mocetinostat and Glomerulonephritis--Membranoproliferative

Immunoglobulin G4-related disease (IgG4-RD) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have different clinical and pathological features. However, differentiation between these 2 disorders is sometimes difficult.. To report a case involving a patient with characteristics of both IgG4-RD and AAV.. Case report with literature review.. We report a case of myeloperoxidase-ANCA-positive otitis media and rhinosinusitis with pathological features of IgG4-RD in a 73-year-old man. The patient was first clinically suspected to have granulomatosis with polyangiitis. All of the main characteristic pathological features of IgG4-RD were present: dense lymphoplasmacytic infiltration, increased numbers of IgG4-positive plasma cells, storiform-type fibrosis, and obliterative phlebitis.. The simultaneous presence of the characteristics of both IgG4-RD and AAV makes diagnosis and treatment difficult.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Audiometry, Pure-Tone; Autoantibodies; Autoimmune Diseases; Glomerulonephritis, Membranoproliferative; Humans; Immunoglobulin G; Male; Nasal Septal Perforation; Otitis Media; Peroxidase; Rhinitis; Sinusitis; Tomography, X-Ray Computed

A 66-year-old man was admitted to our hospital because of a low-grade fever and arthralgia. The symptoms started on the third day after influenza vaccine administration and persisted for two months. Serum creatinine was 1.0 mg/dL; C-reactive protein, 16.1 mg/dL; and myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA), 4,170 IU/mL. A kidney biopsy showed crescentic glomerulonephritis with fibrinoid necrosis of small arteries. Microscopic polyangiitis was diagnosed. After five months of steroid pulse therapy and rituximab administration, the patient entered remission. There have been very few reports of this condition after influenza vaccine administration.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Humans; Influenza Vaccines; Male; Microscopic Polyangiitis; Peroxidase

Previous studies have demonstrated residual complement-mediated deposits in repeat kidney biopsies of C3 glomerulopathies (C3G) (dense deposit disease (DDD) and C3 glomerulonephritis) following eculizumab treatment, despite some clinical improvement. With residual complement deposition, it is difficult to determine whether there is a reduced complement-mediated endothelial cell injury. We validated that myeloperoxidase (MPO) immunohistochemical staining identified glomerular endothelial cell injury in crescentic glomerulonephritis and C3G.. We report that MPO staining in the glomerular endothelium of the post-treatment kidney biopsy was significantly reduced after 3 years of eculizumab treatment and clinical improvement in a 5-year-old boy with initial DDD and secondary crescent formation.. We find that immunostaining for MPO is a useful method to compare glomerular endothelial injury in C3G following eculizumab treatment. This finding also supports the notion that eculizumab, a C5 blocker, may not mainly block C3 deposits in the glomeruli but significantly blocks final activation of the complement cascade, thus reducing glomerular endothelial cell injury.

Topics: Child, Preschool; Endothelial Cells; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Humans; Immunohistochemistry; Male; Peroxidase; Staining and Labeling

Chronic infections may mimic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). We investigated which markers may help in the diagnosis and the prognosis of infections associated with proteinase 3 (PR3) and myeloperoxidase (MPO)-ANCA. In this study (1993-2008)--with an average follow-up of 5.1 years--we compared 66 AAV patients with 17 PR3 and/or MPO-ANCA-positive patients with protracted bacterial (11/17) or viral (6/17) infections. Seven of 17 patients had subacute bacterial endocarditis (SBE), while six of 17 patients had various autoimmune manifestations of chronic hepatitis C virus (HCV) infection. We determined ANCA, antinuclear antibodies, anti-PR3, anti-MPO, anticardiolipin (aCL), antibeta 2 glycoprotein I (beta2-GP I), cryoglobulins, C3, and C4. Patients with infections were younger than AAV patients (p < 0.01). There was no difference in frequency of renal and skin lesions. AAV patients more frequently had pulmonary and nervous system manifestations (p < 0.01). Patients with infections more frequently had dual ANCA (high PR3, low MPO), aCL, anti-beta2-GP I, cryoglobulins, and hypocomplementemia (p < 0.001). Immunosuppressive therapy (IST) was used in five 17 patients who had persistently high ANCA, cryoglobulinemia, and hypocomplementemia. There was no difference in frequency of lethality and renal failure in the two study groups. In patients who are PR3- and/or MPO-ANCA positive, SBE and HCV infection should be excluded. Although similar in renal and skin manifestations in comparison to AAV, only patients with infections developed multiple serological abnormalities. In patients with infections, concomitant presence of ANCA, cryoglobulins, and hypocomplementemia was associated with severe glomerulonephritis. The serological profile should be repeated after specific antimicrobial or surgical therapy, since some cases might require IST.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; Endocarditis, Bacterial; Female; Follow-Up Studies; Glomerulonephritis, Membranoproliferative; Hepatitis C; Humans; Male; Middle Aged; Mycobacterium Infections; Myeloblastin; Peroxidase; Retrospective Studies; Staphylococcal Infections; Streptococcal Infections; Young Adult

Anti-neutrophil cytoplasmic antibodies (ANCA) are the immunodiagnostic markers for idiopathic necrotizing crescentic glomerulonephritis affecting mainly medium to small sized blood vessels. The diagnosis of ANCA associated vasculitis (AAV) is mainly based on clinical and histopathological characteristics along with the serological evidence. Immunofluorescence microscopy (IIF) is considered as the "gold standard" for ANCA detection, and ANCA showing two major patterns ie, cytoplasmic (c-ANCA) and perinuclear (p-ANCA) react with different antigenic targets of neutrophils like Proteinase3 (PR3) and Myeloperoxidase (MPO). A third unusual and rare immunofluorescence pattern called as "X- ANCA" or atypical ANCA is also sometimes seen. The difficulty in identification of ANCA immunofluorescence patterns is mainly seen due to the rare dual patterns seen in the same sera and also the additional nuclear immunofluorescence seen due to presence of anti-nuclear antibodies. ANCA testing by immunofluorescence and Confocal Laser scanning microscopy, as well as by specific ELISAs for detection of anti-PR3 and anti-MPO antibodies have helped in improving the diagnosis. Patients having dual specificities to MPO and PR3 in a patient is a rare finding. Among 425 clinically and histopathologically proven cases of AAV, eight patients (1.9%) had dual specificities, of which five patients showed mixed immunofluorescence pattern and 3 patients showed X-ANCA pattern which was confirmed by both immunofluorescence and Confocal Laser scanning microscopy and the dual specificities to MPO and PR3 were detected by individual ELISAs.

Topics: Adolescent; Adult; Aged; Anti-Glomerular Basement Membrane Disease; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antibody Specificity; Binding, Competitive; DNA; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Granulomatosis with Polyangiitis; Humans; Lupus Nephritis; Male; Microscopy, Confocal; Middle Aged; Myeloblastin; Neutrophils; Peroxidase; Serine Endopeptidases; Vasculitis

A proposed analogy between atherosclerosis and glomerulosclerosis suggests that factors that contribute to the development of atherosclerosis, ie, oxidatively modified (lipo)proteins, may also participate in glomerular injury. Although the nature of the in vivo oxidants has not been clearly identified, increasing evidence suggested the myeloperoxidase (MPO)-H(2)O(2)-halide system to be responsible for the damage observed in leukocyte-dependent glomerulonephritis. MPO, a heme protein secreted by activated phagocytes, may generate modified/oxidized proteins in vivo via intermediate formation of hypochlorous acid (HOCl)/hypochlorite. HOCl, a reactive oxygen species and powerful oxidant, can convert (lipo)proteins into atherogenic forms in vitro and in vivo. Here we demonstrate the presence of HOCl-modified proteins in glomeruli of patients with membranous glomerulonephritis using monoclonal antibodies that do not cross-react with other oxidative modifications. Immunostaining for HOCl-modified epitopes in human minimal change glomerulopathy revealed glomeruli that were unreactive, although the number of MPO-positive cells/glomerulus was slightly increased in comparison to controls. In contrast to minimal change glomerulopathy, a pronounced infiltration of mononuclear cells/glomerulus in membranoproliferative glomerulonephritis is in line with pronounced staining for HOCl-modified epitopes. Immunostaining was detected in intracapillary cells and immune complex deposits within the glomerular basement membrane. In human membranous glomerulonephritis (Stages I to III), staining for HOCl-modified proteins was localized at the basement membrane and podocytes. Staining of serial sections revealed colocalization of HOCl-modified epitopes and MPO in glomerular peripheral basement membranes. Subsequently, tubulointerstitial staining for HOCl-modified epitopes was observed in foam cells at the border of the cytoplasm and in damaged tubular epithelia in focal advanced chronic lesions. Our results indicate that oxidative modification of the basement membrane structure by phagocyte-derived HOCl may be of importance for glomerular defects. The observed colocalization of HOCl-modified proteins and MPO in podocytes and adjacent basement membranes strengthens the assumption that the MPO-H(2)O(2)-halide system contributes to glomerular dysfunction in patients with membranous glomerulonephritis.

Topics: Antibodies, Monoclonal; Biopsy, Needle; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Hypochlorous Acid; Immunohistochemistry; Indicators and Reagents; Kidney; Peroxidase; Proteins; Reference Values

The occurrence of focal fibrinoid necrosis of capillary loops in the very early stages of ANCA-associated necrotizing crescentic glomerulonephritis (NCGN) and the increased prevalence of this disease at older age suggest that renal ischemia may play an additional role in its pathophysiology. In the present study we investigated the contribution of renal ischemia to the induction of anti-myeloperoxidase (MPO) associated NCGN in a previously described rat model of this disease. The development of renal lesions is dependent on the presence of an anti-MPO immune response and the localization of a lysosomal extract containing lytic enzymes and MPO in combination with hydrogen peroxide (H2O2) along the glomerular basement membrane (GBM). The hypothesis tested whether perfusion of hydrogen peroxide (H2O2) could be replaced by ischemia/reperfusion (I/R) injury, as I/R injury activates endothelial cells to produce oxygen metabolites. I/R was induced by clamping the renal artery for 20 minutes in kidneys in which the circulation had been restored several minutes after perfusion with the lysosomal extract in MPO immunized rats. Rats developed lesions characterized by intra- and extracapillary cell proliferation, periglomerular infiltration, ruptures in Bowman's capsule, ischemic tubuli, and interstitial mononuclear infiltrate. Immune deposits, however, persisted for a longer time along the GBM after perfusion of lytic enzymes followed by I/R injury compared to previous studies in which H2O2 in conjunction with lytic enzymes were perfused in MPO-immunized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Complement C3; Glomerulonephritis, Membranoproliferative; Immunization; Immunoglobulin G; Immunophenotyping; Intercellular Adhesion Molecule-1; Peroxidase; Rats; Rats, Inbred BN; Reperfusion Injury; Tissue Adhesions; Up-Regulation

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoimmune Diseases; Female; Glomerulonephritis, Membranoproliferative; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Peroxidase

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Humans; Kidney Transplantation; Male; Peroxidase