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Introduction: Glomerulonephritis is frequent in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and crucial to disease outcomes. We conducted a detailed assessment of renal pathology in Japanese patients with AAV, and developed a new score that would predict renal outcome. Methods: Two hundred twenty-one patients who were diagnosed with AAV and underwent a kidney biopsy were enrolled. Data on glomerular, tubular, interstitial, and vascular lesions from kidney biopsies were analyzed; the 3 established classification and prognostic scoring systems (Berden Classification, Mayo Clinic/RPS Chronicity Score [MCCS], and ANCA Renal Risk Score [ARRS]) were validated. Further, we developed a new prognostic score by including variables relevant for Japanese patients with ANCA-glomerulonephritis. Results: Median follow-up was 60 months (interquartile range: 6-60). End-stage kidney disease (ESKD) risk prediction by the MCCS and the ARRS was confirmed. Moreover, our analysis identified 4 items with significant ESKD risk prediction capacity, namely percentage of cellular, fibrocellular, and fibrous crescents; and sclerotic glomeruli. Based on our findings, we created a score evaluating the percentage of these lesions to total glomeruli, the Percentage of ANCA Crescentic Score (PACS). The area under the receiver operating characteristic (ROC) curve evaluating PACS was 0.783. The PACS had a comparable performance as the ARRS in predicting ESKD. The optimal PACS cut-off for ESKD risk over 60 months was 43%. In addition, the percentage of cellular crescents and presence of interstitial inflammation were independent predictors of kidney function recovery. Conclusion: We developed a new score predicting renal prognosis using histopathological data of Japanese patients with ANCA-glomerulonephritis. Studies are needed to validate our results in international cohorts.
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Accelerated formation and tissue accumulation of advanced glycation end products (AGEs), reflecting cumulative glycemic and oxidative stress, occurs in age-related and chronic diseases like diabetes mellitus (DM) and renal failure, and contributes to vascular damage. Skin autofluorescence (AFR), a noninvasive measurement method, reflects tissue accumulation of AGEs. AFR has been reported to be an independent predictor of mortality in Caucasian hemodialysis patients. We assessed the relationship between levels of AFR and the prevalence of cardiovascular disease (CVD), and clarified the prognostic usefulness of skin AFR levels in Asian (non-Caucasian) hemodialysis (HD) patients. AFR was measured with an autofluorescence reader in 64 HD patients. Overall and cardiovascular mortality was monitored prospectively during the 3-year follow-up. During follow-up, CVD events occurred in 21 patients. The deaths of 10 HD patients were associated with CVD. Multivariate logistic regression analyses showed that initial AFR was an independent risk factor for de novo CVD in HD patients with or without diabetes. When patients were classified on the basis of AFR tertiles, Cochran-Armitage analysis demonstrated that the highest tertile of AFR level showed an increased odds ratio for the prevalence of CVD. These findings suggest that AFR levels can be used to detect the prevalence of CVD in HD patients with or without diabetes.
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Enfermedades Cardiovasculares/epidemiología , Productos Finales de Glicación Avanzada/metabolismo , Imagen Óptica/métodos , Diálisis Renal/métodos , Insuficiencia Renal Crónica/terapia , Piel/metabolismo , Anciano , Análisis de Varianza , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/fisiopatología , Femenino , Humanos , Japón , Modelos Logísticos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Análisis Multivariante , Valor Predictivo de las Pruebas , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/mortalidad , Medición de Riesgo , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
BACKGROUND: Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear. PROCEDURES: The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans. RESULT: Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells. CONCLUSION: The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.
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Diabetes Mellitus Tipo 1/patología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Litostatina/metabolismo , Páncreas/patología , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Páncreas/metabolismoRESUMEN
BACKGROUND: Elevated levels of neutrophil gelatinase-associated lipocalin (NGAL) have been reported in patients with cardiovascular disease (CVD), heart failure, and stroke. We assessed the relationships between serum levels of NGAL and the prevalence of CVD, and clarified the prognostic usefulness of systemic NGAL levels in hemodialysis (HD) patients. METHODS: Eighty-eight HD patients were followed up for 1 year. Logistic regression analyses were used to investigate the relationship between de novo CVD status and NGAL levels as well as other risk factors. RESULTS: During follow-up, CVD events occurred in 20 patients. Initial serum levels of NGAL and brain natriuretic peptide of HD patients with de novo CVD were significantly higher than those of HD patients without de novo CVD. Multivariate logistic regression analyses showed that initial serum levels of NGAL were independent risk factors for de novo CVD in HD patients. When patients were classified on the basis of NGAL quartiles, multiple logistic regression analyses demonstrated that the highest quartile of NGAL level showed an increased odds ratio for the prevalence of CVD. CONCLUSION: These findings suggest that NGAL levels can be used to detect the prevalence of CVD in HD patients with or without diabetes.
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Enfermedades Cardiovasculares/sangre , Lipocalinas/sangre , Proteínas Proto-Oncogénicas/sangre , Insuficiencia Renal Crónica/sangre , Proteínas de Fase Aguda , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Enfermedades Cardiovasculares/complicaciones , Femenino , Estudios de Seguimiento , Humanos , Lipocalina 2 , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicaciones , Rigidez VascularRESUMEN
OBJECTIVE: The contribution of innate immunity responsible for aggressive ß-cell destruction in human fulminant type 1 diabetes is unclear. RESEARCH DESIGN AND METHODS: Islet cell expression of Toll-like receptors (TLRs), cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors, downstream innate immune markers, adaptive immune mediators, and apoptotic markers was studied in three autopsied pancreata obtained 2 to 5 days after onset of fulminant type 1 diabetes. RESULTS: RIG-I was strongly expressed in ß-cells in all three pancreata infected with enterovirus. Melanoma differentiation-associated gene-5 was hyperexpressed in islet cells, including ß- and α-cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated islets. Interferon (IFN)-α and IFN-ß were strongly expressed in islet cells. Major histocompatibility complex (MHC)-class I, IFN-γ, interleukin-18, and CXC motif ligand 10 were expressed and colocalized in affected islets. CD11c+ MHC-class II+ dendritic cells and macrophage subsets infiltrated most islets and showed remarkable features of phagocytosis of islet cell debris. CD4+ forkhead box P3+ regulatory T cells were not observed in and around the affected islets. Mononuclear cells expressed the Fas ligand and infiltrated most Fas-expressing islets. Retinoic acid-receptor responder 3 and activated caspases 8, 9, and 3 were preferentially expressed in ß-cells. Serum levels of IFN-γ were markedly increased in patients with fulminant type 1 diabetes. CONCLUSIONS: These findings demonstrate the presence of specific innate immune responses to enterovirus infection connected with enhanced adoptive immune pathways responsible for aggressive ß-cell toxicity in fulminant type 1 diabetes.
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Inmunidad Adaptativa/inmunología , ARN Helicasas DEAD-box/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Inmunidad Innata/inmunología , Células Secretoras de Insulina/metabolismo , Adolescente , Adulto , Anciano , Análisis de Varianza , Muerte Celular/inmunología , Proteína 58 DEAD Box , Diabetes Mellitus Tipo 1/inmunología , Infecciones por Enterovirus/inmunología , Infecciones por Enterovirus/metabolismo , Femenino , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunohistoquímica , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/virología , Helicasa Inducida por Interferón IFIH1 , Interferón beta/inmunología , Interferón beta/metabolismo , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-18/inmunología , Interleucina-18/metabolismo , Masculino , Persona de Mediana Edad , Receptores Inmunológicos , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismoRESUMEN
OBJECTIVE: Fulminant type 1 diabetes is characterized by the rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetes complications. Causative mechanisms for accelerated beta-cell failure are unclear. RESEARCH DESIGN AND METHODS: Subjects comprised three autopsied patients who died from diabetic ketoacidosis within 2-5 days after onset of fulminant type 1 diabetes. We examined islet cell status, including the presence of enterovirus and chemokine/cytokine/major histocompatibility complex (MHC) expressions in the pancreata using immunohistochemical analyses and RT-PCR. RESULTS: Immunohistochemical analysis revealed the presence of enterovirus-capsid protein in all three affected pancreata. Extensive infiltration of CXCR3 receptor-bearing T-cells and macrophages into islets was observed. Dendritic cells were stained in and around the islets. Specifically, interferon-gamma and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including beta-cells and alpha-cells. No CXCL10 was expressed in exocrine pancreas. Serum levels of CXCL10 were increased. Expression of MHC class II and hyperexpression of MHC class I was observed in some islet cells. CONCLUSIONS: These results strongly suggest the presence of a circuit for the destruction of beta-cells in fulminant type 1 diabetes. Enterovirus infection of the pancreas initiates coexpression of interferon-gamma and CXCL10 in beta-cells. CXCL10 secreted from beta-cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-gamma in the islets, not only damaging beta-cells but also accelerating CXCL10 generation in residual beta-cells and thus further activating cell-mediated autoimmunity until all beta-cells have been destroyed.