Coexistence of anti-glomerular basement membrane disease and IgA nephropathy: an illustrative case and comprehensive literature review.

Anti-glomerular basement membrane (GBM) disease is a rare autoimmune condition characterized by the presence of positive anti-GBM autoantibodies, linear deposition of immunoglobulin G (IgG) along the GBM and severe kidney injury. In a limited number of cases, the association of anti-GBM disease with other glomerulonephritis has been reported. Herein, we present the case of a 66-year-old female patient with progressive worsen kidney function and decreased urine output. A renal biopsy revealed crescent glomerulonephritis with lineal IgG deposition along the GBM and mesangial IgA deposition, which supported the diagnosis of concurrent anti-GBM disease and IgA nephropathy (IgAN). In an extensive literature review, we identified a total of thirty-nine patients were reported anti-GBM disease combined with IgAN. The clinical characteristics of these patients demonstrate that the anti-GBM disease combined with IgAN tends to be milder with a more indolent course and a better prognosis than the classic anti-GBM disease, and its potential pathogenesis deserves to be further explored.

The protease inhibitor E64d might attenuate the development of experimental anti-glomerular basement membrane disease through regulating the activation of Th1 cells.

BACKGROUND: Cathepsins have been recently identified as a regulator in the activation of Th1 and Th17 cells, which play an important role in the pathogenesis of anti-glomerular basement membrane (GBM) disease. Whether cathepsins contribute to the development of anti-GBM disease through regulating the activation of CD4+ T cell is still unclear. METHODS: Rats with experimental anti-GBM disease was established by immunization with the nephritogenic T cell epitope α3127-148. E64d, a cysteine cathepsin inhibitor, was administered in vitro and vivo to evaluate the effect of cathepsins on regulating the activation of antigen specific T cells and the development of anti-GBM disease. RESULTS: In rats with experimental anti-GBM diseases, E64d treatment not only reduced the levels of proteinuria, serum creatinine and anti-GBM antibody, but also ameliorated the kidney injury with less glomerular IgG deposition, a lower percentage of crescents and less infiltration of CD4+ T cells, CD8+ T cells and macrophages, as well as a lower percentage of splenic Th1 cells. In vitro, E64d treatment could significantly reduce the production of IFN-γ in the supernatant which might be produced by the activation of Th1 cells after being recalled with the autoantigen α3127-148. We also found the CD4+ T cells of rats with anti-GBM disease had an increased expression of cathepsin L (Cts-L), and the percentage of CD4+ T cells with extracellular expression of Cts-L was obviously higher, indicating it as a potential key regulator. CONCLUSIONS: E64d might attenuate the development of anti-GBM disease by participating in the activation of Th1 cells, indicating it as a potential drug for anti-GBM disease in the future.

Short-chain fatty acids ameliorate experimental anti-glomerular basement membrane disease.

BACKGROUND: Short-chain fatty acids (SCFAs), as the link between gut microbiota and the immune system, had been reported to be protective in many autoimmune diseases by the modulation of T cell differentiation. The pathogenic role of autoreactive Th1 and Th17 cells and the protective role of Treg cells in the pathogenesis of anti-GBM disease have been fully demonstrated. Thus, the present study aimed to investigate the therapeutic effects of SCFAs in a rat model of anti-GBM disease. MATERIALS AND METHODS: Experimental anti-GBM disease was constructed by immunizing Wistar Kyoto rats with a nephrogenic T cell epitope α3127-148, and intervened by sodium acetate, sodium propionate, or sodium butyrate, 150 mM in the drinking water from day 0 to 42. Kidney injury was accessed by the biochemical analyzer, immunofluorescence, and immunohistochemistry. Antibody response was detected by ELISA. T cell clustering and proliferation were detected by flow cytometry. Human kidney 2 (HK2) cells were stimulated in vitro and cytokines were assessed by quantitative real-time PCR. RESULTS: Treatment with sodium acetate, sodium propionate, or sodium butyrate ameliorated the severity of kidney impairment in rats with anti-GBM glomerulonephritis. In the sodium butyrate-treated rats, the urinary protein, serum creatinine, and blood urea nitrogen levels were significantly lower; the percentage of crescent formation in glomeruli was significantly reduced; and the kidneys showed reduced IgG deposition, complement activation, T cell, and macrophage infiltration as well as the level of circulating antibodies against anti-α3(IV)NC1. The treatment of sodium butyrate reduced the α3127-148-specific T cell activation and increased the Treg cells differentiation and the intestinal beneficial bacteria flora. It also alleviated the damage of HK2 cells treated with inflammatory factors and complement. CONCLUSION: Treatment with SCFAs, especially butyrate, alleviated anti-GBM nephritis in rat model, indicating its potential therapeutic effects in clinical usage.

Goodpasture syndrome: a rare case presenting with recurrent haemoptysis.

Goodpasture syndrome is a rare autoimmune disease which affects young adults with a male preponderance and can be triggered at any point in life with a classical clinical triad of rapidly progressive glomerulonephritis, diffuse pulmonary haemorrhage and circulating anti-glomerular basement membrane antibody (anti-GBM antibody). Here we are presenting a case of a young man with hypertension in his early 20s who presented with fatigue, recurrent haemoptysis, breathlessness and decreased urine output without features of infection. He was diagnosed at an early stage of the disease with the help of clinical, serological and radiological findings. An early diagnosis with effective treatment using plasma exchange, intravenous high-dose methylprednisolone, and cyclophosphamide showed a rapid improvement in the patient's condition with an immediate decrease in anti-GBM titres and proteinuria.

Clinical characteristics of anti-GBM disease with thrombotic microangiopathy: a case report and literature review.

The coexistence of anti-glomerular basement membrane (anti-GBM) disease with thrombotic microangiopathy (TMA) is rarely encountered, and the clinical characteristics of this phenomenon are not well known.A 76-year-old Japanese woman with a history of idiopathic pulmonary disease was diagnosed with anti-GBM disease due to rapidly progressive glomerulonephritis and a positive anti-GBM antibody test result. We treated the patient with hemodialysis, glucocorticoids, and plasmapheresis. During treatment, the patient suddenly became comatose. TMA was then diagnosed because of thrombocytopenia and microangiopathic hemolytic anemia. The activity of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS-13) was retained at 48%. Although we continued the treatment, the patient died of respiratory failure. An autopsy revealed the cause of respiratory failure to be an acute exacerbation of interstitial pneumonia. The clinical findings of the renal specimen indicated anti-GBM disease; however, there were no lesions suggestive of TMA. A genetic test did not reveal an apparent genetic mutation of the atypical hemolytic uremic syndrome.We conducted a literature review of past case reports of anti-GBM disease with TMA. The following clinical characteristics were obtained. First, 75% of the cases were reported in Asia. Second, TMA tended to appear during the treatment course for anti-GBM disease and usually resolved within 12 weeks. Third, ADAMTS-13 activity was retained above 10% in 90% of the cases. Fourth, central nervous system manifestations occurred in more than half of the patients. Fifth, the renal outcome was very poor. Further studies are required to understand the pathophysiology of this phenomenon.

An Unusual Case of Anti-Glomerular Basement Membrane Disease and Phospholipase A2 Receptor-Associated Membranous Nephropathy After Exposure to Hydrocarbons.

We present a rare case of a patient with toluene exposure manifesting as anti-glomerular basement membrane (GBM) disease on a background of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy. A 23-year-old man presented to the emergency department with hypertension, headache, hemoptysis, anemia, acute kidney injury, glomerular hematuria, and proteinuria. He endorsed repeated exposure to toluene-containing products while repairing dirt bikes. Serologies were positive for anti-GBM antibodies. Kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G and granular PLA2R staining by immunofluorescence. He was initially treated with high-dose steroids, plasmapheresis, and hemodialysis for pulmonary-renal syndrome followed by oral cyclophosphamide and prednisone, which were discontinued after 3 months when follow-up biopsies confirmed little chance for renal recovery. He remained on dialysis 1 year later. This case exhibits a unique presentation of anti-GBM syndrome and underlying membranous nephropathy following repeated hydrocarbon exposure. Inhaled toxins promote recurrent localized inflammation, unmasking previously hidden epitopes. Early diagnosis and appropriate use of immunosuppressive and extracorporeal therapies are necessary to prevent morbidity and to improve survival in this rare condition.

Laminin-521: a novel target for pathogenic autoantibodies in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is typically characterized by autoimmunity against the α3 chain of type IV collagen. Rarely, circulating autoantibodies are not detected. These atypical cases follow a more indolent clinical course, and underlying mechanisms, including alternative target antigens, require investigation. In this issue of Kidney International, Kuang et al. describe a case of anti-GBM disease with autoantibodies against the GBM component laminin-521 and demonstrate that laminin-521 is pathogenic in a rat model of anti-GBM glomerulonephritis.

The Immunobiological Agents for Treatment of Antiglomerular Basement Membrane Disease.

Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM) disease, but the prognosis of this disease remains poor. Several immunobiological agents have been administered or are expected to be useful for anti-GBM disease in light of refractory disease or the standard treatments' tolerability. Many data regarding the use of biologic agents for anti-GBM disease have accumulated, verifying the effectiveness and potential of biologic agents as a new treatment option for anti-GBM disease. Tumor necrosis factor (TNF) inhibitors were shown to be useful in animal studies, but these agents have no clinical use and were even shown to induce anti-GBM disease in several cases. Although the efficacy of the TNF-receptor antagonist has been observed in animal models, there are no published case reports of its clinical use. There are also no published reports of animal or clinical studies of anti-B-cell-activating factor, which is a member of the TNF family of agents. Anti-interleukin (IL)-6 antibodies have been demonstrated to have no effect on or to exacerbate nephritis in animal models. Anti-C5 inhibitor was observed to be useful in a few anti-GBM disease cases. Among the several immunobiological agents, only rituximab has been demonstrated to be useful in refractory or poor-tolerance patients or small uncontrolled studies. Rituximab is usually used in combination with steroids and plasma exchange and is used primarily as an alternative to cyclophosphamide, but there is insufficient evidence regarding the efficacy of rituximab for anti-GBM disease, and thus, randomized controlled studies are required.

Antiglomerular basement membrane antibody type rapidly progressive glomerulonephritis with seizures: Two cases and literature review.

BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) is clinically manifestations as a rapidly progressive renal failure and pathologically as crescentic and necrotizing lesions with infiltration of inflammatory cells in the glomeruli. Uremic encephalopathy (UE) usually develops in patients who are suffering from acute or chronic renal failure. OBJECTIVE: The purpose of this article is to provide reference for clinical diagnosis and treatment of renal disease complicated with seizures. Patients Two cases of anti-glomerular basement membrane type rapidly progressive glomerulonephritis complicated with seizures were reported. MATERIALS & METHODS: In case 1, a 40-year-old woman was hospitalized for the treatment of nausea, anorexia, and fever. On admission, she presented with elevated serum inflammatory indicators, moderate anemia, and advanced acute kidney injury requiring hemodialysis. Her anti-glomerular basement membrane (GBM) antibody in serum and renal tissues was found to be extremely high. She was finally diagnosed with anti-GBM disease. She was treated with a combination of corticosteroid pulse therapy, oral cyclophosphamide and prednisolone, and plasma exchange, while continued to require maintenance hemodialysis for end-stage kidney disease. During treatment, she suddenly suffered blindness, seizure, and consciousness disturbance. She was diagnosed as posterior reversible leukoencephalopathy syndrome by magnetic resonance imaging (MRI). The posterior reversible leukoencephalopathy syndrome subsided quickly after control of her hypertension and reinforcement of immunosuppressive treatment. In case 2, the patient also developed epileptic symptoms on the basis of GBM disease, and was given treatment similar to that of Case 1, so that the epileptic symptoms were controlled. RESULT: Reversible posterior leukoencephalopathy syndrome, especially when accompanied by cerebral hemorrhage, may lead to irreversible and lethal neurological abnormalities, and nephrologists should, therefore, be aware of the potential risk of reversible posterior leukoencephalopathy syndrome in patients with anti-GBM disease. We can discuss the current two cases in the light of the previous literature.

Unleashing the power of complement activation: unraveling renal damage in human anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (GBM) disease is a rare but life-threatening autoimmune disorder characterized by rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. Renal biopsies of anti-GBM patients predominantly show linear deposition of IgG and complement component 3 (C3), indicating a close association between antigen-antibody reactions and subsequent complement activation in the pathogenesis of the disease. All three major pathways of complement activation, including the classical, lectin, and alternative pathways, are involved in human anti-GBM disease. Several complement factors, such as C3, C5b-9, and factor B, show a positive correlation with the severity of the renal injury and act as risk factors for renal outcomes. Furthermore, compared to patients with single positivity for anti-GBM antibodies, individuals who are double-seropositive for anti-neutrophil cytoplasmic antibody (ANCA) and anti-GBM antibodies exhibit a unique clinical phenotype that lies between ANCA-associated vasculitis (AAV) and anti-GBM disease. Complement activation may serve as a potential "bridge" for triggering both AAV and anti-GBM conditions. The aim of this article is to provide a comprehensive review of the latest clinical evidence regarding the role of complement activation in anti-GBM disease. Furthermore, potential therapeutic strategies targeting complement components and associated precautions are discussed, to establish a theoretical basis for complement-targeted therapies.

Atypical form of Goodpasture's disease.

Goodpasture's disease and anti-glomerular basement membrane nephritis (anti-GBM nephritis) are rare autoimmune small vessel vasculitis predominantly affecting young men. Goodpasture's disease plays an important part in differential diagnosis of pulmonary - renal syndrome. The evidence of circulating autoantibodies, a typical histological appearance of the kidney biopsy with finding of the crescent glomerulonephritis and clinical presentation of nephritic syndrome play an important role in diagnosis. Our case report describes a case of a young male with anti-GBM nephritis that presents as rapidly progressive glomerulonephritis (RPGN) with progression to dialysis-dependent renal failure. The atypical sign of the case was development of nephrotic syndrome with volume-dependent hypertension. The case was complicated by heparin-induced thrombocytopenia. During combined immunosuppressive therapy with plasmapheresis, the condition of the patient has stabilized. However, renal function did not recover. This previously fatal disease has nowadays a very good survival rate because of immunosuppresion therapy, plasmapheresis and hemodialysis.

NETosis: an emerging therapeutic target in renal diseases.

Introduction: Neutrophil extracellular traps (NETs) are web-like structures composed of nuclear and granular components. The primary role of NETS is to prevent the dissemination of microbes and facilitate their elimination. However, this process is accompanied by collateral proinflammatory adverse effects when the NET release becomes uncontrollable, or clearance is impaired. Although NET-induced organ damage is conducted primarily and indirectly via immune complexes and the subsequent release of cytokines, their direct effects on cells are also remarkable. NETosis plays a critical pathogenic role in several renal disorders, such as the early phase of acute tubular necrosis, anti-neutrophil cytoplasmic antibody-mediated renal vasculitis, lupus nephritis, thrombotic microangiopathies, anti-glomerular basement membrane disease, and diabetic nephropathy. Their substantial contribution in the course of these disorders makes them a desirable target in the therapeutic armamentarium. This article gives an in-depth review of the heterogeneous pathogenesis and physiological regulations of NETosis and its pivotal role in renal diseases. Based on the pathogenesis, the article also outlines the current therapeutic options and possible molecular targets in the treatment of NET-related renal disorders. Methods: We carried out thorough literature research published in PubMed and Google Scholar, including a comprehensive review and analysis of the classification, pathomechanisms, and a broad spectrum of NET-related kidney disorders. Conclusions: NETosis plays a pivotal role in certain renal diseases. It initiates and maintains inflammatory and autoimmune disorders, thus making it a desirable target for improving patient and renal outcomes. Better understanding and clinical translation of the pathogenesis are crucial aspects to treatment, for improving patient, and renal outcomes.

Immunity in the balance: Fatal disseminated adenovirus infection in a patient undergoing plasma exchange and immunosuppressive chemotherapy for anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease (formerly known as Goodpasture's syndrome) is a rare autoinflammatory condition that affects the renal and/or pulmonary capillaries. The standard therapeutic regimen for anti-GBM disease involves therapeutic plasma exchange (TPE), cyclophosphamide, and corticosteroids to rapidly remove and inhibit autoantibody production and reduce organ inflammation. Herein we report an 82-year-old female who developed anti-GBM disease but expired despite therapy, secondary to multi-organ failure in the setting of disseminated adenovirus disease. We discuss the utility and potential adverse effect of daily TPE for a protracted course (ie, 10-14 days), the recommended TPE intensity in the 2023 American Society for Apheresis guidelines, updated from every-other-day TPE in the 2019 guidelines, despite no new data. We also highlight the potential for unusual infections to occur in these patients due to the profound immunosuppression, and discuss the importance of balancing immunosuppression to treat the disease with close surveillance of any potential opportunistic infections.

Autoantibodies against laminin-521 are pathogenic in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against GBM components. Evidence from human inherited kidney diseases and animal models suggests that the α, ß, and γ chains of laminin-521 are all essential for maintaining the glomerular filtration barrier. We previously demonstrated that laminin-521 is a novel autoantigen within the GBM and that autoantibodies to laminin-521 are present in about one-third of patients. In the present study, we investigated the pathogenicity of autoantibodies against laminin-521 with clinical and animal studies. Herein, a rare case of anti-GBM disease was reported with circulating autoantibodies binding to laminin-521 but not to the NC1 domains of α1-α5(IV) collagen. Immunoblot identified circulating IgG from this patient bound laminin α5 and γ1 chains. A decrease in antibody levels was associated with improved clinical presentation after plasmapheresis and immunosuppressive treatments. Furthermore, immunization with laminin-521 in female Wistar-Kyoto rats induced crescentic glomerulonephritis with linear IgG deposits along the GBM, complement activation along with infiltration of T cells and macrophages. Lung hemorrhage occurred in 75.0% of the rats and was identified by the presence of erythrocyte infiltrates and hemosiderin-laden macrophages in the lung tissue. Sera and kidney-eluted antibodies from rats immunized with laminin-521 demonstrated specific IgG binding to laminin-521 but not to human α3(IV)NC1, while the opposite was observed in human α3(IV)NC1-immunized rats. Thus, our patient data and animal studies imply a possible independent pathogenic role of autoantibodies against laminin-521 in the development of anti-GBM disease.

Anti-Glomerular Basement Membrane Disease in a 10-year-old Child: A Case Report.

Anti-glomerular basement membrane disease is an extremely uncommon entity in children. It has an incidence of 0.5 to 1 per million per year in adults and is even more uncommon in children. It occurs due to autoantibody against glomerular basement membrane collagen and is characterized by rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. As the literature on anti-glomerular basement membrane disease is limited from our part of the world, it is important to consider it as the rare cause of rapidly progressive glomerulonephritis as early intervention improves prognosis. We report a case of a 10-year-old male who initially presented with glomerulonephritis and later was diagnosed with anti-glomerular basement membrane disease. Keywords: basement membrane; case reports; glomerulonephritis; kidney.

Prognostic value of complement serum C3 level and glomerular C3 deposits in anti-glomerular basement membrane disease.

Background and objectives: Activation of the complement system is involved in the pathogenesis of anti-glomerular basement membrane (anti-GBM) disease. Glomerular deposits of complement 3 (C3) are often detected on kidney biopsies. The primary objective of this study was to analyze the prognostic value of the serum C3 level and the presence of C3 glomerular deposits in patients with anti-GBM disease. Methods: We conducted a retrospective cohort study of 150 single-positive patients with anti-GBM disease diagnosed between 1997 and 2017. Patients were categorized according to the serum C3 level (forming a low C3 (C3<1.23 g/L) and a high C3 (C3≥1.23 g/L) groups) and positivity for C3 glomerular staining (forming the C3+ and C3- groups). The main outcomes were kidney survival and patient survival. Results: Of the 150 patients included, 89 (65%) were men. The median [interquartile range (IQR)] age was 45 [26-64]. At diagnosis, kidney involvement was characterized by a median [IQR] peak serum creatinine (SCr) level of 578 [298-977] µmol/L, and 106 (71%) patients required dialysis. Patients in the low C3 group (72 patients) had more severe kidney disease at presentation, as characterized by higher prevalences of oligoanuria, peak SCr ≥500 µmol/L (69%, vs. 53% in the high C3 group; p=0.03), nephrotic syndrome (42%, vs. 24%, respectively; p=0.02) and fibrous forms on the kidney biopsy (21%, vs. 8%, respectively; p=0.04). Similarly, we observed a negative association between the presence of C3 glomerular deposits (in 52 (41%) patients) and the prevalence of cellular forms (83%, vs. 58% in the C3- group; p=0.003) and acute tubulo-interstitial lesions (60%, vs. 36% in the C3- group; p=0.007). When considering patients not on dialysis at diagnosis, the kidney survival rate at 12 months was poorer in the C3+ group (50% [25-76], vs. 91% [78-100] in the C3- group; p=0.01), with a hazard ratio [95% confidence interval] of 5.71 [1.13-28.85] (p=0.04, after adjusting for SCr). Conclusion: In patients with anti-GBM disease, a low serum C3 level and the presence of C3 glomerular deposits were associated with more severe disease and histological kidney involvement at diagnosis. In patients not on dialysis at diagnosis, the presence of C3 deposits was associated with worse kidney survival.