exhibited partial or complete remission of proteinuria. Furthermore, EXT1-positive expression was a favourable predictor for proteinuria remission, whereas interstitial fibrosis/tubular atrophy was an unfavourable predictor. A complement C3 level < 0.79g/L was independently associated with EXT1 positivity in PLA2R-positive membranous nephropathy. We describe a subgroup of PLA2R and EXT1 dual-positive patients. Patients in this subset exhibited more signs of autoimmunity and morefrequent clinical remission. In PLA2R-positive membranous nephropathy, a complement C3 level < 0.79g/L was independently associated with EXT1 positivity, which was a favourable predictor for proteinuria remission.

Oxidative stress and inflammation are mediated via aryl hydrocarbon receptor signalling in idiopathic membranous nephropathy.

Membranous nephropathy (MN) patients are diagnosed by the presence of phospholipase A2 receptor (PLA2R) before they progress to renal failure. However, the subepithelium-like immunocomplex deposit-mediated downstream molecular pathways are poorly understood. The aryl hydrocarbon receptor (AHR), NF-ƙB and Nrf2 pathways play central roles in the pathogenesis and progression of chronic kidney disease. However, their mutual effects on MN require further examination. Thus, we investigated the effect of AHR signalling on the NF-ƙB and Nrf2 pathways in IMN patients, cationic bovine serum albumin (CBSA)-injected rats and zymosan activation serum (ZAS)-treated podocytes. IMN patients show significantly decreased serum total protein and albumin levels, increased urine protein levels and intrarenal IgG4 and PLA2R protein expression in glomeruli compared with controls. IMN patients exhibited increased mRNA expression of intrarenal AHR and its target genes, including CYP1A1, CYP1A2, CYP1B1 and COX-2. This increase was accompanied by significantly upregulated protein expression of CD3, NF-ƙB p65 and COX-2 and significantly downregulated Nrf2 and HO-1 expression. Similarly, CBSA-induced rats showed severe proteinuria and activated intrarenal AHR signalling. This was accompanied by significantly upregulated protein expression of intrarenal p-IκBα, NF-κB p65 and its gene products, including COX-2, MCP-1, iNOS, 12-LOX, p47phox and p67phox, and significantly downregulated protein expression of Nrf2 and its gene products, including HO-1, catalase, GCLC, GCLM, MnSOD and NQO1. These results were further verified in ZAS-induced podocytes. Treatment with the AHR antagonist CH223191 and AHRsiRNA significantly preserved podocyte-specific protein expression and improved the NF-ƙB and Nrf2 pathways in ZAS-induced podocytes. In contrast, similar results were obtained in ZAS-induced podocytes treated with the NF-ƙB inhibitor BAY 11-7082 and NF-κBp65 siRNA. However, neither method had a significant effect on AHR signalling. Collectively, these results indicate that the NF-ƙB pathway is a downstream target of AHR signalling. Our findings suggest that blocking AHR signalling inhibits oxidative stress and inflammation, thereby improving proteinuria and renal injury.

Cyclophosphamide induced early remission and was superior to rituximab in idiopathic membranous nephropathy patients with high anti-PLA2R antibody levels

Rituximab (RTX) and cyclophosphamide (CYC) based treatments are both recommended as first-line therapies in idiopathic membranous nephropathy (IMN) by KDIGO 2021 guideline. However, the efficacy of RTX vs. CYC-based treatments in IMN is still controversial. We performed this systemic review and meta-analysis registered in PROSPERO (CRD 42,022,355,717) by pooling data from randomized controlled trials or cohort studies in IMN patients using the EMBASE, PubMed, and Cochrane libraries (till Orc 1, 2022). The primary outcomes were the complete remission (CR) rate + partial remission (PR) rate. CR rate, immunologic response rate, relapse rate, and the risk of serious adverse events (SAE) were secondary outcomes. Eight studies involving 600 adult patients with IMN were included with a median follow-up duration of 12 to 60 months. RTX induced a similar overall remission rate compared with CYC (RR 0.88, 95% CI: 0.71, 1.09, P = 0.23). At the follow-up time of 6 months, RTX was associated with a lower CR + PR rate compared with CYC (RR 0.67, 95% CI: 0.52, 0.88, P = 0.003). Moreover, RTX might be less effective in inducing CR + PR than CYC treatment in IMN patients with high antiPLA2R antibody levels (RR 0.67, 95% CI: 0.48, 0.94, P = 0.02). The occurrences of CRs, relapse rates, immunologic response rates, and SAE were not significantly different between RTX and CYC, respectively. In conclusion, although the long-term efficacy and safety of CYC compared to RTX were comparable, CYC might respond faster and be more advantageous in IMN patients with high antiPLA2R antibody titers.

Correlation Analysis between Intrarenal Small Artery Intimal Thickening and Clinicopathological Features and Prognosis in Primary Membranous Nephropathy Patients

Background: Primary membranous nephropathy (PMN) is the most common pathological type of nephrotic syndrome in adults. Intrarenal small artery intimal thickening can be observed in most renal biopsies. The purpose of this study was to investigate the association between intrarenal small artery intimal thickening and clinicopathological features and prognosis in PMN patients. Methods: Data were continuously collected from patients who were diagnosed with PMN in Shenzhen Second People’s Hospital (The First Affiliated Hospital of Shenzhen University) from 2008 to 2021 for a retrospective cohort study. Regression analysis and survival analysis were used to analyze the relationship between intrarenal small artery intimal thickening and renal prognosis in PMN patients. Results: 300 PMN patients were enrolled in this study, including 165 patients (55%) with intrarenal small artery intimal thickening. Patients with intimal thickening were older, with higher BMI, systolic blood pressure and diastolic blood pressure, serum uric acid, a higher proportion of hypertension, acute kidney injury, nephrotic syndrome, more urine protein, and lower eGFR. Multivariate Cox regression analysis showed that after adjusting for age, gender, hypertension, BMI, urine protein, eGFR, and the use of ACEI/ARB and hormone immunosuppressants, intimal thickening was a risk factor for renal prognosis in PMN patients (HR = 3.68, 95% CI 1.36–9.96, p < 0.05). Kaplan-Meier survival curve analysis showed that the incidence of reaching the renal composite outcome was higher in the intimal thickening group (p < 0.05). Conclusion: The prognosis of PMN patients with intrarenal small artery intimal thickening is worse, so early intervention is very important for these patients.

Comparison of performance and clinical utility of different methods for detecting anti-PLA2R antibody

ObjectivesThis study aimed to compare the performance of enzyme-linked immunosorbent assay (ELISA) and magnetic particle chemiluminescence immunoassay (MP-CLIA) for detecting anti-phospholipase A2 receptor (PLA2R) antibody and their clinical significance in idiopathic membranous nephropathy (IMN) patients. MethodsSerum samples from 448 patients with different types of nephropathy, including 222 with IMN, were tested using both methods. Sensitivity, specificity, and prognostic significance of PLA2R antibody levels were evaluated. ResultsSimilar sensitivity and specificity of ELISA and MP-CLIA in identifying IMN patients was found. However, MP-CLIA performed better than ELISA in predicting the prognosis of IMN patients. Adjusting the cutoff value reduced the false-negative rate in both methods. Logistic regression analysis identified six variables, including MP-CLIA-PLA2R levels, eGFR, lymphocyte count, B lymphocyte count, NK cell count, and complement 4, as predictors of renal function outcomes in IMN patients. ConclusionsBoth ELISA and MP-CLIA are reliable methods for detecting anti-PLA2R antibodies in IMN patients. However, MP-CLIA is more accurate in predicting the prognosis of IMN. Combining MP-CLIA-PLA2R with other variables can help predict renal function outcomes in IMN patients. Our study emphasizes the importance of considering both analytical performance and clinical utility when selecting a PLA2R antibody assay kit.

Serum PLA2R antibody as a predictive biomarker for venous thromboembolism risk in primary membranous nephropathy

BackgroundPatients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE. MethodsIn this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels. ResultsTwenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan–Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01). ConclusionsThe PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l.

#5219 PEROXIREDOXINS ARE RELATED TO EGFR DECLINE IN IGA NEPHROPATHY, MEMBRANOUS NEPHROPATHY AND LUPUS NEPHRITIS: A 5-YEAR FOLLOW-UP

Abstract Background and Aims Oxidative stress (OS) is known as a disturbance between pro- and antioxidant factors, that may lead to DNA or protein oxidation, resulting in cellular damage. Peroxiredoxins (PRDXs) are enzymes with an antioxidant properties. They play dominant role in regulation of cellular peroxide levels, which is crucial in maintaining organisms’ oxidative balance. PRDXs types 1-5 are involved in the pathophysiology of various diseases (e.g. cancer, inflammatory, or renal). We aim to study their role as a prognostic marker of eGFR changes in IgA nephropathy (IgAN), lupus nephritis (LN) and membranous nephropathy (MN) patients. Method This is a retrospective 5-year-follow-up study of 108 IgAN, MN and LN patients, in whom PRDX 1-5 serum levels were assessed with ELISA in 2017. In 2022, we were able to collect the data out of 80 patients: IgAN (n=36); MN (n=22) and LN (n=22). The remaining 28 were considered as lost-to-follow-up, namely: lack of any medical results within last 2 years (n=23); on dialysis (n=2); after renal transplantation (n=2); deceased (n=1). We classified patients depending on the changes of eGFR (decline/stable/increase; Fig. 1) between baseline and after 5 year follow-up and the PRDX levels (high/medium/low; Table 1). The Mann Whitney-U, Kruskal-Wallis and Chi-Square Test were used for statistical analysis, the p-values &amp;lt;0.05 were considered significant. Results Baseline PRDX measurements indicated, that the mean concentrations of serum PRDX 1-5 differ between the glomerulonephropathies (GN). In 2022, we observed significantly different (P = .012) change of eGFR depending on the GN type. 16/80 individuals had eGFR decline and 75% of them were diagnosed with IgAN. The MN and LN groups had increase of eGFR in the last 5 years in most cases, probably as a result of the treatment. We verified if follow-up eGFR was associated with baseline PRDX levels. The 2022 eGFR differed significantly between the GNs depending on the level of serum PRDX 2, 4 and 5 at baseline (P = .002; P = .009; P = .006, respectively, Table 1). Conclusion Our results showed the link between serum PRDXs concentration and IgAN, MN and LN follow-up. Importantly, selected PRDXs’ might be used to predict eGFR decline, particularly in IgAN and LN.