Crescentic Glomerulonephritis: An Update on Pauci-immune and Anti-GBM Diseases

Department of Pathology, Stanford University Medical Center, Stanford, CA.
Advances in anatomic pathology (Impact Factor: 3.23). 03/2012; 19(2):111-24. DOI: 10.1097/PAP.0b013e318248b7a1
Source: PubMed


Crescentic glomerulonephritis (GN) in a renal biopsy is a widely accepted "critical diagnosis" in Anatomic Pathology practice. Prompt biopsy evaluation and notification of the referring physician is essential to facilitate rapid therapeutic intervention. The differential diagnostic categories of crescentic GN include pauci-immune GN, anti-glomerular basement membrane (GBM) nephritis and immune complex-mediated GN, distinguished from one another by immunofluorescence and electron microscopic study of the renal biopsy. Immune complex-mediated GN is characterized by abundant glomerular deposits and encompasses several diseases including but not limited to lupus nephritis, cryoglobulinemic GN and immunoglobulin A nephropathy. Pauci-immune GN, with paucity of deposits, correlates closely with antineutrophil cytoplasmic antibody disease due to the identifiable circulating pathogenic antineutrophil cytoplasmic antibody in most patients. Recent studies have identified other antibodies in pauci-immune GN and implicated infectious organisms in triggering autoimmunity in a susceptible host by molecular mimicry of host antigens. Anti-GBM nephritis is a rare but potentially life-threatening autoimmune disease with circulating antibodies against GBM epitopes in α3 chain of type IV collagen. It is characterized by a linear immunoglobulin G deposition along GBM on immunofluorescence microscopy. Environmental triggers including infections and solvent exposure seem to change the tertiary structure of the type IV collagen α345 hexamer in GBM, expose neoepitopes, and initiate autoimmunity. Even in light of advances in understanding of pathophysiology and serologic testing, renal biopsy remains the mainstay of diagnosis of crescentic GN.

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    • "Anti-GBM nephritis is an autoimmune disorder characterized by rapidly progressive glomerulonephritis and the presence of circulating anti-glomerular basement membrane (anti-GBM) antibodies. If accompanied by pulmonary hemorrhage, this disease is often called Goodpasture’s syndrome, with a high mortality rate [1,2]. Treatment consists of immunosuppressive agents and removal of circulating antibodies. "
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    ABSTRACT: Background Double filtration plasmapheresis (DFPP) and (IA) are both used to clear antibody. However, the clinical efficacy and safety of DFPP in patients with anti-glomerular basement membrane (anti-GBM) disease are unclear. Methods The 28 enrolled patients diagnosed serologically and pathologically with anti-GBM disease from 2003 to 2013 included 16 treated with DFPP and 12 with IA, with all patients administered immunosuppressive agents. DFPP consisted of an EC50W filter for plasma separation and an EC20W filter for plasma fractionation. A double volume of plasma was processed, and each patient received a 30–40 g human albumin supplement during each session. IA consisted of 10 cycles per session, with 8–10 sessions performed daily or every other day and each session regenerating 30–60 L of plasma. Serum anti-GBM antibodies and IgG were measured, and urinary and blood tests were performed, before and after each procedure. Renal function and outcome were determined. Results The 28 patients consisted of 13 males and 15 females, of median age 44.5 years (range, 22.5–57 years). Six patients had pulmonary hemorrhage and 18 had serum creatinine concentrations >500 umol/L. The average serum creatinine concentration at early onset of disease was 525 umol/L while the peak concentration was 813 umol/L. All patients showed progressive increases in serum creatinine and required CRRT during the course of disease. Pathological examination showed an average 73.9% of crescents (range, 54.6–95.4%).The clinical and pathological features of the DPPP and IA groups were similar. Efficacy of clearing anti-GBM antibody was similar in the two groups (59.0 vs. 71.2%, P = 1.00), although fewer patients in the DFPP group experienced reduced IgG (62.7 vs. 83.5%, p = 0.002). One patient each had a pulmonary hemorrhage and a subcutaneous hemorrhage during treatment, but there were no other serious complications. At the end of follow-up, patient survival and renal survival were similar in the DFPP and IA groups. Conclusion DPPP plus immunosuppressive therapy efficiently and safely removed anti-GBM antibodies. The fewer plasma-associated side effects and reduced loss of IgG suggest that DFPP may be a better treatment choice for anti-GBM disease, especially in patients with insufficient plasma.
    Full-text · Article · Aug 2014 · BMC Nephrology
    • "Molecular mimicry between certain components of group A streptococci and GBM can elicit an humoral immune response that cross-reacts with GBM. Similarly , the production of ANCA involves genetic and environmental factors [1] [2] [3] [4]. Silica exposure, certain drugs such as propylthiouracil and infectious agents such as Staphylococcus aureus are known environmental triggers. "
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    ABSTRACT: Anti-glomerular basement membrane (GBM) disease is a severe inflammatory renal disorder due to pathogenic autoantibodies directed mainly against the α3 chain of type IV collagen. In ~ 1/4 of patients with anti-GBM disease, antineutrophil cytoplasmic antibodies (ANCA) predominantly with myeloperoxidase (MPO) specificity can be detected. Although the inciting stimuli leading to the development of an immune response against the type IV collagen and neutrophils are unknown, evidence indicates that both genetic and environmental factors play a role. Of note, molecular mimicry between self-antigens and nonself-antigens such as antigenic determinants of microorganisms has been implicated in the pathogenesis of anti-GBM disease and ANCA-associated vasculitis. A mosquito-borne viral illness highly prevalent in the tropics and subtropics, dengue can be complicated by acute renal failure, proteinuria, hematuria and glomerulonephritis. We present a 66-yearold woman who was diagnosed with dengue infection and rapidly progressive glomerulonephritis during an outbreak of dengue in Honduras in the summer of 2013. Renal biopsy revealed severe crescentic glomerulonephritis. Immunofluorescence examination demonstrated strong linear IgG deposition along glomerular capillary walls. Serologic tests demonstrated antibodies against GBM, MPO and platelet glycoproteins. The patient was diagnosed with anti-GBM disease associated with p-ANCA with MPO specificity. Despite heavy immunosuppression and plasmapheresis, IgG titers against dengue virus continued to rise confirming the diagnosis of acute dengue infection. We present the first reported case of anti-GBM disease associated with p-ANCA with MPO specificity during dengue infection. This report calls for a heightened awareness of autoimmunity leading to crescentic glomerulonephritis in patients with dengue infection.
    No preview · Article · Apr 2014 · Clinical nephrology
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    • "Anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) is an autoimmune disorder in which circulating antibodies against the α-3 chain of type IV collagen bind to renal GBM and initiate an inflammatory reaction [1,2]. Anti-GBM-GN is one of the most severe forms of glomerulonephritis, characterized by crescent formation and linear glomerular deposits of IgG [3]. "
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    ABSTRACT: Oxidative stress is implicated in tissue inflammation and plays an important role in the pathogenesis of immune-mediated nephritis. Using the anti-glomeruli basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) mouse model, we found that increased expression of Glutathione S-transferase Mu 2 (GSTM2) was related to reduced renal damage caused by anti-GBM antibodies. Furthermore, mesenchymal stem cell (MSC)-based therapy has shed light on the treatment of immune-mediated kidney diseases. The object of this study is to investigate if MSCs could be utilized as vehicles to deliver GSTM2 gene product into the kidney and to evaluate its potential therapeutic effect on anti-GBM-GN. Human GSTM2 (hGSTM2) gene was transduced into mouse bone marrow-derived MSCs via a lentiviral vector to create a stable cell line (hGSTM2-MSC). The cultured hGSTM2-MSCs were treated with 0.5mM H2O2 and apoptotic cells were measured by Tunel assay. The 129/svj mice which were challenged with anti-GBM antibodies were injected with 106 hGSTM2-MSCs via the tail vein. The expression of hGSTM2 and inflammatory cytokines in the kidney was detected by QPCR and western blotting. Renal function of mice was evaluated by monitoring the proteinuria and blood urea nitrogen (BUN), and renal pathological changes were analyzed by histochemistry. Immunohistochemical analysis was performed to measure the inflammatory cell infiltration and renal cell apoptosis. MSCs transduced with hGSTM2 exhibited similar growth and differentiation properties as MSCs. hGSTM2-MSCs persistently expressed hGSTM2 and resisted H2O2-induced apoptosis. Upon injection into 129/svj mice, hGSTM2-MSCs migrated to kidney and expressed hGSTM2. The anti-GBM-GN mice treated with hGSTM2-MSCs exhibited reduced proteinuria (by 58%), BUN (by 59%) and ameliorated renal pathological damage, compared with control mice. hGSTM2-MSCs injected mice showed alleviated renal inflammatory cell infiltration and reduced expression of CCL2 (by 53%), IL1beta (by 46%) and IL6 (by 52%), compared with controls. Moreover, hGSTM2-MSCs increased the renal superoxide dismutase and catalase expression, which may associate with detoxifying reactive oxygen species to prevent renal oxidative damage. Our data suggest that the enhanced protective effect of GSTM2-transduced MSCs against anti-GBM-GN might be associated with the inhibition of oxidative stress-induced renal cell apoptosis and inflammation by over expression of hGSTM2 in mouse kidneys.
    Full-text · Article · Jan 2014 · Stem Cell Research & Therapy
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