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• Bacterial enzymes rapidly degrade antibodies for treatment of autoimmune disease. • Imlifidase (IdeS) is a first-in-class medication advancing through clinical trials. • Current research is focused on desensitization for kidney transplantation, anti-GBM disease, antibody-mediated rejection, and Guillain-Barré syndrome. The discovery of bacterial enzymes with specificity for IgG antibodies has led to breakthroughs in several autoantibody-mediated diseases. Two such enzymes, IdeS and EndoS, degrade IgG by different mechanisms, and have separately shown promise in numerous animal models of autoimmune diseases. Recently, imlifidase (the international nonproprietary name for IdeS) has advanced to clinical trials, where it has performed remarkably well in desensitizing patients to enable kidney transplantation, and in anti-glomerular basement membrane disease. Conversely, it performed poorly in thrombotic thrombocytopenic purpura. This review summarizes the development of antibody-degrading enzymes, with a discussion of key clinical studies involving imlifidase. The future of the field is also discussed, including the use of these enzymes in other diseases, and the potential for re-dosing. [ABSTRACT FROM AUTHOR]

Introduction: Glomerular basement membrane (GBM) disease is a severe and exceedingly rare disorder characterized by the presence of circulating antibodies targeting the non-collagen NC1 domain of the α3 chain of collagen type IV in glomerular and alveolar basement membranes. It typically presents as rapidly progressive glomerulonephritis (RPGN), often accompanied by pulmonary hemorrhage. The occurrence of double-seropositivity for anti-GBM antibody and anti-neutrophil cytoplasmic antibody (ANCA), primarily with myeloperoxidase specificity (MPO-ANCA), is particularly uncommon in pediatric cases., Case Presentation: A 9-year-old boy was admitted to the pediatric ward exhibiting macroscopic hematuria, proteinuria, and acute kidney injury, with a gradual decline in kidney function. Pulmonary function remained normal. Circulating anti-GBM antibodies and ANCA, specifically targeting myeloperoxidase (MPO), were detected. Diagnosis was confirmed via percutaneous renal biopsy, which revealed circular glomerular crescents in 9 out of 16 glomeruli. Immunofluorescence examination exhibited a linear staining pattern of the capillary wall for IgG. Treatment involved 5 boluses of methylprednisolone, followed by prolonged oral prednisone, 11 plasma exchange sessions, and initiation of rituximab due to a moderate response to therapy. Subsequently, the patient's condition significantly improved, with normalized renal function observed 24 months post treatment., Conclusion: Despite limited literature on pediatric anti-GBM and double-positive disease, it is imperative to consider these diagnoses in pediatric patients presenting with RPGN. This article offers a comprehensive summary of the main characteristics of this disease in children and emphasizes therapeutic approaches through a review of identified cases in individuals under 18 years of age., Competing Interests: The authors have no competing interests., (© Dustri-Verlag Dr. K. Feistle.)

Anti-glomerular basement membrane disease (Anti-GBM), previously known as Goodpasture syndrome, is an extremely rare cause of rapidly progressive glomerulonephritis and chronic kidney disease stage 5 (CKD5) in children. It is associated with acute pulmonary haemorrhage and it has a poor prognosis. It is classified as an autoimmune, small-vessel vasculitis caused by autoantibody formation against the alpha-3 chain in type IV collagen found in the glomerular basement membrane. Evidence of anti-GBM antibodies in serum or histologically are required for diagnosis. Treatment in children is based on very limited adult data and often involves the use of acute apheresis to rapidly remove circulating factors coupled with intensive immunosuppression such as cyclophosphamide and intravenous corticosteroids. There is also an emerging role for the use of biologic agents such as B cell depletion. The evidence base in children with anti-GBM disease is extremely limited. Multi-centre international collaboration is required to provide insight into this disease, better describe its prognosis and work towards improving outcomes. This review article summarises the key features of this disease in children, highlights treatment options and considers areas of unmet need. [ABSTRACT FROM AUTHOR]

We report a case of a patient double-seropositive for anti-glomerular basement membrane (anti-GBM) and anti-neutrophil cytoplasmic antibodies (ANCA) who reported retrosternal chest pain during a regular hemodialysis session associated with ST-segment depression in electrocardiogram and an increase of serum high-sensitivity troponin T. Urgent coronary angiography excluded obstructive coronary artery disease, suggesting the diagnosis of ischemia with non-obstructive coronary arteries. This case illustrates an unusual presentation of cardiovascular involvement in a patient with double-positive ANCA/anti-GBM disease, emphasizing the possible relevance of coronary microvascular dysfunction and the need for close cardiovascular follow-up in this patient population.

Circulating autoantibodies directed against the kidney glomerular basement membrane (GBM) antigens are important markers in the diagnosis and monitoring of autoimmune glomerulonephritides, including the classic Goodpasture's syndrome. Rapid and reliable diagnostic tools for the detection of anti-GBM autoantibodies are crucial as anti-GBM disease can progress rapidly and, if too late or incorrectly diagnosed, can have serious, even fatal consequences. The performance of the newly developed standardized chemiluminescence immunoassay (ChLIA) was evaluated in comparison with the established Anti-GBM ELISA (IgG) (EUROIMMUN). For the assessment of its diagnostic performance, sera from 67 clinically characterized anti-GBM disease patients and 221 disease controls were analyzed. The clinical sensitivity of the Anti-GBM ChLIA (IgG) reached 100% at a specificity of 98.6%. The Anti-GBM ELISA (IgG) performance was less sensitive (89.6%) without any positive findings in the control group, indicating a specificity of 100%. Both methods were homogeneous (κ = 0.901). The Anti-GBM ChLIA (IgG) represents a promising alternative tool for accurate anti-GBM assessment in routine diagnostic settings with the advantage of rapid turnaround time and fully automated random-access processing.

Objective: Advanced age, need for dialysis and high creatinine values at the time of admission, anti-glomerular basement membrane antibody positivity, pulmonary hemorrhage, and fibrous crescents on pathology are known poor prognostic factors in rapidly progressive glomerulonephritis. Our study aimed to determine the clinical, laboratory, and pathological factors affecting the kidney prognosis in the progression to end-stage kidney failure disease in our rapidly progressive glomerulonephritis patients. Methods: This study was made with 52 patients diagnosed with type 1 and type 3 rapidly progressive glomerulonephritis. The study continued with 37 eligible patients. Results: The patients’ mean age was 52.3 ± 11.06 and 22 (59.4%) were male. In 6 patients (16.2%), anti-glomerular basement membrane positivity, in 11 patients (29.7%), cytoplasmic anti-neutrophilic cytoplasmic antibody positivity, and in 20 patients (54.1%), perinuclear anti-neutrophilic cytoplasmic antibody positivity was detected. Parathyroid hormone value was higher in the perinuclear anti-neutrophilic cytoplasmic antibody-positive group at the time of biopsy (P = .005). Serum sodium levels were lower at the biopsy time in the patient group with a crescent rate above 65% (P = .014). Patients with end-stage kidney failure disease were younger, and their serum sodium levels expressively were lower at the biopsy time (P = .006, P = .02 respectively). When the risk factors affecting end-stage kidney failure disease were examined in multivariate regression analysis, it was observed that while sodium and parathyroid hormone values were not risk factors at the time of biopsy, age (P = .048) and time until diagnosis were risk factors (P = .048). Conclusion: In our study, the risk factors affecting end-stage kidney failure disease progression in rapidly progressive glomerulonephritis patients were age and the time until diagnosis. Kidney biopsy is essential for the kidney prognosis for rapid diagnosis, especially in young patients with suspected rapidly progressive glomerulonephritis. [ABSTRACT FROM AUTHOR]

Abstract Background Monoclonal immunoglobulin deposition disease (MIDD) is a rare condition accounting for

Rapidly progressive glomerulonephritis can result from glomerular deposition of anti-GBM antibody, immune complexes, or may involve pauci-immune mechanisms. The coexistence of IgA nephropathy, anti-GBM, and anti-neutrophilic cytoplasmic antibodies is unheard of, and the pathogenic role of these antibodies in IgA nephropathy or vice versa remains unclear. Herein, we describe a case of a patient with type 4 rapidly progressive glomerulonephritis who was found to have significant mesangial IgA deposits. The prognosis of this remains unclear but our patient responded well to cytotoxic therapy and plasmapheresis and achieved remission by 6 months. The findings suggest an overlap syndrome of IgA nephropathy-associated type 4 crescentic glomerulonephritis that resembles the former histologically and the latter in its potential to respond to aggressive therapy if detected relatively early in its course. [ABSTRACT FROM AUTHOR]

Anti‐glomerular basement membrane (GBM) disease is a rarely described entity in the pediatric population, especially in those less than 3 years old. Even rarer, is double seropositive disease, consisting of anti‐GBM antibody plus anti‐neutrophil cytoplasmic antibodies. Both single and double antibody positive diseases are characterized by rapidly progressive glomerulonephritis, often without pulmonary involvement in the pediatric population. We report the case of a 2‐year‐old child with double seropositive anti‐GBM disease, the youngest in the current literature, along with the role of therapeutic plasma exchange and rituximab in disease treatment. [ABSTRACT FROM AUTHOR]

Background: Monoclonal immunoglobulin deposition disease (MIDD) is a rare condition accounting for < 1% of histopathological diagnoses made on kidney biopsy1. The best outcomes are seen in those diagnosed and treated promptly, but delay to diagnosis is common with the largest series reporting a median time from onset of renal impairment to diagnosis of 12 months2. Here, we report a case of the heavy chain subset of MIDD presenting with positive anti-glomerular basement membrane (anti-GBM) antibodies obscuring the true diagnosis.Case Presentation: Here, we present a challenging case presenting with oedema, haematoproteiuria, and new renal impairment. Anti-GBM antibodies were positive and prompted treatment as atypical anti-GBM disease. However, they were ultimately proven to be monoclonal and secondary to myeloma. The final diagnosis facilitated effective myeloma treatment which led to complete remission and independence from renal replacement therapy.Conclusions: This case reinforces the importance of comprehensive histopathological and haematological assessment in making the correct diagnosis. Here it facilitated effective treatment and recovery of renal function. [ABSTRACT FROM AUTHOR]

Purpose of Review: Idiopathic pulmonary hemosiderosis (IPH) is one of the rarest and least understood causes of pulmonary hemorrhage in children. Illustrated by a complex case presentation, we discuss the clinical manifestations, diagnosis, pathology, proposed etiologies, and treatment of this rare disease. We also compare IPH with anti-glomerular basement membrane antibody syndrome (anti-GBM disease), another rare causes of pediatric pulmonary hemorrhage. Recent Findings: Recent retrospective studies regarding IPH along with advanced immunotherapy have led to an improved understanding of how to best treat this condition, potential associations, and improved prognosis. Pathogenesis remains unknown, but several reports have suggested involvement of the alveolar capillary basement membrane. Summary: IPH is a poorly understood disease of unknown etiology that is a diagnosis of exclusion. Our patient was diagnosed with IPH after an exhaustive workup, including lung biopsy, into other immune-mediated causes of disease. While the pathogenesis of this rare disease remains elusive, our patient's immunofluorescent staining along the alveolar basement membrane without evidence of circulating antibody to type IV collagen raises the question of an immune-mediated pathogenesis of the disease with involvement of the alveolar basement membrane. [ABSTRACT FROM AUTHOR]

La maladie des anticorps anti-membrane basale glomérulaire (anti-MBG) ou syndrome de Goodpasture est une vascularite des petits vaisseaux. Il s'agit d'une maladie auto-immune médiée par des auto-anticorps dirigés sélectivement contre la membrane basale glomérulaire et alvéolaire, entraînant un syndrome pneumo-rénal. Il s'agit d'une maladie rare, monophasique et sévère, associant une glomérulonéphrite rapidement progressive et parfois une hémorragie alvéolaire, réalisant un syndrome pneumo-rénal. On note la présence d'anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA) dans 20 à 60 % des cas. La prise en charge doit être précoce et combine des échanges plasmatiques, une corticothérapie systémique et un traitement immunosuppresseur par cyclophosphamide. L'objectif de cette mise au point est : 1) de décrire les caractéristiques physiopathologiques, cliniques et histologiques de la maladie ; 2) de caractériser les patients double-positifs anticorps anti-MBG/ANCA ; 3) de préciser les facteurs pronostiques de survie rénale et globale, et 4) de faire le point sur la prise en charge thérapeutique de cette affection. Anti-glomerular basement membrane (anti-GBM) disease or Goodpasture's syndrome is a small vessel vasculitis affecting the capillary beds of kidneys and lungs. It is an autoimmune disease mediated by autoantibodies targeting the glomerular and alveolar basement membranes, leading to pneumorenal syndrome. It is a rare, monophasic and severe disease, associating rapidly progressive glomerulonephritis and alveolar hemorrhage. The presence of antineutrophil cytoplasmic antibodies (ANCA) is reported in 20 to 60% of cases. Management should be prompt and combine plasma exchange with systemic corticosteroids and immunosuppressive therapy by cyclophosphamide. The objective of this review is: 1) to describe the pathogenesis, clinical and histological features of the disease; 2) to characterize double-positive anti-GBM/ANCA patients; 3) to highlight the prognostic factors of renal and global survival, and 4) to focus on the treatment of anti-GBM disease. [ABSTRACT FROM AUTHOR]

Wenn das Immunsystem körpereigene Zellen angreift, ist häufig auch die Niere in Mitleidenschaft gezogen: Nierenschäden entstehen dabei entweder durch Autoantikörper, die spezifisch gegen renale Autoantigene gerichtet sind, oder durch lokale Reaktionen bei systemischen Autoimmunerkrankungen. Die Entdeckung neuer spezifischer Antikörper und neue Nachweismethoden führten in den letzten Jahren zu einer bedeutenden Verbesserung der Diagnostik. [ABSTRACT FROM AUTHOR]

Abstract Background Several tumour necrosis factor (TNF) based therapeutics have already been approved for human use and several others are emerging. Therefore, we determined the mRNA expression levels of the TNF superfamily ligands (TNFSF) – e.g. TNF-α, lymphotoxin (LT)-α, LT-β, Fas-L (CD95-L), TNF-related apoptosis-inducing ligand (TRAIL), TNF-related weak inducer of apoptosis (TWEAK), 4-1BBL, OX40-L (CD252) and amyloid precursor protein (APP) in healthy human and mouse solid organs. Methods We used quantitative real time-PCR to analyse mRNA expression levels of TNFSF ligands. Murine models of acute ischemic renal injury, chronic oxalate nephropathy, and immune complex glomerulonephritis were used. Renal injury was assessed by PAS staining, and infiltrating immune cells were analysed by immunohistochemistry. Data was analysed using non-parametric ANOVA (non-parametric; Kruskal-Wallis test). Results We observed significant differences in the mRNA expression levels of TNFSF ligands in human and mouse solid organs. Furthermore, we determined their mRNA expressions during acute and chronic kidney injuries in mice. Our data demonstrate that the mRNA expression levels of TNFSF vary depending on the type of tissue injury – for example, acute ischemic renal injury, chronic crystalline nephropathy, and immune complex glomerulonephritis. In addition, we observed that mRNA expressions of TNFSF ligands are differentially regulated during the course of a transient ischemic renal injury (IRI) and chronic kidney modelling. We observed that TNF-α, LT-β, and 4-1BBL were significantly upregulated during the progression of IRI and crystal-induced chronic kidney disease (CKD), whereas only 4-1BBL and TNF-α were significantly upregulated and LT-β was significantly downregulated during the progression of immune complex glomerulonephritis. The mRNA expression of Fas-L was higher during IRI whereas it decreased in a time dependent manner during the progression of crystal-induced CKD. Conclusion We conclude that the injury- and species-specific differences of TNFSF ligands must be considered in order to avoid the misinterpretation and wrong conclusions during data extrapolation between species.

Background: Goodpasture's disease (GP) is mediated by autoantibodies that bind the glomerular and alveolar basement membrane, causing rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. The autoantibodies bind neoepitopes formed upon disruption of the quaternary structure of α345NC1 hexamer, a critical structural domain of α345 collagen IV scaffolds. Hexamer disruption leads to a conformational changes that transitions α3 and α5NC1 subunits into immunogens, however, the trigger remains unknown. This contrasts with another anti-GBM disease, Alports' post-transplant nephritis (APTN), where the pathogenic alloantibody binds directly to native NC1 hexamer. The current report includes the first study of antigenic specificity and allo-incompatability in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT).Results: The anti-GBM antibodies were found to be directed predominantly against the EA epitope of the α3 NC1 monomer of collagen IV and developed rapidly in patient serum reaching peak level within 5 weeks. Autoantibody binding to native α345NC1 hexamer was minimal; however, binding was greatly increased upon dissociation of the native hexamer. There were no polymorphic genetic differences between donor and recipient collagen IV genes which would be predicted to cause a significant NC1 conformational change or to provide a target for antibody binding. Both patient and donor possessed the Goodpasture's susceptibility HLA-allele DRB1*1501.Conclusions: The current report includes the first in-depth study of allo-incompatability and antigenic specificity in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). No polymorphic genetic differences were identified between donor and recipient collagen IV genes which would be predicted to provide a target for antibody binding. Furthermore, autoantibody binding to native α345NC1 hexamer was minimal, increasing greatly upon dissociation of the native hexamer, resembling wild-type GP diseases and marking this as the first example of a post-HSCT conformeropathy.

Background: Goodpasture's disease (GP) is mediated by autoantibodies that bind the glomerular and alveolar basement membrane, causing rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. The autoantibodies bind neoepitopes formed upon disruption of the quaternary structure of α345NC1 hexamer, a critical structural domain of α345 collagen IV scaffolds. Hexamer disruption leads to a conformational changes that transitions α3 and α5NC1 subunits into immunogens, however, the trigger remains unknown. This contrasts with another anti-GBM disease, Alports' post-transplant nephritis (APTN), where the pathogenic alloantibody binds directly to native NC1 hexamer. The current report includes the first study of antigenic specificity and allo-incompatability in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). Results: The anti-GBM antibodies were found to be directed predominantly against the EA epitope of the α3 NC1 monomer of collagen IV and developed rapidly in patient serum reaching peak level within 5 weeks. Autoantibody binding to native α345NC1 hexamer was minimal; however, binding was greatly increased upon dissociation of the native hexamer. There were no polymorphic genetic differences between donor and recipient collagen IV genes which would be predicted to cause a significant NC1 conformational change or to provide a target for antibody binding. Both patient and donor possessed the Goodpasture's susceptibility HLA-allele DRB1 * 1501. Conclusions: The current report includes the first in-depth study of allo-incompatability and antigenic specificity in anti-GBM disease occurring after allogeneic haematopoietic stem cell transplant (HSCT). No polymorphic genetic differences were identified between donor and recipient collagen IV genes which would be predicted to provide a target for antibody binding. Furthermore, autoantibody binding to native α345NC1 hexamer was minimal, increasing greatly upon dissociation of the native hexamer, resembling wild-type GP diseases and marking this as the first example of a post-HSCT conformeropathy. [ABSTRACT FROM AUTHOR]

We report a 49-year-old man with microscopic hematuria, subnephrotic proteinuria, and rapidly progressive renal failure. His biopsy had features of PhosphoLipase A2 Receptor (PLA2R) positive membranous nephropathy with circumferential cellular crescents. Further work-up revealed IgG antiGlomerular Basement Membrane (anti-GBM) antibody titer of 188 U/mL (normal <7 U/mL). A final diagnosis of membranous nephropathy with anti-GBM disease was made. These two distinct pathological entities can occur together resulting in significant morbidity and mortality unless diagnosed early and treatment initiated promptly. Outcomes have been poor, given the nonspecific presentation and delay in diagnosis. [ABSTRACT FROM AUTHOR]

Copyright of Review of Medicine / Przeglad Lekarski is the property of Wydawnictwo Przegld Lekarski / Publisher Medicine Review and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Review of Medicine / Przeglad Lekarski is the property of Wydawnictwo Przegld Lekarski / Publisher Medicine Review and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Apheresis has been used in the treatment of severe systemic vasculitides, in conjunction with immunosuppressive therapies, for over 40 years. The aim is to rapidly remove autoantibodies or circulating immune complexes from the plasma. The two main indications at present are vasculitis associated with Antineutrophil Cytoplasmic Antibodies (ANCAs) manifesting as severe renal involvement and/or intraalveolar hemorrhage and antiglomerular basement membrane disease (Goodpasture syndrome). The ongoing PEXIVAS randomized controlled trial is assessing plasmapheresis to treat ANCA-associated vasculitis with or without severe renal involvement or intraalveolar hemorrhage. The two main apheresis techniques used to treat systemic vasculitis are plasmapheresis (by filtration, centrifugation, or double filtration) and immunoadsorption. The advantages and drawbacks of each technique are discussed here. Whether one technique is superior over the other in the current indications has not been proven. [ABSTRACT FROM AUTHOR]

Goodpasture's or anti-glomerular basement membrane (GBM) disease is classically characterized by the presence of circulating autoantibodies directed against the non-collagenous domain of the a3 chain of type IV collagen, targeting glomerular and alveolar basement membranes, and associated with rapidly progressive crescentic glomerulonephritis, with alveolar haemorrhage in over half the patients. However, there are increasing examples of variants or atypical presentations of this disease, and novel therapeutic options have been proposed, which nephrologists should be aware of. The pathophysiology of this condition has been understood through molecular analysis of the antibody-antigen interactions and the use of human leucocyte antigen-transgenic animals, while the association of anti-GBM antibodies with antineutrophil cytoplasm antibodies and their combined impact on disease phenotype is increasingly recognized, providing some insights into the basis of glomerular damage and autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Several tumour necrosis factor (TNF) based therapeutics have already been approved for human use and several others are emerging. Therefore, we determined the mRNA expression levels of the TNF superfamily ligands (TNFSF) - e.g. TNF-α, lymphotoxin (LT)-a, LT-β, Fas-L (CD95-L), TNF-related apoptosis-inducing ligand (TRAIL), TNF-related weak inducer of apoptosis (TWEAK), 4-1BBL, OX40-L (CD252) and amyloid precursor protein (APP) in healthy human and mouse solid organs. Methods: We used quantitative real time-PCR to analyse mRNA expression levels of TNFSF ligands. Murine models of acute ischemic renal injury, chronic oxalate nephropathy, and immune complex glomerulonephritis were used. Renal injury was assessed by PAS staining, and infiltrating immune cells were analysed by immunohistochemistry. Data was analysed using non-parametric ANOVA (non-parametric; Kruskal-Wallis test). Results: We observed significant differences in the mRNA expression levels of TNFSF ligands in human and mouse solid organs. Furthermore, we determined their mRNA expressions during acute and chronic kidney injuries in mice. Our data demonstrate that the mRNA expression levels of TNFSF vary depending on the type of tissue injury - for example, acute ischemic renal injury, chronic crystalline nephropathy, and immune complex glomerulonephritis. In addition, we observed that mRNA expressions of TNFSF ligands are differentially regulated during the course of a transient ischemic renal injury (IRI) and chronic kidney modelling. We observed that TNF-a, LT-β, and 4-1BBL were significantly upregulated during the progression of IRI and crystal-induced chronic kidney disease (CKD), whereas only 4-1BBL and TNF-a were significantly upregulated and LT-β was significantly downregulated during the progression of immune complex glomerulonephritis. The mRNA expression of Fas-L was higher during IRI whereas it decreased in a time dependent manner during the progression of crystal-induced CKD. Conclusion: We conclude that the injury-and species-specific differences of TNFSF ligands must be considered in order to avoid the misinterpretation and wrong conclusions during data extrapolation between species. [ABSTRACT FROM AUTHOR]

Résumé Les aphérèses sont utilisées dans les vascularites systémiques sévères, en complément du traitement immunosuppresseur, depuis plus de 40 ans. Leur objectif est l’épuration rapide du plasma d’auto-anticorps ou de complexes immuns circulants. Leurs principales indications sont les vascularites à anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA) avec atteinte rénale sévère et/ou hémorragie intra-alvéolaire, et la maladie à anticorps anti-membrane basale glomérulaire (Goodpasture). Ces indications pourraient s’élargir si l’étude PEXIVAS en cours démontrait un bénéfice des échanges plasmatiques dans les vascularites à ANCA avec atteinte rénale non sévère et/ou hémorragie intra-alvéolaire. Les deux principales techniques d’aphérèse utilisées au cours des vascularites systémiques sont les échanges plasmatiques (par filtration, centrifugation ou double filtration) et l’immunoadsorption. Ces techniques présentent des avantages et des inconvénients revus ici. La supériorité de l’une sur l’autre des techniques n’est pas démontrée dans ces indications. Apheresis has been used in the treatment of severe systemic vasculitides, in conjunction with immunosuppressive therapies, for more than 40 years. The aim is to allow the rapid removal from plasma of auto-antibodies or circulating immune complexes. The main indications of plasmapheresis are ANCA-associated vasculitides with severe renal involvement and/or intra-alveolar hemorrhage, and anti-glomerular basement membrane disease (Goodpasture). Therapeutic use of plasmapheresis may broaden if the ongoing trial PEXIVAS shows their benefit in ANCA-associated vasculitides with moderate renal involvement or intra-alveolar hemorrhage. The two main techniques of apheresis used in systemic vasculitides are plasma exchange (by filtration, centrifugation or double filtration) and immunoadsorption. Their respective advantages and drawbacks are presented here. No superiority of one technique upon the other has been demonstrated to date in this indication. [ABSTRACT FROM AUTHOR]

Goodpasture's disease is a clinical entity with an immunological pathophysiological basis, where the union to terminal NC1 domain mainly affects glomerular and lungs; thus, its diagnosis is oriented to such organ failure; its incidence varies from 0.5 to 1 cases per million population, for this reason it is considered a rare disease with high mortality due to complications from immune mechanism. Isolated lung presentation accounts for an even fewer percentage; in two thirds of cases hemoptysis is the most common clinical expression of the disease. Prognosis of these patients is associated to the presentation of the disease and the quality of care provided during the same. The definitive diagnosis is made by biopsy; however, the presence of anti-GBM antibodies (glomerular basement membrane) by ELISA can be handled in the diagnosis with good sensitivity. [ABSTRACT FROM AUTHOR]

Anti-glomerular basement membrane (anti-GBM) antibody disease is a rapidly progressive glomerulonephritis characterized by (i) positivity to anti-GBM in serum reacting with a specific antigen present in type IV collagen at both the glomerular and alveolar levels (ii) presence of crescent on light microscopy and positivity to linear deposits of IgG and C3 on immunofluorescence. In the classic variant, the clinic is that of a nephro-pneumological syndrome but there are variants. Rarely, the glomerular damage is pauci-immune. We describe a case of a variant in which there is anti-MBG positivity in serum but negative immunofluorescence and offer a review of the literature and potential treatments., (Copyright by Società Italiana di Nefrologia SIN, Rome,Italy.)

Anti-glomerular basement membrane (anti-GBM) disease is a major cause of rapidly progressive glomerulonephritis (RPGN). On the other hand, fibrillary glomerulonephritis (GN) typically presents as proteinuria, hematuria and renal insufficiency, but rarely as RPGN. Without electron microscopy, the diagnosis of fibrillary GN can be missed.We report a 68-year-old white woman who presented with RPGN with kidney biopsy demonstrating diffuse crescentic GN on light microscopy. By immunofluorescence, there was bright linear staining of the GBMs and smudgy mesangial staining for immunoglobulin G, C3, and kappa and lambda light chain. Electron microscopy revealed fibrillary deposits in the GBM and mesangium. A serum test for anti-GBM antibody was positive. To our knowledge, this is the first report of coexistence of fibrillary GN in a patient with anti-GBM disease. Electron microscopy is critical to identify the coexistence of other GN in patients presenting with crescentic GN. [ABSTRACT FROM AUTHOR]

Background: Anti-glomerular basement membrane (GBM) antibody disease is a rare autoimmune disorder characterized by rapidly progressive glomerulonephritis caused by autoantibodies against the α3-chain of type IV collagen in the GBM.Case Presentation: An 8-year-old girl with hematuria and proteinuria due to anti-GBM nephritis was diagnosed with hematuria and proteinuria during a school urine screening program. Her blood pressure and serum creatinine levels were normal. Her hematuria and proteinuria persisted for several months. Since a spot urine protein to creatinine ratio was around 7 g/g Cre, a percutaneous renal biopsy was performed. Immunofluorescent staining demonstrated a linear pattern for immunoglobulin G along the entire GBM. Chest computed tomography was normal. Anti-GBM antibody assays were reported as slightly raised; thus, the diagnosis was anti-GBM disease with normal renal function. Treatment included plasma exchange, intravenous high-dose methylprednisolone, and cyclophosphamide as a mainstay medication. The treatment was rapidly effective with an immediate decrease in anti-GBM titers and proteinuria.Conclusions: Cases of anti-GBM disease with normal renal function in children are rare. Treatment in children has not been established; therefore, clinicians need to carefully select an effective treatment because the prognosis is poor. [ABSTRACT FROM AUTHOR]

Key Clinical Message Shock wave lithotripsy may unmask epitopes within the glomerular basement membrane, leading to the formation of anti-glomerular basement membrane ( GBM) antibodies and clinical disease in susceptible individuals. Although rare, our case highlights the need for vigilant monitoring of renal function following extracorporeal shock wave lithotripsy. This may allow for early recognition, treatment and improved outcome of anti- GBM disease. [ABSTRACT FROM AUTHOR]

Background Outside of pregnancy, anti-glomerular basement membrane (GBM) antibody disease is associated with significant morbidity and mortality. However, there is limited knowledge regarding de novo anti-GBM disease in pregnancy. Methods A systematic review was performed to identify maternal, pregnancy and fetal outcomes in de novo anti-GBM disease in pregnancy. Studies were selected from PubMed, EMBASE, Cochrane Library databases and conference proceedings, without language restriction. Results Data from eight patients were derived from seven case reports and one unpublished case. Most (6/8) patients presented after the first trimester. During pregnancy, acute kidney injury (5/8), anemia (5/8), hematuria (8/8) and proteinuria (8/8) were common. When hemodialysis was required antepartum (5/8), renal function recovery to independence of renal replacement was unlikely (2/5). While pulmonary involvement was common (5/8), no permanent damage was reported (0/8). The majority of cases ended in live births (6/8) although prematurity (6/6), intrauterine growth restriction (2/6), small for gestational age (4/6) and complications of prematurity (1/6) were common. When anti-GBM levels were tested in the living newborn, they were detectable (2/5), but no newborn renal or lung disease was reported (0/6). Complications in pregnancy included gestational diabetes (3/8), hyperemesis gravidarum (2/8) and preeclampsia (2/8). Conclusions Live births can be achieved in de novo anti-GBM disease in pregnancy, but are commonly associated with adverse maternal, pregnancy and fetal outcomes. Only with awareness of common presentations, and management strategies can outcomes be optimized. [ABSTRACT FROM AUTHOR]

Circulating autoantibodies directed against the kidney glomerular basement membrane (GBM) antigens are important markers in the diagnosis and monitoring of autoimmune glomerulonephritides, including the classic Goodpasture's syndrome. Rapid and reliable diagnostic tools for the detection of anti-GBM autoantibodies are crucial as anti-GBM disease can progress rapidly and, if too late or incorrectly diagnosed, can have serious, even fatal consequences. The performance of the newly developed standardized chemiluminescence immunoassay (ChLIA) was evaluated in comparison with the established Anti-GBM ELISA (IgG) (EUROIMMUN). For the assessment of its diagnostic performance, sera from 67 clinically characterized anti-GBM disease patients and 221 disease controls were analyzed. The clinical sensitivity of the Anti-GBM ChLIA (IgG) reached 100% at a specificity of 98.6%. The Anti-GBM ELISA (IgG) performance was less sensitive (89.6%) without any positive findings in the control group, indicating a specificity of 100%. Both methods were homogeneous (κ = 0.901). The Anti-GBM ChLIA (IgG) represents a promising alternative tool for accurate anti-GBM assessment in routine diagnostic settings with the advantage of rapid turnaround time and fully automated random-access processing., Competing Interests: AK, LH, and CD are employees of EUROIMMUN, a company that develops and manufactures immunoassays for the detection of disease-associated antibodies. WS is a board member of EUROIMMUN., (Copyright © 2022 Kühnl, Hartwig, Dähnrich and Schlumberger.)

Goodpasture's disease, or anti-glomerular basement membrane (anti-GBM) disease, is a systemic autoimmune disorder defined by anti-GBM antibody-mediated damage (mainly immunoglobulin G-1) resulting in progressive crescentic glomerulonephritis and, frequently, diffuse pulmonary alveolar hemorrhage. It may be regarded as a 'conformeropathy' where the quaternary structure of the α345NC1 hexamer that constitutes GBM undergoes a conformational change, exposing pathogenic epitopes on the α3 and α5 chains, eliciting a pathogenic autoantibody anti-GBM response. Goodpasture's disease accounts for 20% of all patients presenting with a pulmonary-renal syndrome and may be associated with detectable perinuclear antineutrophil cytoplasmic autoantibody positivity in up to a third of patients. Associated triggers may include tobacco smoking, hydrocarbon solvent exposure, and cocaine abuse. Cough, hemoptysis, and dyspnea with fatigue are the commonest presenting features. It is critical to rapidly distinguish Goodpasture's disease from other causes of pulmonary-renal syndromes such as Wegener's granulomatosis. Early and intensive treatment with plasmapheresis and immunosuppression with systemic corticosteroids pending results of diagnostic testing, and later cyclophosphamide, is often beneficial, with 90% of patients surviving the acute presentation of Goodpasture's disease. The need for hemodialysis on initial presentation, a serum creatinine >5 mg/dL, and 50% to 100% crescents on renal biopsy, portend the necessity of long-term hemodialysis. Further elucidation of the molecular pathobiology of Goodpasture's disease, particularly the regulation of involved antigen-specific T cells, may improve early diagnosis, treatment, and outcomes in this rare but potentially lethal autoimmune disorder. [ABSTRACT FROM AUTHOR]

Anti-glomerular basement membrane (anti-GBM) disease, which is extremely uncommon in children, is characterized by rapidly progressive glomerulonephritis (RPGN) and autoantibodies against GBM collagen. Pulmonary hemorrhage is the third component in Goodpasture Syndrome. Cigarette smoking and exposure to hydrocarbons have been linked to anti-GBM disease in adults, but such an association has not been established in children. We reviewed renal biopsy and autopsy specimens over 25 years from a major tertiary care U.S. children's hospital, diagnosing anti-GBM by clinical RPGN, crescentic glomerulonephritis, and linear immunofluorescence (IF) immunoglobulin G staining in patients under 18 years of age. We identified four patients, with and without pulmonary manifestations. The sole autopsy case showed diagnostic IF despite undetectable serum anti-GBM antibodies and positive testing for serum anti-neutrophil cytoplasmic antibodies (ANCA). Three patients have survived 1-18 years following diagnosis, one of whom is recovering renal function. One adolescent had a history of smoking cigarettes and one had a probable hydrocarbon exposure. Anti-GBM disease is unusual in children, and the relationship to inhaled agents is incompletely understood. Serum anti-GBM antibodies are typically present, but cases with undetectable levels can occur. Some patients are anti-GBM and ANCA positive, with a small subset ANCA-positive, anti-GBM-negative. Ours is the first such described pediatric case. [ABSTRACT FROM AUTHOR]

Sle3 is a NZM2410/NZW-derived lupus-susceptibility interval on murine chromosome 7, which is associated with spontaneous lupus nephritis (SLN), and also anti-GBM-induced glomerulonephritis (GN). The tissue kallikrein gene cluster is located within the Sle3 interval and constitutes potential candidate genes for this locus. We have recently reported that renal kallikrein expression was upregulated by anti-GBM antibody challenge in a strain-specific manner and that it was significantly underexpressed in the anti-GBM-sensitive strains, including B6.Sle3. Further sequencing and functional studies reported earlier provided evidence that kallikreins could constitute disease genes in lupus. In this report, we have used an adenoviral vector to deliver the klk1 gene to B6.Sle3 congenics to directly test if kallikreins might have a protective effect against anti-GBM-induced nephritis. Our data show that klk1 gene delivery ameliorated anti-GBM-induced nephritis in B6.Sle3 congenics. Taken together with earlier studies, these findings indicate that kallikreins play an important protective role in autoantibody-initiated GN and could constitute potential candidate genes for anti-GBM-induced GN and SLN.Genes and Immunity (2009) 10, 503–508; doi:10.1038/gene.2009.7; published online 5 March 2009 [ABSTRACT FROM AUTHOR]

Renal involvement in autoimmunity has many facets. Glomerular, tubular and vascular structures are targeted and damaged as a consequence of autoimmune processes. Most dramatic and life-threatening causes are observed with diseases that result in rapidly progressive glomerulonephritis (GN), frequently accompanied by involvement of additional non-renal organs. Typical diseases with these characteristics are anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitidis, anti-glomerular basement membrane (anti-GBM) GN and proliferative lupus nephritis. The leading cause of rapidly progressive GN is ANCA-associated GN and is the main focus of this article. Two major ANCA antigens have been described, namely proteinase 3 (PR3), with a cytoplasmic immunfluorescence staining pattern, and myeloperoxidase (MPO), with a perinuclear pattern. ANCA-associated diseases include Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and a renal limited disease form that presents solely with necrotizing crescentic GN. Because of the strong ANCA association with the aforementioned diseases, ANCA has become a valuable diagnostic tool for clinicians. Moreover, a variety of in vitro and in vivo findings have established the causal role of ANCA in the disease development. Recently, the membrane-PR3 expression pattern on neutrophils was shown to have clinical significance, suggesting membrane-PR3 as a novel biomarker. Furthermore, the data demonstrate that membrane-PR3 expression is restricted to a stable subset of neutrophils. This subset is determined by the existence of the glycosylphosphatidylinositol (GPI)-anchored NB1 receptor (CD177). Better understanding of the PR3-NB1 interaction may have therapeutic implications with the development of more selective drugs. [ABSTRACT FROM AUTHOR]

Anti-neutrophil cytoplasmic autoantibodies (ANCA) and anti-glomerular basement membrane (GBM) necrotizing and crescentic glomerulonephritis are aggressive and destructive glomerular diseases that are associated with and probably caused by circulating ANCA and anti-GBM antibodies. These necrotizing lesions are manifested by acute nephritis and deteriorating kidney function often accompanied by distinctive clinical features of systemic disease. Prompt diagnosis requires clinical acumen that allows for the prompt institution of therapy aimed at removing circulating autoantibodies and quelling the inflammatory process. Continuing exploration of the etiology and pathogenesis of these aggressive inflammatory diseases have gradually uncovered new paradigms for the cause of and more specific therapy for these particular glomerular disorders and for autoimmune glomerular diseases in general. [ABSTRACT FROM AUTHOR]

Abstract: Decay-accelerating factor (DAF) and complement receptor 1-related gene/protein y (Crry) are two membrane-anchored complement regulatory proteins in rodent. Although both proteins are broadly distributed and exert complement regulation at the same steps of the complement cascade, DAF knockout mice are viable whereas Crry knockout mice die in utero as a result of maternal complement attack. The latter outcome has prevented the dissection of overlapping functions of DAF and Crry in adult mouse tissues in vivo. By crossing female DAF−/−/Crry−/−/C3−/− mice with male DAF−/−/Crry+/−/C3+/− mice, we circumvented maternal complement attack during fetal development and generated viable DAF−/−/Crry−/−/C3+/− mice to address the consequence of DAF/Crry double deficiency. DAF−/−/Crry−/−/C3+/− mice were born at the expected frequency and survived to adulthood. However, they were found to have greatly reduced systemic complement activity due, at least in part, to spontaneous C3 activation and consumption. Plasma C3 proteins in DAF−/−/Crry−/−/C3+/− mice were 30% of that of wild-type mice, and serum complement activity, as assessed by zymosan and immune complex C3 opsonization assays, was 90% reduced in DAF−/−/Crry−/−/C3+/− mice. Remarkably, despite greatly reduced systemic complement activity, DAF−/−/Crry−/−/C3+/− mice developed more severe proteinuria after induction of nephrotoxic serum nephritis as compared with DAF−/−/Crry+/−/C3+/− and DAF−/−/Crry−/−/C3−/− littermate controls. The results highlight the critical and overlapping role of Crry and DAF in vivo in preventing complement activation and tissue injury. [Copyright &y& Elsevier]

We report a case of anti-glomerular basement membrane (GBM) disease in association with human leucocyte antigen (HLA) DRB1 15:01. A 71-year-old woman presented with oligoanuric acute kidney injury accompanied by high titre anti-GBM antibodies. Renal biopsy revealed a severe crescentic glomerulonephritis. Her brother had presented 6 years earlier with oligoanuric acute kidney injury. He was dual positive for MPO ANCA and anti-GBM antibodies. Renal biopsy was not performed. Both had an absence of pulmonary involvement. Tissue typing confirmed both were heterozygous for HLA DRB1 15:01 and DRB1 04:03. [ABSTRACT FROM AUTHOR]

Therapeutic apheresis (TA) as a treatment for antibody-associated vasculitis (AAV) was questioned by the PEXIVAS although the MEPEX study favored TA. The aim of this study was to evaluate the efficacy of TA to improve renal function in patients consecutively included in the WAA-apheresis registry versus patients not treated with TA. Included were 192 patients that suffered from anti-glomerular basement membrane disease (anti-GBM, n = 28) and antineutrophil cytoplasmic antibody-associated vasculitis of MPO or PR3 origin. Of these 119 had performed TA and the other 73 had not performed TA for theses diagnoses (CTRL). Elderly had an increased risk to die within 12 months (p = 0.002). All 28 anti-GBM had renal involvement, 21 dialysis dependent. At 3 month nine (36 %) did not need dialysis. Baseline data regarding renal function of AAV patients, subtype MPO and PR3, were worse in the TA groups than in CTRL. Recovery out of dialysis was better for the PR3-TA group compared with 1) the controls of MEPEX (RR 0.59, CI 0.43−0.80) and 2) the MPO-TA patients (RR 0.28, CI 0.12−0.68). The MPO-TA recovered similarly as the MEPEX-CTRL. Renal function improved most for TA-patients from baseline during the first 3 months (MPO-TA and PR3-TA) and stabilized thereafter and less for MPO-CTRL and PR3-CTRL. PR3-TA patients seem to have best chances to get out of dialysis. PR3-TA and MPO-TA improved residual renal function better than CTRL. The present study recommends reconsiderations to use TA for AAV especially those with PR3-vasculitis with severe renal vasculitis. [ABSTRACT FROM AUTHOR]