scholarly journals Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Andreas Kronbichler ◽  
Jun Oh ◽  
Björn Meijers ◽  
Gert Mayer ◽  
Jae Il Shin
Keyword(s):  
Membranous Nephropathy ◽  
Treatment Resistance ◽  
Spontaneous Remission ◽  
Neutral Endopeptidase ◽  
Rapid Decline ◽  
Special Focus ◽  
Risk Alleles ◽  
Phospholipase A2 Receptor

Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50–100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens.

scholarly journals Membranous nephropathy associated with viral infection

2020 ◽  
Author(s):  
Aikaterini Nikolopoulou ◽  
Catarina Teixeira ◽  
H Terry Cook ◽  
Candice Roufosse ◽  
Thomas H D Cairns ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Viral Infection ◽  
Membranous Nephropathy ◽  
Spontaneous Remission ◽  
Outcome Data ◽  
Phospholipase A2 Receptor ◽  
B Virus ◽  
Immunodeficiency Virus ◽  
Hepatitis Infection

Abstract Background Membranous nephropathy (MN) can be associated with hepatitis infection and less commonly with human immunodeficiency virus (HIV) infection. The significance of anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin type 1 domain-containing 7A (THSD7A) antibodies in this setting is unclear. Methods We describe the clinical, histopathological and outcome data of 19 patients with MN and hepatitis B virus (HBV), hepatitis C virus (HCV) or HIV infection identified through our renal biopsy database and the association with anti-PLA2R antibodies and anti-THSD7A antibodies. Results The cohort consisted of 19 patients, 8 male and 11 female, with a median age of 42 years (range 23–74). HBV infection was found in six cases, HCV in four and HIV in nine (two HIV patients had HBV co-infection and one HCV co-infection). PLA2R staining on biopsy was positive in 10/19 patients: 4 with HBV-MN, 3 with HCV-MN and 3 with HIV-MN and circulating anti-PLA2R antibodies were detected in 7/10 cases. THSD7A staining on biopsy was positive in three PLA2R-negative cases, one with HBV-MN and two with HIV-MN. Mean proteinuria was higher in the PLA2R-positive group and the median urinary protein:creatinine ratio (uPCR) was 963 mg/mmol (range 22–2406) compared with the PLA2R-negative group [median uPCR 548 mg/mmol (range 65–1898); P = 0.18 Mann–Whitney]. Spontaneous remission occurred in 6/19 patients and after-treatment remission occurred in 7/11 patients. Renal function was preserved in all but two patients who required haemodialysis 2 and 11 years from diagnosis. Conclusions We describe a cohort of patients with MN associated with viral infection, including rare cases of HIV-MN with PLA2R and THSD7A positivity. The mechanism of coincidental or viral-related MN needs to be investigated further.

scholarly journals Anti-PLA2R Antibodies as a Prognostic Factor in PLA2R-Related Membranous Nephropathy

2015 ◽  
Vol 42 (1) ◽  
pp. 70-77 ◽  
Author(s):  
Sjoerd A.M.E.G. Timmermans ◽  
Myrurgia A. Abdul Hamid ◽  
Jan Willem Cohen Tervaert ◽  
Jan G.M.C. Damoiseaux ◽  
Pieter van Paassen ◽  
...  
Keyword(s):  
Membranous Nephropathy ◽  
Immunosuppressive Agents ◽  
Immunosuppressive Treatment ◽  
Survival Rates ◽  
Spontaneous Remission ◽  
Correct Selection ◽  
Persistent Proteinuria ◽  
Phospholipase A2 Receptor ◽  
Elisa Testing

Background: The natural course of idiopathic membranous nephropathy (MN) varies, as it is known through favorable outcomes in most patients. However, one third of patients with idiopathic MN will slowly progress to end-stage renal disease (ESRD). To prevent disease progression, patients at high risk to develop ESRD are treated with immunosuppressive agents. Therefore, a correct selection of patients who need immunosuppressive treatment is important. Methods: Here, we evaluated the prognostic value of anti-phospholipase A2 receptor 1 antibody (anti-PLA2R) levels regarding clinical outcome in a well-defined cohort of 73 PLA2R-related MN patients with long-term follow-up. At baseline, patients were subdivided into patients with either low or high antibody levels based on ELISA testing. Results: Spontaneous remission rates were highest among patients with low anti-PLA2R levels (79%; hazard ratio 2.72 (95% CI 1.22-6.08), p = 0.02) after a median follow-up of 2.9 (95% CI 0.8-5.0, p < 0.001) years, whereas high anti-PLA2R levels were associated with persistent proteinuria (p = 0.04) and/or the need for immunosuppressive therapy (p < 0.001). Renal survival rates were 97% at 5 years, 93% at 10 years, and 89% at 15 years; however, this was not different between the anti-PLA2R groups. ESRD occurred significantly faster in patients with severe proteinuria as compared to patients with either mild (p = 0.02) or moderate proteinuria (p = 0.05). Conclusions: Low anti-PLA2R levels may predict spontaneous remissions in patients with PLA2R-related MN. Therefore, we suggest that quantification of anti-PLA2R is of value to monitor these patients.

Neural Epidermal Growth Factor–Like 1 Protein–Positive Membranous Nephropathy in Chinese Patients

2021 ◽  
pp. CJN.11860720
Author(s):  
Guoqin Wang ◽  
Lijun Sun ◽  
Hongrui Dong ◽  
Yanyan Wang ◽  
Xiaoyi Xu ◽  
...  
Keyword(s):  
Membranous Nephropathy ◽  
Clinical Characteristics ◽  
Chinese Patients ◽  
Double Positive ◽  
Immunohistochemistry Staining ◽  
Phospholipase A2 Receptor ◽  
Pathologic Features ◽  
Glomerular Deposits ◽  
Epidermal Growth

Background and objectivesThe neural EGF-like 1 (NELL-1) protein is a novel antigen in primary membranous nephropathy. The prevalence and clinical characteristics of NELL-1–positive membranous nephropathy in Chinese individuals with primary membranous nephropathy are unclear.Design, setting, participants, & measurementsA total of 832 consecutive patients with biopsy-proven primary membranous nephropathy were enrolled. The glomerular expression of phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A) was screened. Glomerular immunohistochemistry staining for NELL-1 was performed in 43 patients with PLA2R- and THSD7A-negative membranous nephropathy, 31 patients with PLA2R-positive membranous nephropathy, and two patients with PLA2R and THSD7A double positivity. The NELL-1 antibody was also detected in the sera of patients with NELL-1–positive membranous nephropathy by western blot. Clinical and pathologic features were comparable between patients with isolated NELL-1–positive, isolated PLA2R/THSD7A-positive, and triple antigen–negative membranous nephropathy.ResultsAmong the 832 patients with primary membranous nephropathy, 11 of 54 (20%) patients with PLA2R-negative membranous nephropathy had THSD7A-positive membranous nephropathy. NELL-1–positive membranous nephropathy accounted for 35% (15 of 43) of all patients with PLA2R- and THSD7A-negative membranous nephropathy. One patient was double positive for NELL-1 and PLA2R in glomerular deposits and positive for only the PLA2R antibody in the serum. Most patients with NELL-1–positive membranous nephropathy were women. No tumors were found. There were significant differences in the prevalence of IgG subtypes between patients with different antigen positivity. Among patients with isolated NELL-1–positive membranous nephropathy, although 80% (12 of 15) were IgG4 staining positive, the proportion of IgG4 dominance was only 67% (ten of 15).ConclusionsAbout one third of patients who were PLA2R and THSD7A negative were NELL-1 positive in Chinese patients with primary membranous nephropathy. NELL-1–positive membranous nephropathy was more common than THSD7A-positive membranous nephropathy in PLA2R-negative membranous nephropathy.

Routine immunohistochemical staining in membranous nephropathy: in situ detection of phospholipase A2 receptor and thrombospondin type 1 containing 7A domain

2018 ◽  
Vol 31 (4) ◽  
pp. 543-550 ◽  
Author(s):  
Vincenzo L’Imperio ◽  
Federico Pieruzzi ◽  
Renato Alberto Sinico ◽  
Manuela Nebuloni ◽  
Antonio Granata ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Membranous Nephropathy ◽  
Immunohistochemical Staining ◽  
Phospholipase A2 Receptor ◽  
In Situ Detection

scholarly journals Membranous nephropathy in patients with HIV: a report of 11 cases

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Vivek Charu ◽  
Nicole Andeen ◽  
Vighnesh Walavalkar ◽  
Jessica Lapasia ◽  
Jin-Yon Kim ◽  
...  
Keyword(s):  
Membranous Nephropathy ◽  
Viral Loads ◽  
Phospholipase A2 Receptor ◽  
Immunodeficiency Virus ◽  
Antibody Titers ◽  
Stage Renal Disease ◽  
End Stage ◽  
Nephrotic Range Proteinuria ◽  
Tissue Reactivity

Abstract Background Membranous nephropathy (MN) has been recognized to occur in patients with human immunodeficiency virus (HIV) infection since the beginning of the HIV epidemic. The prevalence of phospholipase A2 receptor (PLA2R)-associated MN in this group has not been well studied. Methods We conducted a retrospective review of electronic pathology databases at three institutions to identify patients with MN and known HIV at the time of renal biopsy. Patients with comorbidities and coinfections known to be independently associated with MN were excluded. Results We identified 11 HIV-positive patients with biopsy-confirmed MN meeting inclusion and exclusion criteria. Patient ages ranged from 39 to 66 years old, and 10 of 11 patients (91%) were male. The majority of patients presented with nephrotic-range proteinuria, were on anti-retroviral therapy at the time of biopsy and had low or undetectable HIV viral loads. Biopsies from 5 of 10 (50%) patients demonstrated capillary wall staining for PLA2R. Measurement of serum anti-PLA2R antibodies was performed in three patients, one of whom had positive anti-PLA2R antibody titers. Follow-up data was available on 10 of 11 patients (median length of follow-up: 44 months; range: 4–145 months). All patients were maintained on anti-retroviral therapy (ARV) and 5 patients (52%) received concomitant immunosuppressive regimens. Three patients developed end-stage renal disease (ESRD) during the follow-up period. Conclusions MN in the setting of HIV is often identified in the setting of an undetectable viral loads, and similar to other chronic viral infection-associated MNs, ~ 50% of cases demonstrate tissue reactivity with PLA2R antigen, which may be seen without corresponding anti-PLA2R serum antibodies.

Membranous Nephropathy in Pregnancy

2020 ◽  
Vol 51 (4) ◽  
pp. 304-317 ◽  
Author(s):  
Zi-ning Liu ◽  
Zhao Cui ◽  
Ying-dong He ◽  
Yi-miao Zhang ◽  
Fang Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Serum Albumin ◽  
Membranous Nephropathy ◽  
Fetal Loss ◽  
Urinary Protein ◽  
Fetal Outcomes ◽  
Child Bearing ◽  
Phospholipase A2 Receptor ◽  
Birth Weight Percentile

Background: Primary membranous nephropathy (pMN) is less common in women of child-bearing age. The kidney risk factors to adverse maternal-fetal outcomes and the effects of pregnancy on pMN process need to be investigated. Methods: We retrospectively screened all the patients with biopsy-proven pMN from 2008 to 2018. Any cases of pregnancy that occurred at the time of pMN diagnosis or during follow-up were included in the study. Clinical and pathological data were collected from all patients at the time of kidney biopsy and their gestational results were recorded. Results: Of the 27 pregnancies with gestational time of 35.9 ± 4.5 weeks, 10 adverse maternal-fetal events occurred, including fetal loss (11%), preterm delivery (26%), and severe preeclampsia (15%). The kidney parameters were relatively stable with all preserved kidney function. Time-averaged urinary protein (p < 0.001) and serum albumin (p < 0.001), maximum urinary protein (p = 0.001) and minimum serum albumin (p = 0.01) before week 20, anti-phospholipase A2 receptor (PLA2R) positivity (p = 0.03), and no remission during pregnancy (p = 0.004) were risk factors to adverse maternal-fetal outcomes. Time-averaged urinary protein and serum albumin correlated with the birth weight percentile of neonates. Conclusions: Pregnancy in pMN patients showed risks to adverse maternal-fetal events. Heavy proteinuria, especially before week 20 of gestation, severe hypoalbuminemia, positive anti-PLA2R, and no remission were risk factors to worse outcomes.

P0417THE ABSENCE OF C3 DEPOSIT IN MEMBRANOUS NEPHROPATHY IS ASSOCIATED WITH SPONTANEOUS REMISSION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Cristina Rabasco ◽  
Ana Martínez ◽  
Rosa Ortega ◽  
Mario Espinosa
Keyword(s):  
Membranous Nephropathy ◽  
Interstitial Fibrosis ◽  
Immunosuppressive Treatment ◽  
Spontaneous Remission ◽  
Glomerular Sclerosis ◽  
Tubular Atrophy ◽  
Positive Group ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of biopsied nephrotic syndrome in adults. Recently, it has been reported that the pathogenesis of MN may be associated with an activation of the complement system. The pathway of activation is not clearly established. The intensity of C3 deposition could be a good marker of this activation in MN as has been shown in other diseases (IgA nephropathy, crescentic GN). The aim of this study is to evaluate clinical-pathological data in a cohort of patients with MN and the significance of glomerular C3 staining as a possible predictor of renal outcomes. Method We analysed patients with idiopathic MN biopsied in our department between January 2000 and December 2019, excluding those who had no material for IF (n = 115). The patients were divided into positive (87 cases) and negative (28 cases) based on glomerular C3 deposition. We assessed the clinical and histological characteristics and the percentage of spontaneous remission (SR) and end-stage renal disease (ESRD). Results A total of 115 patients with MN were followed with a median follow-up of 65 (25-161) months. We found no differences in baseline characteristics between both groups, with the exception that patients with C3 deposit had less albumin at the time of biopsy that negative patients [2.4 (2-2.9) vs 2.8 (2.3-3.1) g/dl, P=0.011)]. Patients with C3-negative had a higher percentage of SR than patients with C3-positive (75 vs 24%, P = 0.000) and less need for immunosuppressive treatment (18 vs 56%, P =0.001). At the most recent follow-up, C3-positive group had higher creatinine [1.42 (0.8-1.7) vs 0.97 (0.71-1) mg/dl, P=0.045] and proteinuria [1.64 (0.08-3.2) vs. 0.62 (0.05-0.79) g / 24h, P = 0.039]. Regarding histology, we found no differences in glomerular sclerosis, tubular atrophy and interstitial fibrosis. The renal survival analysis showed no statistically significant differences between both groups (P = 0.091). We analysed a subgroup of patients (n = 23) with antibodies against the phospholipase receptor on blood at the time of the biopsy (13/23 were positive). 84% of this positive group presented C3-positive in the renal biopsy vs 25% of the C3-negative group (P =0.008). Conclusion Patients without C3 staining show a higher rate of SR and less need for immunosuppressive treatment than patients with C3-positive. These results would support the theory that complement activation in this entity can play an important role. It is possible that these patients with negative C3 deposit represent a MN with evolution to SR and in these patients and that these patients do not need immunosuppressive treatment.

scholarly journals Exostosin 1/Exostosin 2–Associated Membranous Nephropathy

2019 ◽  
Vol 30 (6) ◽  
pp. 1123-1136 ◽  
Author(s):  
Sanjeev Sethi ◽  
Benjamin J. Madden ◽  
Hanna Debiec ◽  
M. Cristine Charlesworth ◽  
LouAnn Gross ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Autoimmune Disease ◽  
Lupus Nephritis ◽  
Membranous Nephropathy ◽  
Validation Cohort ◽  
Laser Microdissection ◽  
Immunohistochemistry Staining ◽  
Phospholipase A2 Receptor ◽  
And Control

BackgroundIn membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain–containing 7A are target antigens in approximately 70% and 1%–5% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown.MethodsWe studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry.ResultsMass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2R-negative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 patients); only one of the 14 cases of mixed class 5 and 3/4 lupus nephritis was positive for EXT1/EXT2. Tests in seven patients with EXT1/EXT2-associated MN found no circulating anti-exostosin antibodies.ConclusionsA subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.

scholarly journals Remissions in Patients with Idiopathic Membranous Nephropathy Treated with Rituximab in Senegal

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Moustapha Faye ◽  
Fabrice Arnold Tcheumagam Tiako ◽  
Ahmed Tall Lemrabott ◽  
Bacary Ba ◽  
Niakhaleen Keita ◽  
...  
Keyword(s):  
Side Effects ◽  
Membranous Nephropathy ◽  
Partial Remission ◽  
Analytical Study ◽  
Spontaneous Remission ◽  
Idiopathic Membranous Nephropathy ◽  
The Mean ◽  
Change In Mean

Objectives: This study aimed to evaluate the efficacy of Rituximab in the management of idiopathic membranous nephropathy (IMN) based on the following criteria: (I) Biological remission at three months (M3) and six months (M6); (II) change in mean proteinuria (24PU), mean serum albumin, and mean serum creatinine at M3 and M6; (III) and side effects. Methods: This retrospective descriptive and analytical study included patients with histologically confirmed IMN with positive plasma anti-PLA2R antibodies who received at least one dose of Rituximab after six months of follow-up without spontaneous remission. Patients with unexplainable records were not included. Results: A total of five patients (P1, P2, P3, P4, and P5), including four males and one female were analyzed. The mean age was 44.20 ± 23.14 years. All patients had IMN type 2. At inclusion, the mean albuminemia, mean creatinine, and mean 24hPU levels were 15.56 ± 5.27 g/L, 6.54 ± 1.13 g/24h, and 17.3 ± 7.60 mg/L, respectively. The median anti-PLA2R antibody titer was 100 IU with extremes of 10 and 800 IU. Partial remission was noted in three patients at M3 (P2, P4, and P5), and it was maintained until M6 in P2. No complete remission was observed. A significant decrease in mean 24hPU at M3 was noted (P < 0.001). Generalized pruritus associated with seizures was noticed in P4 after the first dose of Rituximab. Conclusions: Partial remission was noted in three patients at M3, and one patient maintained this remission at M6. Rituximab significantly reduced 24hPU at M3 after administration. Rituximab administration was well tolerated by the patients.

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