Summary Membranous nephropathy is a major cause of nephrotic syndrome of non-diabetic origin in adults. It is the second or third leading cause of end-stage renal disease in patients with primary ...glomerulonephritis, and is the leading glomerulopathy that recurs after kidney transplantation (occurring in about 40% of patients). Treatment with costly and potentially toxic drugs remains controversial and challenging, partly because of insufficient insight into the pathogenesis of the disease and absence of sensitive biomarkers of disease activity. The disease is caused by the formation of immune deposits on the outer aspect of the glomerular basement membrane, which contain podocyte or planted antigens and circulating antibodies specific to those antigens, resulting in complement activation. In 2002, podocyte neutral endopeptidase was identified as an antigenic target of circulating antibodies in alloimmune neonatal nephropathy, and in 2009, podocyte phospholipase A2 receptor (PLA2 R) was reported as an antigenic target in autoimmune adult membranous nephropathy. These major breakthroughs were translated to clinical practice very quickly. Measurement of anti-PLA2 R antibodies in serum and detection of PLA2 R antigen in glomerular deposits can now be done routinely. Anti-PLA2 R antibodies have high specificity (close to 100%), sensitivity (70–80%), and predictive value. PLA2 R detection in immune deposits allows for retrospective diagnosis of PLA2 R-related membranous nephropathy in archival kidney biopsies. These tests already have a major effect on diagnosis and monitoring of treatment, including after transplantation.
To the Editor:
Membranous nephropathy is a common cause of the nephrotic syndrome in adults. Treatment is controversial and challenging because of the heterogeneity of the disease and a lack of ...reliable biomarkers.
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M-type phospholipase A
2
receptor (PLA
2
R) was recently identified as a major target antigen involved in idiopathic membranous nephropathy in adults.
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Circulating autoantibodies against PLA
2
R were found in 70 to 80% of patients with idiopathic membranous nephropathy but not in those with secondary membranous nephropathy or other renal diseases. It has been suggested that the serum level of PLA
2
R autoantibody . . .
Factor H Autoantibodies and Membranous Nephropathy Seikrit, Claudia; Ronco, Pierre; Debiec, Hanna
New England journal of medicine/The New England journal of medicine,
12/2018, Letnik:
379, Številka:
25
Journal Article
Recenzirano
Odprti dostop
The authors of this research letter describe a case of rapidly progressive renal failure in a patient with membranous nephropathy, related to the appearance of antibodies against the complement ...regulatory protein, factor H. Inhibition of factor H led to hyperactivation of the alternative complement pathway.
Membranous nephropathy is an autoimmune disease caused by antibodies mostly directed to podocyte antigens. PLA2R and THSD7A antigens were described in 2009 and 2014 using classical immunochemical ...techniques. In the last 2 years, thanks to the combination of laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins, several antigens associated with various causes have been described in patients with membranous nephropathy. The purpose of this review is to report on those "new" antigens and to analyse the clinicopathological correlations that make each of this antigen unique.
This article covers the literature of the last 2 years devoted to the description of those new antigens and biomarkers including NELL-1 and Semaphorin 3B in primary membranous nephropathy, and exostosins 1 and 2 and NCAM in lupus class V membranous nephropathy, which will be compared with the previously described antigens. These findings will lead to propose a new classification of membranous nephropathy based on serology and tissue antigen identification that could/should substitute for the classical distinction between primary and secondary membranous nephropathy.
The discovery of the latest antigens has major implications for the care of patients with membranous nephropathy as they drive the etiologic investigations and provide invaluable markers for treatment monitoring.
Membranous nephropathy is characterized by deposition of immune complexes along the glomerular basement membrane. PLA2R and THSD7A are target antigens in 70% and 1-5% of primary membranous ...nephropathy cases, respectively. In the remaining cases, the target antigen is unknown. Here, laser microdissection of glomeruli followed by mass spectrometry was used to identify novel antigen(s) in PLA2R-negative membranous nephropathy. An initial pilot mass spectrometry study in 35 cases of PLA2R-negative membranous nephropathy showed high spectral counts for neural tissue encoding protein with EGF-like repeats, NELL-1, in six cases. Mass spectrometry failed to detect NELL-1 in 23 PLA2R-associated membranous nephropathy and 88 controls. NELL-1 was localized by immunohistochemistry, which showed bright granular glomerular basement membrane staining for NELL-1 in all six cases. Next, an additional 23 NELL-1 positive cases of membranous nephropathy were identified by immunohistochemistry in a discovery cohort of 91 PLA2R-negative membranous nephropathy cases, 14 were confirmed by mass spectrometry. Thus, 29 of 126 PLA2R-negative cases were positive for NELL-1. PLA2R-associated membranous nephropathy and controls stained negative for NELL-1. We then identified five NELL-1 positive cases of membranous nephropathy out of 84 PLA2R and THSD7A-negative cases in two validation cohorts from France and Belgium. By confocal microscopy, both IgG and NELL-1 co-localized to the glomerular basement membrane. Western blot analysis showed reactivity to NELL-1 in five available sera, but no reactivity in control sera. Clinical and biopsy findings of NELL-1 positive membranous nephropathy showed features of primary membranous nephropathy. Thus, a subset of membranous nephropathy is associated with accumulation and co-localization of NELL-1 and IgG along the glomerular basement membrane, and with anti-NELL-1 antibodies in the serum. Hence, NELL-1 defines a distinct type of primary membranous nephropathy.
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In 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.
We 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.
Mass 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.
A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.
Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of ...the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients.
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Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among ...treatment effect, circulating nephritogenic anti-phospholipase A2 receptor (anti-PLA2R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m(2)) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximab-treated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA2R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA2R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio HR, 7.90; 95% confidence interval 95% CI, 2.54 to 24.60; P<0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA2R antibody depletion. On average, 50% anti-PLA2R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P<0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.
BSA ingested in food can escape the intestinal barrier and induce antibovine serum albumin antibodies. The authors of this study identified circulating BSA in patients with membranous nephropathy and ...in immune deposits in four children.
Membranous nephropathy is the most common cause of the nephrotic syndrome in adults but is rare in children.
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The central pathogenesis involves the formation of subepithelial immune deposits that are responsible for functional impairment of the glomerular capillary wall.
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Two major antigens have been identified. The first is neutral endopeptidase, the alloantigen involved in neonatal cases of membranous nephropathy,
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and the second is the M-type phospholipase A
2
receptor (PLA
2
R), which has been identified in idiopathic membranous nephropathy.
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Idiopathic membranous nephropathy is considered an autoimmune disease, whereas secondary forms involve exogenous antigens such as viral, bacterial, . . .
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