RESUMO
A 76-year-old man was admitted with general fatigue, weight loss, fever, headache, renal failure, and a high serum level of myeloperoxidase-antineutrophil cytoplasmic antibody. Biopsy revealed citrullinated histone H3 (citH3)-positive neutrophils adherent to the temporal artery endothelium. Three days after completing pulse steroid therapy, he suffered from a sudden disturbance of consciousness and died. On autopsy, the kidneys showed the most severe vasculitis with dense infiltration of citH3-positive neutrophils. The lungs showed intra-alveolar hemorrhage due to capillaritis. Severe brain hemorrhage was found in the left frontal lobe and putamen with uncal herniation. No vasculitis or thrombi was observed in the brain. The right dura mater was thickened due to fibrosis and inflammation. In conclusion, autopsy revealed systemic vasculitis with infiltration of abundant citH3-positive neutrophils, suggesting that the neutrophil extracellular trap formation and citH3 might play important roles in the early phases and development of microscopic polyangiitis.
Assuntos
Armadilhas Extracelulares , Histonas/metabolismo , Poliangiite Microscópica/patologia , Neutrófilos/patologia , Idoso , Autopsia , Citrulina , Humanos , MasculinoRESUMO
BACKGROUND: It has been well-recognized that cancer patients occasionally develop renal disorders independently of direct tumor invasion. However, the clinical entity of paraneoplastic glomerulopathy remains poorly understood, in part due to the lack of an animal model for basic research. In the present study, we investigated whether cancer-bearing rats develop features of glomerulopathy. METHODS: RCN-9 rat colon cancer cells (1 × 10(7)) were injected into F344 rats (n = 13) and T cell-deficient F344 rats (nude rats; n = 7) via the portal system. Urinalysis and histological examinations were performed in comparison with control rats (n = 6) that received a vehicle injection. RESULTS: Metastatic growth of RCN-9 cells exclusively in the liver was observed in the cancer-injected F344 rats, whereas direct invasion into the kidney was not evident even microscopically. Two of the cancer-injected F344 rats died within 2 days, but 9 of the 11 that avoided early death showed elevation of urinary protein (up to 158.0 mg/day) compared to controls (mean values: 60.8 ± 12.9 versus 17.8 ± 2.1 mg/day, P = 0.0291). Although morphological changes were not evident in light microscopy, abundant IgG in the glomerular tufts of the proteinuric rats was shown immunohistochemically. Ultrastructure analysis revealed electron-dense deposits in the glomerular basement membrane zone and effacement of the podocytic foot process. Interestingly, none of the nude rats showed proteinuria despite of cancer growth, suggesting that a specific immune response was involved. CONCLUSIONS: The tumor-bearing rats developed features of glomerulopathy, as expected from the clinical perspective, and this animal model may provide new insights into the development of paraneoplastic glomerulopathies.
Assuntos
Adenocarcinoma/complicações , Modelos Animais de Doenças , Nefropatias/etiologia , Neoplasias Hepáticas/complicações , Adenocarcinoma/secundário , Animais , Contagem de Células , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Membrana Basal Glomerular/patologia , Membrana Basal Glomerular/ultraestrutura , Nefropatias/patologia , Glomérulos Renais/patologia , Neoplasias Hepáticas/secundário , Masculino , Proteinúria/etiologia , Ratos , Ratos Endogâmicos F344 , Ratos NusRESUMO
In ordinary settings, human immunodeficiency virus (HIV)-associated nephropathy should be considered when HIV infection is associated with heavy proteinuria. On the other hand, hepatitis B virus (HBV) may also play a role in the development of glomerular injury among patients with HIV infection, since HIV and HBV infections commonly occur together due to shared modes of transmission. We present here a case of nephrotic syndrome in an HIV-positive patient complicated with HBV infection. A renal biopsy revealed sparse granular deposits of immunoglobulin G in the subepithelial region, consistent with membranous nephropathy (MN) stage I. Moreover, immunostaining exhibited weak anti-hepatitis B core activity within glomeruli. These results led us to consider that HBV-associated MN might play a role in the development of nephrotic syndrome. Although anti-viral treatment for patients with HBV-associated MN has been suggested to be clinically effective, the use of two anti-HIV agents (tenofovir and emtricitabine), both of which have anti-HBV activities, was not effective for the patient's nephrotic syndrome, despite obtaining a decrease in the serum HBV-DNA levels. A lack of prospective data suggests that many decisions on the treatment of glomerulopathies with HIV infections are potentially empirical. Obviously, further studies and accumulated clinical experience are required to better determine the pathogenesis and management of HBV-associated MN among patients with HIV infections.
Assuntos
Glomerulonefrite Membranosa/complicações , Infecções por HIV/complicações , Hepatite B/complicações , Síndrome Nefrótica/complicações , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Emtricitabina , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Síndrome Nefrótica/tratamento farmacológico , Organofosfonatos/uso terapêutico , Prednisolona/uso terapêutico , TenofovirRESUMO
We report on a case of severe renal failure in a 61-year-old female with multiple myeloma (MM). Two months prior to admission, the patient was diagnosed to have anemia and progressive renal failure associated with urinary Bence Jones protein and was referred to our hospital. A bone marrow biopsy revealed 40% plasma cells with κ light chain restriction. Thus, she was considered to have MM. A renal biopsy revealed neoplastic plasma cell infiltration within the kidney, moderate interstitial fibrosis, tubular atrophy, and punctate, electron-dense material along the peripheral capillary walls, tubular basement membrane, and in the interstitium of the kidney. This suggested that a combination of compression of the tubules and the microvasculature by the infiltrative process, and local light chain deposition-mediated tissue damage might be implicated in the development of renal failure in this patient. Despite a remission of bone marrow plasmacytosis with a bortezomib-based regimen, her renal function gradually deteriorated and a periodic hemodialysis program was finally required. Although the clinical impact of the direct kidney infiltration of neoplastic plasma cells on the longitudinal changes in renal function remains to be delineated, it is reasonable to consider that the infiltration of neoplastic plasma cells associated with local light chain depositions may result in irreversible renal injuries. Obviously, further studies and accumulation of additional experience with renal biopsy are required to better determine the precise and prognostic relationship between renal outcome and morphological alterations among MM patients with varying degrees of renal impairment.
Assuntos
Rim/patologia , Mieloma Múltiplo/complicações , Plasmócitos/patologia , Insuficiência Renal/etiologia , Proteína de Bence Jones/urina , Ácidos Borônicos/uso terapêutico , Bortezomib , Feminino , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Pirazinas/uso terapêutico , Insuficiência Renal/patologiaRESUMO
Genetic crossing experiments were performed between tuberous sclerosis-2 (Tsc2) KO and expressed in renal carcinoma (Erc) KO mice to analyze the function of the Erc/mesothelin gene in renal carcinogenesis. We found the number and size of renal tumors were significantly less in Tsc2+/-;Erc-/- mice than in Tsc2+/-;Erc+/+ and Tsc2+/-;Erc+/- mice. Tumors from Tsc2+/-;Erc-/- mice exhibited reduced cell proliferation and increased apoptosis, as determined by proliferating cell nuclear antigen (Ki67) and TUNEL analysis, respectively. Adhesion to collagen-coated plates in vitro was enhanced in Erc-restored cells and decreased in Erc-suppressed cells with siRNA. Tumor formation by Tsc2-deficient cells in nude mice was remarkably suppressed by stable knockdown of Erc with shRNA. Western blot analysis showed that the phosphorylation of focal adhesion kinase, Akt and signal transducer and activator of transcription protein 3 were weaker in Erc-deficient/suppressed cells compared with Erc-expressed cells. These results indicate that deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 KO mice and inhibits the phosphorylation of several kinases of cell adhesion mechanism. This suggests that Erc/mesothelin may have an important role in the promotion and/or maintenance of carcinogenesis by influencing cell-substrate adhesion via the integrin-related signal pathway.
Assuntos
Carcinoma de Células Renais/prevenção & controle , Transformação Celular Neoplásica/patologia , Proteínas Ligadas por GPI/fisiologia , Neoplasias Renais/prevenção & controle , Proteínas Supressoras de Tumor/fisiologia , Animais , Apoptose , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Adesão Celular , Proliferação de Células , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Mesotelina , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Nus , Fosforilação , RNA Interferente Pequeno/genética , Transdução de Sinais , Proteína 2 do Complexo Esclerose TuberosaRESUMO
The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse is a model of human crescentic glomerulonephritis and vasculitis associated with the production of the myeloperoxidase (MPO)-specific antineutrophil cytoplasmic autoantibody (MPO-ANCA). Although the disease is mediated initially by mutation of the Fas gene (lpr), SCG/Kj mice also have non-Fas predisposing genetic factors. To define these factors, genome-wide quantitative trait locus (QTL) mapping was performed on female (B(6)x SCG/Kj) F(2) intercross mice. Fourteen non-Fas QTLs were identified. QTLs of glomerulonephritis were located on chromosomes 1, 10, 13, 16, and 17, vasculitis on chromosomes 1 and 17, splenomegaly on chromosome 1, hypergammaglobulinemia on chromosomes 1, 2, 4, 6, 7, 11, 13, and 17, antinuclear Ab on chromosomes 1, 8, 10, and 12, and MPO-ANCA production on chromosomes 1 and 10. Significant QTLs derived from SCG/Kj on chromosomes 1, 2, 7, and 13 were designated Scg-1 to Scg-5, respectively, and those derived from B(6) on chromosomes 4, 6, 17, and 10 were designated Sxb-1 to Sxb-4, respectively. Two loci linked to MPO-ANCA production on chromosomes 1 and 10 were designated Man-1 and Man-2 (for MPO-ANCA), respectively. Although both Scg-1 and Scg-2 were on chromosome 1 and shared several functions, it was of interest that aberrant MPO-ANCA production was exclusively controlled by Man-1, the centromeric half region of the Scg-2 chromosomal segment. We also examined the epistatic effects between the lpr mutation and non-Fas susceptibility genes. QTLs are discussed in relation to previously described loci, with emphasis on their candidate genes.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/biossíntese , Glomerulonefrite/imunologia , Glomerulonefrite/metabolismo , Peroxidase/imunologia , Peroxidase/metabolismo , Vasculite/genética , Vasculite/imunologia , Animais , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Cromossomos/genética , Modelos Animais de Doenças , Proteína Ligante Fas , Feminino , Genótipo , Glomerulonefrite/patologia , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Imunoglobulina M/biossíntese , Imunoglobulina M/imunologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos , Fenótipo , Baço/imunologia , Baço/metabolismo , Fatores de Necrose Tumoral/genética , Vasculite/metabolismo , Vasculite/patologiaRESUMO
FcgammaRIIB1 molecules serve as negative feedback regulator for B cell Ag receptor-elicited activation of B cells; thus, any impaired FcgammaRIIB1 function may possibly be related to aberrant B cell activation. We earlier found deletion polymorphism in the Fcgr2b promoter region among mouse strains in which systemic autoimmune disease-prone NZB, BXSB, MRL, and autoimmune diabetes-prone nonobese diabetic, but not NZW, BALB/c, and C57BL/6 mice have two identical deletion sites, consisting of 13 and 3 nucleotides. In this study, we established congenic C57BL/6 mice for NZB-type Fcgr2b allele and found that NZB-type allele down-regulates FcgammaRIIB1 expression levels in germinal center B cells and up-regulates IgG Ab responses. We did luciferase reporter assays to determine whether NZB-type deletion polymorphism affects transcriptional regulation of Fcgr2b gene. Although NZW- and BALB/c-derived segments from position -302 to +585 of Fcgr2b upstream region produced significant levels of luciferase activities, only a limited activity was detected in the NZB-derived sequence. EMSA and Southwestern analysis revealed that defect in transcription activity in the NZB-derived segment is likely due to absence of transactivation by AP-4, which binds to the polymorphic 13 nucleotide deletion site. Our data imply that because of the deficient AP-4 binding, the NZB-type Fcgr2b allele polymorphism results in up-regulation of IgG Ab responses through down-regulation of FcgammaRIIB1 expression levels in germinal center B cells, and that such polymorphism may possibly form the basis of autoimmune susceptibility in combination with other background contributing genes.